Note: Descriptions are shown in the official language in which they were submitted.
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Improved dosage of baloxavir marboxil for pediatric patients
The present invention relates to a method for treating an influenza virus
infection, wherein said
method comprises administering an effective amount of a compound to a patient
having an
influenza virus infection, wherein the compound has one of the formulae I and
II or is a
pharmaceutically acceptable salt thereof, and wherein the following dosage is
used: (1) in a patient
that is younger than 1 year: (a) if the patient is younger than 4 weeks, then
the effective amount is
0.8-1.2 mg/kg body weight, preferably about 1 mg/kg body weight; (b) if the
patient is 4 weeks or
older but younger than 3 months, then the effective amount is 0.8-1.2 mg/kg
body weight,
preferably about 1 mg/kg body weight; (c) if the patient is 3 months or older
but younger than 12
months, then the effective amount is 1.8-2.2 mg/kg body weight, preferably
about 2 mg/kg body
weight; (ii) in a patient that is 1 year or older but younger than 12 years:
(a) if the patient has a
body weight of less than 20 kg, then the effective amount is 1.8-2.2 mg/kg
body weight, preferably
about 2 mg/kg body weight; or (b) if the patient has a body weight of 20 kg or
more, then the
effective amount is 35-45 mg, preferably about 40 mg.
Influenza is an acute respiratory infectious disease caused by a virus of the
orthomyxovirus family.
Two forms are known to infect humans, influenza A and B. These viruses cause
an acute febrile
infection of the respiratory tract after an incubation period of 1 to 4 days,
characterized by the
sudden onset of fever, cough, fatigue, headache, and myalgia. Annual influenza
epidemics are
thought to result in between 3 to 5 million cases of severe illness, and
between 250,000 and
500,000 deaths every year around the world (WHO fact sheet 211: influenza
(seasonal). 2018).
Although the condition is usually self-limiting in healthy adults, it can be
associated with substantial
morbidity and occasional mortality in children, the elderly, and the
immunocompromised (Paules,
Subbarao. Lancet 2017; 390: 697-708). Children play a central role in the
dissemination of
influenza in the community by virtue of their relative serosusceptibility and
consequently higher
illness attack rates. In addition to the acute illness, young children are at
particular risk of
secondary bacterial infections. Such secondary bacterial infections lead to
poor prognosis,
particularly in children. Other serious complications can also develop,
including cardiac and
neurological complications. Children develop more severe disease compared with
adults, with
higher hospitalization rates particularly in children aged < 5 years
(Rotrosen, Neuzil. Pediatr Clin
North Am 2017; 64: 911-36). Although NA inhibitors, such as oseltamivir,
zanamivir, and peramivir,
can be used for the treatment of pediatric patients at present, more
convenient and potent anti-
influenza virus drugs without restriction of use are needed for the following
reasons: 1) zanamivir is
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not licensed for treatment of influenza in very young children due to the
difficulty with inhalation in
this group (< 5 or 7 years of age, depending on country), 2) peramivir needs
to be intravenously
administered, and 3) oseltamivir requires twice daily (BID) dosing orally for
5 days. In addition, the
efficacy of currently marketed antivirals against preventing complications in
pediatric patients has
not been demonstrated.
Baloxavir marboxil is a compound discovered by Shionogi & Co., Ltd. that
exerts antiviral effects
against influenza. Baloxavir marboxil (also referred to as S-033188, Shionogi
Compound
Identification Number) is a pro-drug that is converted to the active form
baloxavir (also referred to
as 5-033447, Shionogi Compound Identification Number) in the blood, liver, and
small intestine
through a metabolic process called hydrolysis. Baloxavir marboxil acts on the
cap-dependent
endonuclease, an enzyme specific to influenza viruses, and inhibits viral cap-
snatching, thereby
suppressing the growth of influenza viruses.
Baloxavir marboxil has been tested in several clinical trials. However, it is
commonly known that
the results of a given clinical trial cannot be simply transferred to the
response of any patient to the
pharmaceutical compound. More specifically, there are several factors that may
have significantly
influenced the outcome of the clinical trial, such as the patient population
(e.g. adults, pediatrics,
elderly, ethnicity) and the dosing regimen.
For example, it is known that the results of clinical trials on adults cannot
be transferred to pediatric
patients. To find a dose that produces the desired therapeutic effect and at
which no side effects
occur must be determined separately in minors, even if suitable doses are
known for adults.
Finding a dose which is particularly suitable for minors is very important
because a young
organism processes drugs very differently from an adult Newborns, for example,
only degrade
drugs slowly because the liver and kidneys are not yet mature. Children over
two years of age, on
the other hand, have a faster metabolism and their bodies sometimes excrete
the substances more
quickly. Furthermore, medicaments which are usually harmless in adults can be
dangerous for
children. For example, the compound acetylsalicylic acid (ASS), which is
commonly used by adults
suffering from pain or fever, can trigger the life-threatening Reye syndrome
in children, which can
severely damage the brain and the liver. Therefore, clinical trials on adults
cannot be used for
determining whether a given compound can be used in minors, even less for
finding a suitable
dose of the medicament in minors, children and newborns.
Indeed, the oral clearance of baloxavir (CUF) was influenced by bodyweight The
lower
bodyweight, the higher CL/F. This relationship suggest that CUF will increase
with age. In a
population pharmacokinetic (PK) analysis based on a Japanese pediatric trial
(1618T0822), the
CUF relationship was defined as follow: C1JF=3.05*(Bodyweight/24.3)"32. A
similar impact of
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bodyweight was observed on the baloxavir apparent volume of distribution.
Similarly, a lower
central volume of distribution was observed in patients with lower bodyweight
(Vc=105*(Bodyweight/24.3)"3). Due to this impact of bodyweight on PK of
baloxavir, the dose
which is used in adults cannot simply be extrapolated for obtaining optimal
drug exposure in
pediatric patients matching drug exposure of adults in terms of both total
area under the plasma
concentration-time curve (AUC) and plasma concentration 72 hours after dosing
(C72).
Two phase III clinical trials have been conducted for testing baloxavir
marboxil in pediatric patients
from 6 months to 12 years of age in Japan (studies 1618T0822 and 1705T0833).
All participants of
these studies had Asian heritage (Japanese) and the highest administered
dosage was 40 mg. In
the first study 1618T0822 (also called T0822) tablets of 10mg and 20mg were
used. Patients were
dosed per bodyweight as follows: 40 kg: 40 mg dose (n=8), 20 kg ¨ 40 kg: 20 mg
dose (n=66),
kg ¨ 20 kg: 10 mg dose (n=31), 5 kg- < 10 kg: 5 mg (n=2). In the second
paediatric study in
Japanese patients 1705T0833 (also called T0833) baloxavir marboxil 2% granules
were
administered to paediatric subjects weighing less than 20 kg and less than 12
years of age. 33
patients aged between 0 and 6 year-old were included in this study. 6 were
less than 1 year, 13
between 1 and 3, and 14 were 3 years or older. 12 subjects had bodyweight
lower than 10 kg, and
21 had bodyweight lower than 20 kg.
Concern that ethnic differences may affect the medication's safety, efficacy,
dosage and dose
regimen in a new region has limited the willingness to rely on foreign
clinical data. Indeed, it is
known that the varieties in metabolism of persons having a different ethnicity
are associated with
interethnic variation in drug pharmacokinetics (Kim, The Journal of Clinical
Pharmacology 44.10
(2004): 1083-1105). It was also known that such interethnic variations
particularly exist between
Asians (such as Japanese persons) and white persons (e.g. Caucasians), and can
lead to
differences in efficacy and toxicity of a given drug (Kim, The Journal of
Clinical Pharmacology
44.10 (2004): 1083-1105). The ICH (International Council for Harmonisation of
Technical
Requirements for Pharmaceuticals for Human Use) guidelines E5(R1) defined
ethic factors and
their inclusion in multiregional clinical trials (see IHC guideline E5(R1) of
February 5, 1998
including corrections of March 11, 1998). For example, the ICH guideline E5
makes clear that
clinical data which has been obtained with patients having a particular
heritage cannot simply be
transferred to patients having a different heritage. The reason is that
several medical compounds
are sensitive to ethnic factors, which means that ethnic factors (such as
genetic polymorphisms)
have significant impact on safety, efficacy, or dose response of the
compounds. There are several
examples where the ethnic heritage considerably influenced the response to a
drug (Bjornsson,
The Journal of Clinical Pharmacology 43.9 (2003): 943-967). Indeed,
interethnic variability in
pharmacokinetics can cause unexpected outcomes such as therapeutic failure,
adverse effects,
and toxicity in subjects of different ethnic origin undergoing medical
treatment (Kim, The Journal of
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Clinical Pharmacology 44.10 (2004): 1083-1105). For example, it is known in
the art that a
particular splicing polymorphism in the enzyme UGT2B10 which is common in
African populations
can greatly increase drug exposure (Fowler, Journal of Pharmacology and
Experimental
Therapeutics 352.2 (2015): 358-367). This UGT2B10 splice site mutation is
almost unrepresented
in Caucasians (Fowler, Journal of Pharmacology and Experimental Therapeutics
352.2 (2015):
358-367). Similarly, a clinical study on the treatment of gastric cancer with
bevacizumab showed
regional differences in efficacy outcomes (Ohtsu, J Clin Oncol 29.30 (2011):
3968-3976).
In the treatment of influenza it is of high importance to use an appropriate
dosage of the anti-
influenza drug. For example, a dosage too low can lead to the occurrence of
treatment-resistant
viruses (e.g. viruses having the 138 amino acid substitution). A dosage too
low can further lead to
rebound of virus titer or double-peak fever. Therefore, in the treatment of
influenza it is of high
importance to use a dose of the anti-influenza drug which is as high as
necessary for obtaining a
fast therapeutic response by avoiding overdose.
As described above, baloxavir marboxil has been tested in various clinical
studies in adults as well
as in a small number of clinical studies in Asian pediatric patients. However,
as also explained
above, these data cannot simply be transferred to non-Asian pediatric
patients. In addition, as also
explained above, usage of the correct dose is of high importance in the
treatment of influenza.
Thus, the technical problem underlying the present invention is the provision
of an improved
dosage of baloxavir marboxil for pediatric patients.
The technical problem is solved by provision of the embodiments as
characterized in the claims.
Accordingly, the present invention relates to a method for treating an
influenza virus infection,
wherein said method comprises administering an effective amount of a compound
to a patient
having an influenza virus infection, wherein the compound has one of the
following formulae I and
(I) (II)
0
Me 0 0 0 OH 0
Otri:r4 ......tri/L,14
_14 )440.,0
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or is a pharmaceutically acceptable salt thereof,
and wherein the following dosage is used:
(i) in a patient that is younger than 1 year:
(a) if the patient is younger than 4 weeks, then the effective amount is 0.8-
1.2 mg/kg body
weight, preferably about 1 mg/kg body weight
(b) if the patient is 4 weeks or older but younger than 3 months, then the
effective amount
is 0.8-1.2 mg/kg body weight, preferably about 1 mg/kg body weight;
(c) if the patient is 3 months or older but younger than 12 months, then the
effective
amount is 1.8-2.2 mg/kg body weight, preferably about 2 mg/kg body weight;
(ii) in a patient that is 1 year or older but younger than 12
years:
(a) if the patient has a body weight of less than 20 kg, then the effective
amount is 1.8-2_2
mg/kg body weight, preferably about 2 mg/kg body weight; or
(b) if the patient has a body weight of 20 kg or more, then the effective
amount is 35-45
mg, preferably about 40 mg.
As mentioned above, in the treatment of influenza, a dosage too low can affect
the occurrence of
treatment-resistant viruses (e.g. viruses having the 138 amino acid
substitution), and can further
lead to rebound of virus titer and double-peak fever. The dosage of the
present invention
preferably reduces the occurrence of treatment-resistant viruses (e.g. viruses
having the 138 amino
acid substitution) as compared to pediatric baloxavir marboxil dosages of the
prior art. In addition,
the dosage of the present invention preferably reduces the occurrence of viral
rebound as
compared to pediatric baloxavir marboxil dosages of the prior art. As used
herein the term "viral
rebound" means: For observed time points after administration of the compound,
influenza virus
titer [log10(TC1D50/mL)] at a certain time point is equal to 0.6 or 0.6
greater than that at just before
time point. Furthermore, the dosage of the present invention preferably
reduces the occurrence of
double-peak fever as compared to pediatric baloxavir marboxil dosages of the
prior art. The
dosage of the present invention may further shorten the time to alleviation of
influenza illness
and/or resolution of fever as compared to pediatric baloxavir marboxil dosages
of the prior art.
Es shown in the appended Examples, there was a clear difference in the median
time to cessation
of viral shedding between baloxavir (24 his) and oseltamivir (76 hrs). These
data indicate that
baloxavir-treated patients are no longer infective after a median time of
about 1 day compared to
about 3 days in oseltamivir-treated patients. Accordingly, the dosage of the
present invention
advantageously reduces transmission of influenza. More specifically, the
dosage of the present
invention preferably reduces transmission of the influenza virus of a patient
who received the
dosage of the present invention as compared to patients who received
oseltamivir. The patient is a
pediatric patient which is newborn or older but younger than 12 years, e.g., 1
year or older but
younger than 12 years.
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As discussed above, in the treatment of influenza it is of high importance to
use an appropriate
dose of the anti-influenza drug which is as high as necessary for preventing
occurrence of
treatment-resistant viruses or viral rebound, however, by avoiding overdose.
Predicting the suitable
dose of a drug for a desired patient group is an important measure for
ensuring that the drug is
administered to the patients in a sufficient dose to obtain the desired
therapeutic effect while
avoiding overdose. Such predictions can be performed in silk by using a
suitable descriptive or
mechanistic model. Of course, modeling techniques do not provide complete
certainty that a given
patient shows the desired response to the tested drug. However, the same holds
true for every
clinical testing. Favorable results from biochemical or cell-based assays
which test the effects of a
drug as well as animal experiments or even clinical trials involving patients
can only increase the
probability that the drug shows the desired therapeutic effects in the
subsequently treated patients.
For example, early phase studies usually have a small sample size or may be
biased for an
unknown reason, which may lead to an incorrect assessment of the physiological
effects of the
drug at issue. It is nearly impossible to absolutely proof that a medicament
will (always) show the
desired therapeutic effect in the intended patient group without leading to
any unwanted side-
effects. As mentioned, all possible methods for verifying the physiological
effects of a drug can only
increase the possibility that the drug will lead to this particular
physiological effect in the later on
treated patient. As explained above, predicting a suitable dose of a drug by
in silico modeling is
one of these models, which is particularly useful for establishing a suitable
dose for a new patient
group.
In the context of the present invention comprehensive model simulations to
predict a suitable dose
of baloxavir marboxil in pediatric patients (preferably non-Asian pediatric
patients) have been
performed. The model used for the simulations was developed by considering
previous studies
conducted in Japanese pediatric patients. The model integrates both patient's
demographics
characteristics and drug PK characteristics in the studied population.
Baloxavir plasma
concentrations after various dosing regimen can then be simulated in pediatric
patients based on
patient characteristics such as age or bodyweight. Consequently, this model
advantageously
provides the basis for a suitable dose of baloxavir marboxil in pediatric
patients, preferably non-
Asian (such as white) pediatric patients, which, in all likelihood, ensures
baloxavir plasma
exposures comparable to exposures in adult patients and appropriate
pharmacologic effect in the
treatment of influenza by avoiding potential side-effects.
More specifically, in the context of the present invention suitable doses for
non-Asian (e.g. white,
such as Caucasian) pediatric patients were determined using a modeling and
simulation approach.
Based on a model developed in Japanese pediatric patients, plasma
concentrations of baloxavir
(S-033447) pharmacokinetics in a non-Asian (e.g. white, such as Caucasian)
pediatric population
were simulated for different dosing regimen. More specifically, a population
pharmacokinetic
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analysis had been performed in Japanese pediatric populations by using
unpublished
pharmacokinetic data obtained in a phase III study involving pediatric
patients in Japan
(1618T0822); the suitable dose of baloxavir marboxil for non-Asian pediatric
patients was then
obtained by simulating non-Asian pediatric drug exposure after several
different dosing regimen,
the ones matching the best adult exposures were then selected. In particular,
the simulation of
pediatric drug exposure was performed as described in the following:
With respect to non-Asian pediatric patients that are younger than 1 year,
simulations were
performed for 1,000 patients for each age in months for < 2-year old infants
(26,000 patients in
total). Thus, several sets of 1000 patients were conducted. For instance, 1000
between 0 and 1
month, 1000 between 1 and 2 months, ...for a total of 26000 simulations (i.e.
26 x 1000). For
patients that are between 1 and 12 years old, simulation of non-Asian
pediatric drug exposure was
perfon-ned for 1,000 patients for every 5-kg body weight for 10- to 60-kg
pediatric patients (26,000
patients in total).
In both cases, various dosing regimens were evaluated with respect to their
ability to match adult
drug exposure in terms of area under the plasma concentration-time curve
(AUG), maximum
plasma concentration (G.), plasma concentration 24 hours after dosing (G24;
acceptable time
window: 20 to 28 hours), and 72 hours after dosing (G72). The optimal dose and
appropriate age
and bodyweight cut-off were based on a comparison of the simulated drug
exposures with those
obtained in the phase III study (1601T0831) for patients receiving 40 mg
baloxavir marboxil (body
weight < 80 kg) and patients receiving 80 mg baloxavir marboxil (body weight 2
80 kg), those
obtained in the pediatric phase III study (1618T0822), and those obtained in
the phase I thorough
corrected QT interval (QTc) study (1527T0816) for patients receiving 80 mg
baloxavir marboxil.
With respect to patients that are younger than 1 year simulations showed that
optimal exposure
matching to adults in terms of both total (AUG) and sustained (Cu) drug
exposure was achieved
with 2 mg/kg in infants of 3 months and older, and 1 mg/kg in younger infants
(4 weeks-3 months)
as well as for newborns (0-4 weeks). Accordingly, in patients which are
younger than 1 year
baloxavir marboxil can be administered according to the infant's age recorded
at the time point
when the patient is diagnosed as having an influenza virus infection (i.e., 2
mg/kg a. 3 months, 1
mg/kg < 3 months) to obtain similar exposure of baloxavir (S-033447) to that
resulting from the
administration of 40 mg or 80 mg baloxavir marboxil (based on the patient's
body weight) to adults
in the phase III and Japanese pediatric phase III studies.
With respect to patients that are 1 to 12 years old simulations showed that
optimal exposure
matching to adults in terms of both total (AUG) and sustained (C72) drug
exposure was achieved
with 2 mg/kg in children weighing less than 20 kg and flat dosing of 40 mg in
children weighing a.
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20 kg. Accordingly, patients which are 1 to 12 years old baloxavir marboxil
can be administered
based to the body weight recorded at the time point when the patient is
diagnosed as having an
influenza virus infection (i.e., 2 mg/kg for patients weighing < 20 kg or 40
mg for patients weighing
a 20 kg) to obtain similar exposure of baloxavir (6-033447) to that resulting
from the administration
of 40 mg or 80 mg baloxavir marboxil (based on body weight) to adults in phase
III and Japanese
pediatric phase III studies.
As explained above, the clinical studies which have been conducted with
baloxavir marboxil and
Asian pediatric patients cannot be simply transferred to non-Asian (e.g.
white, such as Caucasian)
pediatric patients. Therefore, and in order to provide an optimal dose for
children younger than 12
years (and therewith improve the chances of these young patients to recover
from an influenza
virus infection) an improved dosage schedule for non-Asian (e.g. white)
pediatric patients has been
developed in accordance with the present invention. Therefore, in accordance
with the present
invention, the patient to be treated may have the racial designation non-
Asian, e.g. "white". Thus,
the invention relates to the herein provided method, wherein the patient is
white. The term "white"
refers to a person having origins in any of the original peoples of Europe,
the Middle East, or North
Africa (cf., e.g., US Food and Drug Administration. "Collection of Race and
Ethnicity Data in
Clinical Trials Guidance for Industry and Food and Drug Administration Staff."
Issued on October
26 (2016)). For example, the white pediatric patient may be Caucasian.
As described above, the guidelines of the ICH make clear that clinical data
which has been
obtained with patients having a particular heritage cannot simply be
transferred to patients having
a different heritage. According to the ICH guidelines a clinical trial which
has been conducted in
one region (like Japan) cannot be transferred to another region (such as
Europe or the United
States). For example, evaluation of the pharmacokinetics in the three major
racial groups most
relevant to the ICH regions (Asian, Black, and Caucasian) is critical to the
registration of medicines
in the ICH regions. With respect to baloxavir marboxil, clinical trials have
been conducted with
pediatric patients in Japan. The present invention is based on the finding of
an optimal baloxavir
marboxil dose for non-Asian (e.g. white, such as Caucasian) pediatric
patients. Accordingly, in
accordance with the present invention the patient has preferably a non-Asian
heritage and is not
living in Asia. Thus, in the present invention the patient may not have an
Asian ethnicity. The term
"Asian" refers to a person having origins in any of the original peoples of
the Far East, Southeast
Asia, or the Indian subcontinent, including, for example, Cambodia, China,
India, Japan, Korea,
Malaysia, Pakistan, the Philippine Islands, Thailand, and Vietnam. (cf., e.g.,
US Food and Drug
Administration. "Collection of Race and Ethnicity Data in Clinical Trials
Guidance for Industry and
Food and Drug Administration Staff." issued on October 26 (2016)). For
example, the patient may
not be Japanese.
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Thus, it is preferred that the patient does not have an Asian (e.g. Japanese)
ethnicity and does not
live in Asia (e.g. Japan). As mentioned above, a clinical trial with baloxavir
marboxil has been
conducted with Japanese pediatric patients (studies 1618T0822 and 1705T0833).
However, in
these studies the efficacy of a maximum of 1 mg/kg body weight of baloxavir
marboxil was used in
patients aged 6 months to < 12 years. Thus, these Japanese clinical trials are
significantly different
from the dosages which are provided herewith, since in the context of the
present invention the
patients can be younger than 6 months, and/or receive 2 mg/kg body weight of
baloxavir marboxil.
In addition, as explained above, the results of clinical trials cannot be
directly transferred from one
ethnicity to another. Therefore, the clinical trials which have been conducted
in Japan with Asian
pediatric patients (studies 1618T0822 and 1705T0833) cannot be directly
transferred to non-Asian
(e.g. white, such as Caucasian) pediatric patients. As mentioned above, the
dosages provided with
the present invention are optimized dosages for non-Asian, (e.g. white, such
as Caucasian)
pediatric patients_ Therefore, in the present invention it is preferred that
the pediatric patients are
white, e.g. Caucasian. Europeans and "white" Americans are usually referred to
as "Caucasians"
(Bjomsson, The Journal of Clinical Pharmacology 43.9 (2003): 943-967). Thus,
in accordance with
the present invention the patient may have Caucasian (i.e. European or "white"
American) heritage
and may be living in Europe or North-America (e.g. in the United States).
Baloxavir marboxil is mostly administered in the form of tablets. However,
tablets have the
disadvantages that the acceptability is usually low in pediatric patients,
leading to inconsequent
drug intake, splitting out of the drug or vomiting the medicine before it
takes effect. In addition,
newborn and young children are often not able to swallow tablets. Also
patients with a nasogastric
tube in situ (e.g., intubated patients) are unable to swallow tablets.
Therefore, in the context of the
present invention the compound may be administered in the form of a suspension
of granules.
Particularly if the patient is younger than 1 year (i.e. patients as defined
under (i), above), or if the
patient is 1 year or older and has a body weight of less than 20 kg (i.e.
patients as defined under
(ii)(a), above) the compound may be administered in the form of a suspension
of granules. For
example, the granules as described in PCT/JP2019/017146 may be used. It has
been shown that
such granules (in particular 2% baloxavir marboxil, i.e. 5-033188, granules)
have bioequivalence
with 20 mg baloxavir marboxil (5-033188) tablets (Clinical Study Report Study
No. 1703T081G,
Shionogi & Co., Ltd.; 2018). Therefore, in the present invention the granules
are preferably 2%
baloxavir marboxil (i.e. 5-033188) granules.
In the clinical trial with Japanese paediatric patients weighing less than 20
kg (1705T0833)
granules have been used as administration form. The finished granule product
configuration
developed for the Japanese market by Shionogi consists of granules packaged in
a sachet The
granules are intended for administration directly into the mouth of the
subject. In the context of the
present invention the granules are preferably resuspended (e.g. in a bottle)
and a specific volume
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is given orally (e.g. by a syringe). In particular, the granules to be used in
the present invention
may be reconstituted with water. For example, 2 g of granules, which contain
40 mg of the
compound to be used in the present invention (nominal), may be reconstituted
with 20 mL water,
which corresponds to a final concentration of 2 mg of the compound per
millilitre (mL). These
resuspended granules can advantageously be administered to children, even to
young children
(infants) and patients having a nasogastric tube.
The granules for oral suspension may have a composition as shown Table 1.
Table 1: Components and composition of baloxavir marboxil granules for oral
suspension
Nominal Concentration
amount in
Granule
Component (mg/bottle) (%)
Function Quality Standard
Active
Baloxavir Marboxil 40 2
In-house standard
ingredient
Mannitol 1120 56
Diluent Ph. Eur./USP/JP
MaItitol 700 35
Diluent Ph. Eur./NF/JPE
Taste
Sodium Chloride 60 3
masking Ph. Eur./USP/JP
agent
Hypromellose 6 0.3
Dispersant Ph. Eur./USP/JP
Povidone (K value: 25) 20 1
Binder Ph. Eur./USP/JP
Silica, Colloidal
40 2
Fluidizer Ph. Eur./NF/JP
Anhydrous
Sucralose 10 0.5
Sweetener Ph. EuriNF/JPE
Talc 2 0.1
Lubricant Ph. Eur./USP/JP
Strawberry Flavour 2 0.1
Flavour In-house standard
Purified Water a
Vehicle Ph. Eur./USP/JP
Total Weightb 2,000 100
a Purified water is removed during manufacturing process.
b An overfill of, e.g. 0.13 g of granules is applied to
obtain the targeted maximum extractable
volume of 20 mL after reconstitution; fill weight may be adjusted based on
assay value for bulk
granules.
Bitter taste has been reported in adult clinical studies with baloxavir
marboxil and several
excipients have been included in the formulation to mask the bitter taste and
ensure palatability,
such as sodium chloride, sucralose and strawberry flavor. Thus, the granules
provided with the
present invention have the advantages that they are to be administered in the
form of an oral
suspension and that the bitter taste of the active compound is masked.
Accordingly, these granules
improve acceptance of the compound in pediatric patients, which contributes to
the achievement of
the therapeutic effect. Indeed, in clinical trials wherein baloxavir marboxil
was administered to
pediatric Japanese patients (i.e. studies 1618T0822 and 1705T0833) the most
common adverse
event was vomiting. Although the vomiting was considered to be not related to
the study drug by
the investigators, reducing or avoiding vomiting which is induced by the
administration form can
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provide a therapeutic benefit In addition, the oral suspension provides
flexibility to more precisely
implement weight-based dosing.
As dosing device an oral dosing syringe or an oral dosing cup (both
volumetric) may be used to
provide the sufficient degree of accuracy to deliver the recommended doses of
the compound to be
used in the present invention (e.g. baloxavir marboxil). For example, a 3 mL
oral dosing syringe
that could be used in infants typically includes volumetric demarcations in
tenths of a milliliter,
which would be adequate to deliver accurate doses. Alternatively, a 10 mL oral
dosing syringe may
be used.
Examples for dosages which may be used are shown below in Table 2.
Table 2. Examples for age/weight dependent dosing
dose volume of
2% suspension
Age group weight (kg) (mL)
dose regime Age
2 1
3 1.5
4 2
2.5 1 mg/kg < 3 months
6 6 2
mg/kg
Infants 7 7
(i.e. young 8 8
children) 9 9
10 <12 months
11 11 2
mg/kg
12 12
13 13
14 14
15
Children 16 16
17 17
18 18
19 19
<20 20
20 40 mg (flat
dose)
The dosing shown in Table 2, above, is merely an example. For example, the
dosage of patients
as defined in the inventive method under item (i), above, (i.e. patients who
are younger than 1
year) is performed according to their age (e.g., 1 mg/kg for patients who are
younger than 3
months; and 2 mg/kg for patients who are 3 months or older but younger than 12
months). For
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example, a child who is younger than 3 months and has a body weight of 6 kg
would receive about
1 mg/kg of the compound.
As described above, the compound to be used in the present invention can be
administered in the
form of a suspension of granules. Such granules for oral suspension can be
reconstituted with
water to provide the desired dose. However, according to the present invention
a patient who is 1
year old or older and has a body weight of 20 kg or more (i.e. the patient as
defined in item (ii)(b),
above) receives a 40 mg flat dose of the compound. This 40 mg dose is
preferably administered in
the form of a tablet. For example, the 40 mg dose may be administered in the
form of a film-coated
tablet.
However, the invention is not limited to any specific route of administration
of the compound to be
used herein. All possible routes of administration that the attending
physician deems useful or
necessary are within the scope of the present invention. For example, the
compound may be
administered oral, rectal, nasal, topical, intradermal, as aerosol, vaginal,
or parenteral, such as
intramuscular, intravenous, subcutaneous, intraarterial, or intracardial. It
is preferred that the
compound is orally administered. Dosage forms for oral administration include
coated and
uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges,
troches, solutions,
emulsions, suspensions, syrups, elixirs, powders and granules for
reconstitution, dispersible
powders and granules, medicated gums, chewing tablets and effervescent
tablets. Dosage forms
for parenteral administration include solutions, emulsions, suspensions,
dispersions and powders
and granules for reconstitution. Dosage forms for rectal and vaginal
administration include
suppositories and ovula. Dosage forms for nasal administration can be
administered via inhalation
and insufflation, for example by a metered inhaler. Dosage forms for topical
administration include
creams, gels, ointments, salves, patches and transdermal delivery systems.
However, it is
preferred in the present invention that the compound is orally administered.
It is envisaged in the
present invention that the compound is given as a single dose.
As indicated above, particularly for the patients as defined under (i) and
(ii)(a), above, it is
preferred that the compound to be used in the present invention is in the form
of the granules for
suspension, and is administered as single oral dose, or as single dose which
is administered via a
nasogastric tube. For example, the granules comprising baloxavir marboxil as
described above can
be reconstituted with water to provide the desired dose in a suspension. If
the patient is 1 year
but < 12 years and has a body weight of 20 kg or more (i.e. the patient as
defined in (ii)(b), above),
then the effective amount of the compound to be used herein is 35-45 mg,
preferably about 40 mg.
For these patients administration of two 20 mg tablets or one 40 mg tablet as
single oral dose is
preferred.
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Children usually reach 20 kg with the age of about 3 to 8 years, mostly
between 5 and 6 years.
Therefore, in the context of the present invention the patient as defined in
(ii)(a), above (i.e. the
patient that is al year but <12 years, and has a body weight of <20 kg) may
have an age between
1 and 8 years, e.g. between 1 and 6 years. For example, the patient as defined
under (ii)(a),
above, may be 1 year old or older but younger than 5 years. 1 year old
children have usually a
weight between 7 and 13 kg. Therefore, the patient as defined in (iiXa) may
have a body weight
which is about 7 kg or more, e.g. about 11 kg or more.
In the present invention the patient as defined under (ii)(b), above (i.e. the
patient that is M year
but <12 years, and has a body weight of
kg) may be 5 years old or
older but younger than 12
years. In addition or alternatively, the patient as defined under (ii)(b),
above, may have a body
weight which is less than 40 kg. According to the present invention a patient
that is 1 year or older
but younger than 12 years and has a body weight of 20 kg or more is
administered with an
effective amount of the compound to be used in the invention which is 3545 mg,
preferably about
40 mg. It is preferred that the compound is administered to this patient in an
amount which is more
than 1 mg/kg body weight (e.g. 1.5-2 mg/kg body weight).
In accordance with the present invention a comprehensive simulation has been
performed in order
to find optimal doses of baloxavir marboxil for pediatric patients,
particularly non-Asian (e.g. white
such as Caucasian) pediatric patients. This simulation shows that the regimen
of the present
invention matches adult drug exposure optimally in terms of both total drug
exposure as well as
drug levels up to 72 hours after dosing, especially in pediatrics with a body
weight less than 25 kg.
Therefore, the patient as defined in item (ii)(b), above (i.e. the patient
having a body weight of 20
kg or more) has preferably a body weight which is less than 25 kg.
In the present invention the patient may be healthy except for the influenza
virus infection. The
influenza virus may have no substitution in at least one of the genes selected
from the viral acidic
polymerase (PA) gene, the viral basic polymerase 1 (PB1) gene, and the viral
basic polymerase 2
(PB2) gene. For example, the influenza virus may have no substitution in all
of these genes. In a
preferred aspect of the present invention the influenza virus strain does not
carry an I38X mutation,
such as the 138T mutation, in the viral acidic polymerase (PA) protein. The
I38T mutation is
commonly known in the art and described, e.g., in Omoto, Scientific reports
8.1 (2018): 9633.
Thus, it is preferred that the influenza virus stain does not carry an I38T
mutation in the viral acidic
polymerase (PA) protein. The I38T substitution is a mutation in the viral
acidic polymerase (PA)
protein of some mutated influenza A strains. The sequence of the PA protein of
an influenza A
virus having the I38T mutation is shown in SEQ ID NO:1. Thus, in a preferred
aspect of the present
invention the influenza virus strain does not comprise a PA protein having the
sequence of SEQ ID
NO:1. It is also preferred that the influenza virus strain does not comprise a
PA protein having a
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sequence which has at least 80%, preferably at least 90%, more preferably at
least 95%, at least
96%, at least 97%, at least 98%, or at least 99% sequence identity to the
sequence of SEQ ID
NO:1 and comprising a substitution (e.g. an 1 to T substitution) at the
position corresponding to
position 138 of SEO ID NO:1. A fraction of the PA protein of an influenza A
virus comprising the
I38T mutation is shown in SEO ID NO:2. Thus, in a preferred aspect of the
present invention the
influenza virus strain does not comprise a PA protein comprising the sequence
as shown in SEO
ID NO:2.
In one aspect of the present invention an influenza virus infection is present
if the influenza virus
can be detected. The influenza virus may be detected via PCR. In addition or
alternatively the
influenza virus may be detected by using an influenza test kit Rapid Influenza
Diagnostic Test
(RIDTs) based on immunologic detection of viral antigen in respiratory
secretions offer point of
care (on-site) tests with results available within 30 minutes. Thus, a RIDT
may be used for
detecting the influenza virus. RIDTs can identify the presence of influenza A
or B viral
nucleoprotein antigens and display the result in a qualitative way (positive
vs. negative) (Ali T, Gun
Infect Dis. 2004 Mar 1;38(5):760-2). RIOT assays are ELISA based assays which
are less accurate
than PCR, but have the advantage that they are cheaper and faster.
The influenza virus infection may further be detected by using the Roche cobas
Liat point of care
(POC) polymerase chain reaction (PCR) system (Chen, Eur J Micro biol Immunol
(Bp).
2015;5(4):236-245). The cobase Liat system enables rapid and accurate
diagnosis of influenza A
or B nasopharyngeal swab specimens. The system comprises the cobas Liat
Analyzer and the
cobas Influenza NB assay. The detection of the influenza virus may also be
carried out by using
a PCR-based molecular test (Prodesse ProFlu+ assay, Chen, Fur J Microbiol
lmmunol (Bp).
2015;5(4):236-245) or the Alere i Influenza A & B rapid PCR system (Mercloc,
Ann Intern Med.
2017;167(6 ):394-409).
The influenza virus infection may also be detected by virus culture
techniques, which involve
inoculation of clinical specimens onto cell culture lines. By using this
method, over 90% of positive
cultures can be detected within 3 days of inoculation (Newton, Journal of
clinical microbiology
40.11 (2002): 4353-4356). The influenza virus infection may also be detected
via molecular
diagnostic tests, which use detection of viral nucleic acids in clinical
specimens to achieve greater
sensitivity than cell culture and in addition allow detection of virus in
samples that have lost
viability.
As indicated above, the influenza virus infection may be detected via
polymerase chain reaction
(PCR) assays, which allow both qualitative and quantitative assessments in
addition to rapid
subtyping of the virus. The PCR detection and quantification of the influenza
virus is commonly
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known in the art. For Example, real-time reverse transcription PCR (RT-PCR)
amplification of the
influenza matrix gene may be employed as the method for determining the
presence or absence,
or the quantity of influenza RNA. Influenza virus RNA extraction and
purification is a routine
technique and can, e.g., be performed by using a MagNA Pure LC 1.0 or 2.0
isolation station
(Roche Applied Science, product # 05197686001). To perform the test, nucleic
acids are extracted
from swab specimen aliquots using the MagNA Pure LC isolation station and the
MagNA Pure LC
nucleic acid extraction kit according to the manufacturer's instructions
(Roche Applied Science).
Reverse transcription and amplification reactions can be set up using Taqman
Fast Virus
Mastermix. During clinical analysis, a 4 point (low, middle and high)
influenza A and B standard
curve with known virus particles/m1 can be used as control and can accompany
every run. To
monitor the whole process from isolation to real-time detection, a universal
internal control, the
Phocine Distemper Virus (PDV), may be added to each isolate. In addition, to
monitor
contamination in every isolation a No Amplification Control (NAC) may be
included for every PCR
mix that is made. The positive controls must give a positive signal that lies
between specified
action limits. lithe value of the positive control lies outside the action
limit, all samples tested with
the same PCR mix need to be retested. If the negative control gives a positive
signal for influenza,
all samples run with the same PCR mix need to be retested. The output of the
influenza RT-PCR
assay is what is known as a Cycle threshold, or Ct value and a Ct value is
recorded for each test.
The Ct values are converted to quantitative virus particles/ml values with the
standard curves ran
concurrent with the samples.
For influenza A positive subjects an influenza A subtype PCR assay can also be
performed. More
specifically, for influenza A positive subjects, sub-typing can be performed
directly from a subject's
swab sample using a real time RT-PCR assay. RNA can be isolated from clinical
isolates as
described above using the Roche MagNA Pure Total Nucleic Acid kit, and can be
amplified using a
one-step RT-PCR with influenza A-subtype specific primers. Further methods for
the detection of
particular influenza virus subtypes including suitable primer sequences are
commonly known in the
art, and described, e.g., in the "WHO information of the molecular detection
of influenza viruses" of
July 2017.
Serological tests, such as complement fixation and haemagglutination
inhibition, can be used to
establish retrospectively a diagnosis of an influenza virus infection. Because
individuals may have
been previously infected with influenza viruses, paired serum specimens,
consisting of an acute
serum specimen and a convalescent serum specimen, obtained 28 days later, may
be used for
testing.
Most cases of influenza are diagnosed based on compatible clinical symptoms
and seasonal
epidemiology. Thus, also the presence of at least one symptom of influenza
indicates that an
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influenza virus infection is present. Therefore, in accordance with the
present invention the patient
may be diagnosed as having an influenza virus infection:
(i) due to the presence of fever of 38 C or more (tympanic
temperature); and at least one
respiratory symptom, preferably cough and/or nasal congestion; and/or
(ii) by using an influenza test kit.
Influenza viruses cause an acute febrile infection of the respiratory tract
characterized by the
sudden onset of fever, cough, fatigue, headache, and myalgia. The principal
clinical presentation of
influenza disease is essentially common between adults and children,
characterized by rapid onset
fever and cough, symptoms generally accepted to be directly consequential to
viral replication and
the host immune response (innate especially) to viral replication. Beyond the
cardinal symptoms of
flu, gastrointestinal symptoms, such as vomiting and/or diarrhea (Minodier,
Virology journal 12.1
(2015): 215) can be more common in infants and young children than in adults,
and children,
particularly those aged <5 years, may have higher maximum temperatures and
higher
hospitalisation rates than adults (Paules and Subbarao, 2017, Rotrosen and
Neuzil, 2017). For
example, young children usually have temperatures over 39.5 C and may have
febrile seizures
(convulsions).
In one aspect of the present invention an influenza virus infection is present
if both features apply,
i.e. the influenza virus can be detected, and at least one symptom of an
influenza virus infection is
present. Said at least one symptom of an influenza virus infection may be a
sudden onset of fever,
cough, fatigue, headache, and myalgia. The symptoms may further include
chills, a sore throat
and/or nasal congestion. The symptoms may also include gastrointestinal
symptoms. The
diagnosis of influenza may also comprise testing whether the body temperature
reaches 38 C to
40 C within 24 hours from the onset of influenza symptoms (Wright, Fields
Virology. 5th ed. (2).
Wolters Kluwer Health/Lippincott Williams & Wilkins; 2007. P. 1691-1740;
Monto, Arch Intern Med.
2000;160:3243-3247).
In addition or alternatively, the diagnosis of influenza may be confirmed by
all of the following:
(a)Fever a=38 C (axillary) in the predose examinations or >4 hours after
dosing of antipyretics if
they were taken.
(b)At least one of the following general systemic symptoms associated with
influenza with a
severity of moderate or greater:
(b)-1 Headache;
(b)-2 Feverishness or chills;
(b)-3 Muscle or joint pain;
(b)-4 Fatigue.
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(c)At least one of the following respiratory symptoms associated with
influenza with a severity of
moderate or greater:
(c)-1 Cough;
(c)-2 Sore throat;
(c)-3 Nasal congestion.
(c)-4 Influenza A or B infection confirmed by POC PCR testing.
There are three types of influenza viruses: A, B. and C. Types A and B cause
widespread
outbreaks of influenzal illness nearly every year. Influenza C is associated
with sporadic, often
asymptomatic infection with little or no mortality and therefore is not of
public health concern. In
accordance with the present invention the influenza virus may be an influenza
A virus or an
influenza B virus. For example, the influenza virus may be a type A influenza
virus. However, the
influenza virus infection may also be a mixed infection involving the
influenza A virus as well as the
influenza B virus.
The means and methods provided herein are particularly advantageous if the
influenza virus strain
does not have a resistance against the compound to be used in the present
invention. However,
the influenza virus strain may have a resistance against other anti-viral
drugs (such as peramivir,
laninamivir, oseltamivir, zanamivir, rimantadine, umifenovir or amantadine).
Tests for determining
whether a given virus has a resistance against one or more drugs are commonly
known in the art
and comprise, e.g., the phenotypic resistance assay and the NA-Star assay,
which are both
described below.
The phenotypic resistance assay may be performed as described in the
following: Phenotypic
resistance assays (spot/focus reduction assay) can be performed by using the
sensitive Virospot
detection technology which combines classic virus culture in multi-well
microtiter plates and virus-
specific immunostaining with automated imaging, detection of infected cells
using a CTL
Immunospot UV analyzer equipped with Biospot analysis software. The Virospot
technology
platform determines sensitivity of virus isolates to antiviral drugs measuring
IC50/1C90. In brief, the
method is based on inoculation of infectious virus on MDCK cell monolayers in
96-well plates in the
presence of a drug concentration range. After incubation the cells are fixed
and immunostained
with virus-specific antibodies followed with TrueBlue substrate and image
capture using the UV
Analyzer.
The NA-Star assay is particularly useful for determining phenotypic resistance
to neurarninidase
inhibitors (such as, e.g. oseltamivir), and can be performed as follows: This
assay uses a
chemiluminescent substrate for highly sensitive detection of neuraminidase
enzyme activity.
Neuraminidase activity yields a luminescent compound which is quantified by
using a reader. Virus
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neuraminidase activity is determined in the presence of serial dilutions of
the neuraminidase
inhibitor. Sensitivity to neuraminidase inhibitor is expressed as 1050/1C90
values.
In a preferred aspect of the invention the compound is administered within 96
hours from the time
of symptom onset, preferably within 48 hours from the time of symptom onset.
For example, in a
patient as defined under item (i), above (i.e. a patient that is <1 year) the
compound may be
administered within 96 hours from the time of symptom onset. In a patient as
defined under item
(ii), above, (i.e. a patient that is 1 to <12 years) the compound may be
administered within 48
hours from the time of symptom onset. The symptom onset may be the time point
of the onset of at
least one systemic symptom andfor at least one respiratory symptom. Said at
least one systemic
symptom may be at least one symptom selected from headache, feverishness,
chills, muscular
pain, joint pain, and fatigue. Said symptom(s) may be noticed by the patient,
parent or caregiver.
Said at least one respiratory symptom may be at least one symptom selected
from coughing, sore
throat, and nasal congestion. Preferably, the time point of the onset of
influenza symptoms is
confirmed by verifying that within 24 hours from the above time point, that
the body temperature
reaches 38 C to 40 C or more.
After administration of the compound to be used in the present invention the
plasma concentration
of the compound of formula (II) may lead to similar exposures to the ones
achieved in non-Asian
adult patient population at the dose of 40 mg in the T0831 study, i.e.
AUC=3371 ng.h/mL, Cmax=
56.9 ng/ml and C24=33.1 ng/mL. Administration of the compound to be used in
the present
invention preferably leads to an accelerated recovery from the influenza virus
infection of the
treated patient as compared to an untreated patient to whom the compound has
not been
administered. Or, in other words, preferably the treated patient to whom the
compound to be used
in the present invention has been administered has a reduced time to recovery
as compared to an
untreated patient to whom the compound has not been administered. Herein, the
term "untreated
patient" means that said patient did not receive the compound to be used in
the present invention,
i.e. did not receive the compound having the formula (I) or (II) or a
pharmaceutically acceptable
salt thereof. However, said "untreated patient" may or may not have received
another medicament,
e.g. another antiviral drug. For example, in the present invention the
untreated patient may have
been administered with oseltamivir. In one example a patient which receives
the compound to be
used in the present invention is 1 year or older but younger than 12 years and
the untreated patient
has been administered with oseltamivir. The treatment regimen of oseltamivir
is commonly known
in the art. For example, oseltamivir may be administered twice daily for 5
days. Appropriate doses
for oseltamivir are based on body weight and commonly known in the art. It is
preferred in the
present invention that the compound to be used herein leads to a better
therapeutic effect as
compared to oseltamivir administration.
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The treated patient to whom the compound has been administered preferably has
a decreased
virological activity as compared to an untreated patient to whom the compound
has not been
administered. For example, it is preferred that the change from baseline in
the virus titer is at least
-4.20 logio (TCID50/mL), and/or that the change from baseline in the amount of
viral RNA is at least
-1.75 logic, (virus particles/mL) on Day 2 (i.e. two days after administration
of the compound to be
used herein, which is administered on Day 0).
For example, the virological activity may be decreased in the treated patient
within 86 hours after
administration of the compound to be used in the present invention, and may
remain decreased for
at least 21.5 hours. Measurement of the virological activity is commonly known
in the arg. For
example, the virological activity may be measured by:
(a)determination of the time to cessation of viral shedding;
(b)determination of the influenza virus titer; and/or
(c)determination the amount of virus RNA.
In this regard, the duration of influenza virus shedding may be measured as
time to shedding
cassation following symptom onset. The amount of virus RNA may be measured by
using reverse
transcriptase-polymerase chain reaction (RT-PCR). The virus titer may be
measured in the
following manner.
(1)MDCK-SIAT1 cells seeded in a flat-bottom 96-well microplate are cultured in
a 6% CO2
incubator at 37 1 C for 1 day.
(2)A standard strain (e.g. influenza virus AH3N2, ANictoria/361/2011, storage
condition: -80 C,
origin: National Institute of Infectious Diseases), a sample (collected from a
patient and stored in
an ultra-low-temperature freezer), and a medium for cell control are diluted
101 to 107 folds by
a 10-fold serial dilution method.
(3)After cells present in a sheet form are confirmed under an inverted
microscope, the medium is
removed, and a new medium is added at 100 pUwell.
(4)The medium is removed.
(5)Each of the samples (101 to 107) prepared in (2) above is inoculated at 100
pL/well, using 4
wells per sample.
(6)Centrifugal adsorption is performed at room temperature at 1000 rpm for 30
minutes.
(7)After centrifugation, the medium is removed, and cells are washed once with
a new medium.
(8)A new medium is added at 100 p1./well.
(9)Incubation is performed in a 5% CO2 incubator at 33 1 C for 3 days.
(10)After incubation, the CytoPathic Effect (CPE) is evaluated under an
inverted microscope.
It is preferred that the compound to be used in the present invention reduces
the time to alleviation
of influenza signs and symptoms (TASS) by at least 6 hours, preferably by at
least about 12 hours
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(e.g. by about 24 hours or more) as compared to an untreated patient to whom
the compound has
not been administered. More specifically, the compound preferably reduces TASS
by at least 6
hours, preferably by at least about 12 hours (e.g. by about 24 hours or more)
relative to their
respective placebos (or relative to an untreated patient). In line with this,
it is preferred that the time
from diagnosis of the influenza virus infection until recovery is decreased in
the treated patient to
whom the compound has been administered as compared to an untreated patient to
whom the
compound has not been administered. In this regard the patient may be
classified as being
recovered when at least one of the following recovery criteria is met and
remains met for at least
21.5 hours:
(a)return to afebrile state (tympanic temperature 37.2 C);
(b)a score of 0 (no problem) or 1 (minor problem) for cough and nasal symptoms
as specified in
items 14 and 15 of the Canadian Acute Respiratory Illness and Flu Scale
(CARIFS), preferably
a score of 0 (no problem) or 1 (minor problem) for all 18 symptoms specified
in the (CARIFS);
(c) cessation of viral shedding; and/or
(d)return to normal health and activity.
The Canadian Acute Respiratory Illness and Flu Scale (CARIFS) can be used to
identify a
treatment benefit of the compound to be used in the present invention (e.g.
baloxavir marboxil).
The CARIFS is commonly known in the art and shown in Figure 9. The CARIFS is a
reliable
questionnaire which is composed of 18 questions, each with a 4-point Liken
response. The
CARIFS questionnaire can be completed by the patient, parent, caregiver and/or
physician and
covers three domains: symptoms (e.g., cough), function (e.g., play), and
parental impact (e.g.,
dinginess). The CARIFS is calculated as the sum of the items and measures
duration of illness.
The return to normal health and activity may be achieved if the patient is
able to return to day care
or school, and/or to resume his or her normal daily activity in the same way
as performed prior to
developing the influenza virus infection.
Administration of the compound to be used in the present invention may prevent
the occurrence of
an influenza-related complication. Said influenza-related complication may be
at least one of the
complications selected from the group consisting of radiologically confirmed
pneumonia, bronchitis,
sinusitis, otitis media, encephalitis/encephalopathy, febrile seizures, and
myositis. Generally
subsequent or partially overlapping with the initial acute viral illness, the
most common
complications of influenza in children are otitis media, pneumonia (primary
influenza virus and
secondary bacterial pneumonia), respiratory failure, and seizures (Mistry,
Pediatrics 134.3 (2014):
e684-e690). These most common complications are preferably prevented in the
patient who is
treated with the compound to be used in the present invention. It is further
envisaged that death of
the patient caused by the influenza virus infection is prevented by the
administration of the
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compound. Usually, influenza infected persons do not die from the influenza
infection per se but
because of the development of a bacterial superinfection. Herein the term
"death (of the patient)
caused by the influenza virus infection" also includes death which is caused
by a bacterial
superinfection which had developed in an influenza infected person.
In the context of the present invention it is further envisaged that the
requirement of antibiotics is
prevented by the administration of the compound. Usually, a bacterial
superinfection leads to the
requirement of antibiotics. Thus, in accordance with the present invention, a
bacterial
superinfection may be prevented in the treated patient. Another condition
which usually leads to a
requirement of antibiotics is an asthma attack. Administration of the compound
to be used in the
present invention may also prevent hospitalization of the treated patient.
As detailed herein above and below, the compound to be used in the present
invention may have
the formula (I), (II) or may be a pharmaceutically acceptable salt of the
compound of formula (I) or
(II). In a preferred aspect of the present invention the compound has the
formula (I). The
compound to be used in accordance with the present invention may be combined
with other anti-
influenza drugs. Four antiviral drugs are currently approved in the EU for the
prevention and
treatment of influenza: the M2 ion-channel inhibitor amantadine and the NAls
oseltamivir
phosphate, zanamivir and peramivir. A second M2 inhibitor, rimantadine, holds
marketing
authorisations in the Czech Republic, France and Poland but is not marketed in
these countries.
Therefore, the compound to be used in the present invention may be
administered as co-therapy
with amantadine, oseltamivir phosphate, zanamivir, peramivir, and/or
rimantadine. Neuraminidase
inhibitors (NAls) are the mainstay of treatment for influenza infections.
Therefore, if the compound
to be used in the present invention is administered as co-therapy, then it is
preferably combined
with oseltamivir phosphate or zanamivir. Both oseltamivir phosphate and
zanamivir are
administered twice daily for 5 days.
The patient to be treated in the present invention is preferably healthy
beside the influenza virus
infection. It is preferred that the patient is not treated with any medicament
beside the compound to
be used in the present invention. For example, it is preferred that the
patient is not treated with an
investigational therapy, a systemic antiviral drug (e.g. peramivir,
laninamivir, oseltamivir, zanamivir,
rimantadine, umifenovir or amantadine), immunosuppressants, corticosteroids,
antifungal drugs, or
a drug which is administered to the eyes, nose or ears, or by inhalation.
However, if influenza
symptoms, such as fever and headache, are so severe (e.g. in the opinion of
the patient and/or
caregiver) that the patient needs pain treatment, then the compound to be used
in context of the
present invention may be combined with acetaminophen (i.e. paracetamol).
Acetaminophen may
be administered at a dose appropriate to the age and body weight of the
pediatric patient.
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In one aspect of the present invention the patient does not meet one of the
following exclusion
criteria:
(i) requires hospitalization (e.g. because of severe symptoms of influenza,
complications of
influenza or significant comorbidities);
(ii) has concurrent infections requiring systemic antiviral therapy;
(iii) is a preterm neonate (born at < 37 weeks gestation) and/or weighing <
2.5 kg at screening;
(iv) is obtaining concomitant treatment with steroids or other
immunosuppressant therapy;
(v) has an HIV infection or another immunosuppressive disorder;
(vi) has an uncontrolled renal, vascular, neurologic, or metabolic disease
(e.g., diabetes, thyroid
disorders, adrenal disease), hepatitis, cirrhosis, or pulmonary disease or
patients with known
chronic renal failure;
(vii) has active cancer at any site;
(viii) has a history of organ transplantation;
(ix) has a known allergy to the compound of the invention or to acetaminophen
(also known as
paracetamol); and
(x) is a female who has commenced menarche (i.e., child-bearing potential).
The meaning of the term "influenza virus infection" or variations thereof is
commonly known in the
art and refers to a disease which is caused by the influenza virus. More
specifically, an influenza
virus infection is an acute respiratory infectious disease caused by a virus
of the orthomyxovirus
family. Two forms are known to principally infect humans and to cause disease
in humans, the
influenza A virus and the influenza B virus. The influenza viruses have a
segmented, negative-
sense, single-stranded, lipid encapsulated ribonucleic acid (RNA) genome; they
range between 80
and 100 nm in size. Subtypes are defined according to haemagglutinin (HA) and
neuraminidase
(NA) glycoproteins present in the viral lipid coat. Influenza viruses enter
the respiratory epithelial
cell by attachment of the viral HA to sialic acid-containing receptors on the
cell membrane, followed
by internalisation of the virus into an acidic endosome. In the acidic
environment of the endosome,
the HA undergoes a conformational change that liberates a fusion peptide and
results in fusion of
the viral envelope with the endosomal membrane. At the same time the matrix-2
(M2) protein acts
as an ion channel allowing hydrogen ions to enter the virion from the
endosome. This allows the
viral gene segments to leave the virion and enter the cytoplasm, a process
known as uncoating.
Viral gene segments are transported to the nucleus where the viral polymerase
complex,
composed of the proteins polymerase basic protein 1 (PB1), polymerase basic
protein 2 (PB2),
and polymerase acidic protein (PA), directs the synthesis of the plus-sense
messenger RNA
(mRNA) as well as, via a plus-sense full length complementary RNA, synthesis
of negative-sense
full length copies that will serve as progeny genomic RNA. The polymerase
proteins also play a
role in disruption of host cell protein synthesis. Assembly of progeny virions
occurs at the plasma
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membrane, and the viral NA protein plays a role in release of virus from the
cell surface by
cleavage of surface sialic acid.
The "compound" to be used in the present invention is a compound which has one
of the following
formulae I and II:
(I) (II)
0
ti#190Ate¨I-0 0 OH 0
0 N'Th Otrki õANA
t'STA
N
or its pharmaceutically acceptable salt (i.e. of the compound having a formula
of (I) or (II)). The
compound to be used in the present invention is also referred to herein as
"compound", "compound
for use", "compound to be used (herein/in the present invention)" or "compound
of the present
invention".
The compound to be used in the present invention acts as a selective cap-
dependent
endonuclease (GEN) inhibitor, inhibiting the 'cap-snatching' function of the
PA subunit of the
influenza polymerase, which is used to cleave 5' cap structures from host cell
mRNAs, which are
used as primers for viral mRNA transcription. By inhibiting this essential
function, the compound as
used herein suppresses the replication of influenza viruses.
The compound to be used in the present invention has a broad spectrum of
activity against
seasonal (e.g. A/H1N1, A/H3N2, and B) and highly pathogenic avian (e.g.
A/H5N1, A/H7N9)
influenza viruses, with more potent antiviral activity (lower half maximal
inhibitory concentration
[ICA) compared with other common anti-influenza drugs such as oseltamivir,
zanamivir, or
peramivir. The compound's ability to be efficacious as a single dose
administration simplifies
treatment and improves patient compliance compared to neuraminidase inhibitors
(NAls).
Preferably, the compound has the formula of (I) or (II), most preferably of
(I). The compound of
formula (I) can also be displayed as follows:
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N H
N yekt-ek,
0 0
I
0 0
0
Baloxavir marboxil (BXM)
This compound (i.e. the compound of formula (I)) has a molecular formula of
C27F123F2N307S. This
compound is a pro-drug which is known as baloxavir marboxil. Baloxavir
marboxil is known in the
art and described, e.g., in Noshi, Antiviral research 160 (2018): 109-117.
Baloxavir marboxil (i.e. the compound of formula (I)) is an anti-influenza
virus drug with a novel
mechanism of action. It was discovered and is being developed by Shionogi &
Co., Ltd. and F.
Hoffman-La Roche, Ltd. Baloxavir marboxil (8-033188) is a pro-drug and is
converted to an active
form baloxavir (S-033447) through metabolism (hydrolysis). The active form is
shown herein as
formula (II). The active form baloxavir (S-033447) selectively inhibits cap-
dependent endonuclease
(CEN) activity necessary for replication of influenza viruses (Omoto, Sd Rep.
2018; 8(1):9633). A
broad spectrum of activity against seasonal influenza viruses and on
alleviating effects of influenza
symptoms were shown in nonclinical efficacy studies and clinical studies in
patients with influenza,
including the phase 2 proof of concept and dose-finding study, the phase 3
double-blind study in
otherwise healthy patients (Portsmouth S, Kawaguchi K, Arai M, Tsuchiya K,
Uehara T. Cap-
dependent endonuclease inhibitor baloxavir marboxil (8-033188) for the
treatment of influenza:
results from a phase 3, randomized, double-blind, placebo- and active-
controlled study in
otherwise healthy adolescents and adults with seasonal influenza. Abstract LB-
2. Oral presentation
at ID Week 2017, October 4-8 2017, San Diego, CA, USA.), and the Phase 3 open-
label study in
otherwise healthy pediatric patients.
The compound as shown in formula (II) is the active form of baloxavir marboxil
(i.e. of the pro-drug
of formula (I)). The compound of formula (I) can also be displayed as follows:
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H ft` H
"---y
N
0 014
Sataxavir acid (MA)
The compound of formula (II) is also known as baloxavir or baloxavir acid.
Baloxavir acid is known
in the art and described, e.g., in Noshi, Antiviral research 160 (2018): 109-
117.
The pharmaceutically acceptable salts of the compounds used in the present
invention include, for
example, salts with alkaline metal (e.g., lithium, sodium, potassium or the
like), alkaline earth metal
(e.g., calcium, barium or the like), magnesium, transition metal (e.g., zinc,
iron or the like),
ammonia, organic bases (e.g., trimethylamine, triethylamine,
dicyclohexylamine, ethanolamine,
diethanolannine, triethanolannine, nneglunnine, ethylenediannine, pyridine,
picoline, quinoline or the
like) or amino acids, or salts with inorganic acids (e.g., hydrochloric acid,
sulfuric acid, nitric acid,
carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid or the like)
or organic acids (e.g.,
formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid,
lactic acid, tartaric acid,
oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic
acid, benzoic acid,
phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid,
nnethanesulfonic acid,
ethanesulfonic acid or the like). Especially, salts with sodium, potassium,
calcium, magnesium,
iron and the like are included. These salts can be formed by the usual
methods.
The production of the compound of the present invention is well known in the
art. For example, the
compound of the present invention can be prepared with the methods described
in the patent
application PCT/JP2016/063139, which is published as WO 2016/175224A1.
As mentioned above, in accordance with the present invention, it is preferred
that the influenza
virus strain does not comprise a PA protein having a sequence which has at
least 80%, preferably
at least 90%, more preferably at least 95%, at least 96%, at least 97%, at
least 98%, or at least
99% sequence identity to the sequence of SEQ ID NO:1 and comprising a
substitution (e.g. an Ito
T substitution) at the position corresponding to position 138 of SEQ ID NO:1 .
In particular, FASTA
sequences of two sequences of viral PA proteins can be generated and aligned
in order to
evaluate the degree of identity between the two viral PA proteins. To
determine the percent identity
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of two sequences, the sequences are aligned for optimal comparison purposes
(e.g., gaps can be
introduced in one or both of a first and a second amino acid sequence for
optimal alignment and
non-homologous sequences can be disregarded for comparison purposes). The
percent identity
between the two sequences is a function of the number of identical positions
shared by the
sequences, taking into account the number of gaps, and the length of each gap,
which need to be
introduced for optimal alignment of the two sequences. Percent identity
between two
polypeptides/amino acid sequences is determined in various ways which are
known by the skilled
person, for instance, using publicly available computer software such as Smith
Waterman
Alignment (Smith, T. F. and M. S. Waterman (1981) J Mol Biol 147:195-7);
"BestFit" (Smith and
Waterman, Advances in Applied Mathematics, 482 489 (1981)) as incorporated
into GeneMatcher
Plus Tm, Schwarz and Dayhof (1979), Atlas of Protein Sequence and Structure,
Dayhof, M.O., Ed,
pp 353-358; BLAST program (Basic Local Alignment Search Tool; (Altschul, S.
F., W. Gish, et al.
(1990) J Mol Biol 215: 403-10), BLAST-2, BLAST-P, BLAST-N, BLAST-X, WU-BLAST-
2, ALIGN,
ALIGN-2, CLUSTAL, or Megalign (DNASTAR) software. In addition, those skilled
in the art can
determine appropriate parameters for measuring alignment, including any
algorithms needed to
achieve maximal alignment over the length of the sequences being compared.
Preferably, the viral
PA protein sequences are compared over their entire lengths. For purposes of
the present
invention, the comparison of sequences and determination of percent identity
between two
sequences can be accomplished using a Blossum 62 scoring matrix (with a gap
penalty of 12, a
gap extend penalty of 4, and a frameshift gap penalty of 5).
As described above, the present invention provides means and methods for
treating an influenza
virus infection of patients that are younger than 12 years, in particular by
providing an optimized
dosage for these pediatric patients. In line with this, the invention also
relates to the following
aspects. All explanations, definitions and preferred aspects which are
explained above and below
also relate, mutatis mutandis, to the inventive aspects described below.
The invention also relates to a compound for use in treating an influenza
virus infection, wherein
the compound has one of the formulae (I) and (II) or its pharmaceutically
acceptable salt, and
wherein the following dosage is used:
(i) in a patient that is younger than 1 year:
(a)if the patient is younger than 4 weeks, then the effective amount is 0.8-
1.2 mg/kg
body weight, preferably about 1 mg/kg body weight;
(b)if the patient is 4 weeks or older but younger than 3 months, then the
effective
amount is 0.8-1.2 mg/kg body weight, preferably about 1 mg/kg body weight;
(c)if the patient is 3 months or older but younger than 12 months, then the
effective
amount is 1.8-2.2 mg/kg body weight, preferably about 2 mg/kg body weight;
(ii) in a patent that is 1 year or older but younger than 12 years:
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(a)if the patient has a body weight of less than 20 kg, then the effective
amount is 1.8-
2.2 mg/kg body weight, preferably about 2 mg/kg body weight; or
(b)if the patient has a body weight of 20 kg or more, then the effective
amount is 35-45
mg, preferably about 40 mg.
The invention further relates to a pharmaceutical composition for use in
treating an influenza virus
infection, wherein the pharmaceutical composition comprises the compound
having one of the
formulae (I) and (II) or its pharmaceutically acceptable salt, and optionally
comprising a
pharmaceutically acceptable carrier, wherein the following dosage is used:
(i) in a patient that is younger than 1 year:
(a)if the patient is younger than 4 weeks, then the effective amount is 0.8-
1.2 mg/kg
body weight, preferably about 1 ring/kg body weight;
(b)if the patient is 4 weeks or older but younger than 3 months, then the
effective
amount is 0.8-1.2 mg/kg body weight, preferably about 1 mg/kg body weight;
(c)if the patient is 3 months or older but younger than 12 months, then the
effective
amount is 1.8-2.2 mg/kg body weight, preferably about 2 mg/kg body weight;
(ii) in a patient that is 1 year or older but younger than 12 years:
(a)if the patient has a body weight of less than 20 kg, then the effective
amount is 1.8-
2.2 mg/kg body weight, preferably about 2 mg/kg body weight; or
(b)if the patient has a body weight of 20 kg or more, then the effective
amount is 35-45
mg, preferably about 40 mg.
Also encompassed by the present invention is a method for treating influenza,
comprising: reading
a dosage instruction on a package insert or in a package for a pharmaceutical
formulation
comprising a compound having one of the formulae (I) and (II)) or being a
pharmaceutically salt
thereof, and administering an effective amount of the compound to an influenza-
infected patient,
and wherein the following dosage is used:
(i) in a patient that is younger than 1 year:
(a)if the patient is younger than 4 weeks, then the effective amount is 0.8-
1.2 mg/kg
body weight, preferably about 1 mg/kg body weight;
(b)if the patient is 4 weeks or older but younger than 3 months, then the
effective
amount is 0.8-1.2 mg/kg body weight, preferably about 1 mg/kg body weight;
(c)if the patient is 3 months or older but younger than 12 months, then the
effective
amount is 1.8-2.2 mg/kg body weight, preferably about 2 mg/kg body weight
(ii) in a patient that is 1 year or older but younger than 12 years:
(a)if the patient has a body weight of less than 20 kg, then the effective
amount is 1.8-
2.2 mg/kg body weight, preferably about 2 mg/kg body weight; or
(b)if the patient has a body weight of 20 kg or more, then the effective
amount is 35-45
mg, preferably about 40 mg.
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The invention also relates the use of a compound which has one of the formulae
(I) and (II), or its
pharmaceutically acceptable salt, for the preparation of a medicament for
treating an influenza-
infected patient, wherein the following dosage is used:
(i) in a patient that is younger than 1 year:
(a)if the patient is younger than 4 weeks, then the effective amount is 0.8-
1.2 mg/kg
body weight, preferably about 1 mg/kg body weight;
(b)if the patient is 4 weeks or older but younger than 3 months, then the
effective
amount is 0.8-1.2 mg/kg body weight, preferably about 1 mg/kg body weight;
(c)if the patient is 3 months or older but younger than 12 months, then the
effective
amount is 1.8-2.2 mg/kg body weight, preferably about 2 mg/kg body weight;
(ii) in a patient that is 1 year or older but younger than 12 years:
(a)if the patient has a body weight of less than 20 kg, then the effective
amount is 1.8-
2_2 mg/kg body weight, preferably about 2 mg/kg body weight; or
(b)if the patient has a body weight of 20 kg or more, then the effective
amount is 35-45
mg, preferably about 40 mg.
Also provided by the present invention is a package comprising a
pharmaceutical formulation
comprising a compound which has one of the formulae (I) and (II), or its a
pharmaceutically salt,
and further comprising a dosage instruction for administering an effective
amount of the compound
to an influenza-infected patient, wherein the following dosage is used:
(i) in a patient that is younger than 1 year:
(a)if the patient is younger than 4 weeks, then the effective amount is 0.8-
1.2 mg/kg
body weight, preferably about 1 mg/kg body weight;
(b)if the patient is 4 weeks or older but younger than 3 months, then the
effective
amount is 0.8-1.2 mg/kg body weight, preferably about 1 mg/kg body weight;
(c)if the patient is 3 months or older but younger than 12 months, then the
effective
amount is 1.8-2.2 mg/kg body weight, preferably about 2 mg/kg body weight;
(ii) in a patient that is 1 year or older but younger than 12 years:
(a)if the patient has a body weight of less than 20 kg, then the effective
amount is 1.8-
2.2 mg/kg body weight, preferably about 2 mg/kg body weight; or
(b)if the patient has a body weight of 20 kg or more, then the effective
amount is 35-45
mg, preferably about 40 mg.
As mentioned above, one aspect of the present invention relates to a
pharmaceutical composition
comprising a compound which has one of the formulae (I) and (II), or its
pharmaceutically
acceptable salt, and optionally comprising a pharmaceutically acceptable
carrier. The
pharmaceutical compositions can be formulated with a pharmaceutically
acceptable carrier by
known methods. For example, the compositions can be formulated by
appropriately combining the
ingredients with a pharmaceutically acceptable carrier or a medium,
specifically, sterile water or
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physiological saline, vegetable oils, emulsifiers, suspending agents,
surfactants, stabilizers,
flavoring agents, excipients, vehicles, preservatives, binding agents, and
such, by mixing them at a
unit dose and form required by generally accepted pharmaceutical
implementations. Specific
examples of the carriers include light anhydrous silicic acid, lactose,
crystalline cellulose, mannitol,
starch, carmellose calcium, carmellose sodium, hydroxypropyl cellulose,
hydroxypropyl
methylcellulose, polyvinylacetal diethylaminoacetate, polyvinylpyrrolidone,
gelatin, medium-chain
triglyceride, polyoxyethylene hardened castor oil 60, saccharose,
carboxymethyl cellulose, corn
starch, inorganic salt, and such. The content of the active ingredient in such
a formulation is
adjusted so that an appropriate dose within the required range can be
obtained.
The pharmaceutical composition may optionally comprise one or more
pharmaceutically
acceptable excipients, such as carriers, diluents, fillers, disintegrants,
lubricating agents, binders,
colorants, pigments, stabilizers, preservatives, antioxidants, or solubility
enhancers. Also, the
pharmaceutical compositions may comprise one or more solubility enhancers,
such as, e.g.,
poly(ethylene glycol), including poly(ethylene glycol) having a molecular
weight in the range of
about 200 to about 5,000 Da, ethylene glycol, propylene glycol, non-ionic
surfactants, tyloxapol,
polysorbate 80, macrogo1-15-hydroxystearate, phospholipids, lecithin,
dimyristoyl
phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl
phosphatidylcholine, cyclodextrins,
hydroxyethyl-p-cyclodextrin, hydroxypropyl-p-
cyclodextrin, hydroxyethyl-y-
cyclodextrin,
hydroxypropyl-y-cyclodextrin, dihydroxypropyl-P-cyclodextrin, glucosyl-a-
cyclodextrin, glucosyl-p-
cyclodextrin, diglucosyl-p-cyclodextrin, maltosyl-o-cyclodextrin, maltosyl-p-
cyclodextrin, maltosyl-y-
cyclodextrin, maltotriosyl-p-cyclodextrin, rnaltotriosyl-y-cyclodextrin,
dimaltosyl-P-cyclodextrin,
methyl-p-cyclodextrin, carboxyalkyl thioethers,
hydroxypropyl methylcellulose,
hydroxypropylcellulose, polyvinylpyrrolidone, vinyl acetate copolymers, vinyl
pyrrolidone, sodium
lauryl sulfate, dioctyl sodium sulfosuccinate, or any combination thereof.
The pharmaceutical compositions are not limited to the means and methods
described herein. The
skilled person can use his/her knowledge available in the art in order to
construct a suitable
composition. Specifically, the pharmaceutical compositions can be formulated
by techniques
known to the person skilled in the art such as the techniques published in
Remington's
Pharmaceutical Sciences, 20th Edition.
The content of all documents cited herein above and below is incorporated by
reference in its
entirety.
The present invention is further described by reference to the following non-
limiting figures and
examples.
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The Figures show:
Figure 1: Simulated total drug exposure for three different dosing regimens in
pediatrics (Non-
Asian, Age 1-12 year olds). Bottom and top of the boxplot represent 25th and
75' percentile;
middle line in the box represents 50th percentile; lower and upper whisker
represent 10th and 901h
percentile. Note: for ease of simulations of regimen 2, the weight at which
bodyweight-based
dosing converts to flat dosing was 26.6 kg.
Figure 2: Simulated peak drug exposure for three different dosing regimens in
pediatrics (Non-
Asian, Age 1-12 year olds). Bottom and top of the boxplot represent 251h and
75th percentile;
middle line in the box represents 50th percentile; lower and upper whisker
represent 10th and 90th
percentile. Note: for ease of simulations of regimen 2, the weight at which
bodyweight-based
dosing converts to flat dosing was 26.6 kg.
Figure 3: Simulated drug exposure at 24 hours after dosing for three different
dosing regimens in
pediatrics (Non-Asian, Age: 1-12 year olds). Bottom and top of the boxplot
represent 251h and 75th
percentile; middle line in the box represents 50th percentile; lower and upper
whisker represent 10th
and 90th percentile. Note: for ease of simulations of regimen 2, the weight at
which bodyweight-
based dosing converts to flat dosing was 26.6 kg.
Figure 4: Simulated drug exposure at 72 hours after dosing for three different
dosing regimens in
pediatrics (Non-Asian, Age: 1-12 year olds). Bottom and top of the boxplot
represent 251h and 75"
percentile; middle line in the box represents 50th percentile; lower and upper
whisker represent 10th
and 90th percentile. Note: for ease of simulations of regimen 2, the weight at
which bodyweight-
based dosing converts to flat dosing was 26.6 kg.
Figure 5: Simulated total drug exposure for three different dosing regimens in
pediatrics (Non-
Asian, Age: <1 year old). Bottom and top of the boxplot represent 25th and
75th percentile; middle
line in the box represents 50th percentile; lower and upper whisker represent
10" and 90th
percentile. Grey box with rounded edges indicates nearly identical match with
adult exposures in
this model.
Figure 6: Simulated peak drug exposure for three different dosing regimens in
pediatrics (Non-
Asian, Age: <1 year olds). Bottom and top of the boxplot represent 25th and
75th percentile; middle
line in the box represents 50th percentile; lower and upper whisker represent
10th and 901h
percentile.
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Figure 7: Simulated drug exposure at 24 hours after dosing for three different
dosing regimens in
pediatrics (Non-Asian, Age: <1 year olds). Bottom and top of the boxplot
represent 25th and 75th
percentile; middle line in the box represents 50th percentile; lower and upper
whisker represent 10th
and 90th percentile.
Figure 8: Simulated drug exposure at 72 hours after dosing for three different
dosing regimens in
pediatrics (Non-Asian, Age: <1 year olds). Bottom and top of the boxplot
represent 25" and 75th
percentile; middle line in the box represents 50th percentile; lower and upper
whisker represent 10th
and 90th percentile.
Figure 9: Canadian Acute Respiratory Illness and Flu Scale (CARIFS)
Questionnaire.
Figure 10: The powder X-ray diffraction pattern of the crystal of compound I
of Example 6.
The Examples illustrate the invention.
Example 1: Materials and Methods of the Simulation of pediatric doses
1. Population Pharmacokinetic (mg Analysis
Population PK analysis were conducted using Japanese pediatric patient study
information.
1.1 Background Data
Following background data available for subjects were summarized and were used
as the
candidate of covariates: age (years and weeks), body weight, body mass index
(BM!), aspartate
anninotransferase (AST), alanine anninotransferase (ALT), total bilirubin
(Tbil), estimated glonnerular
filtration rate (eGFR), and creatinine clearance (CLcr) at baseline as
continuous data, and gender
(male, female), race ("Asian", "Non-Asian", wherein the "Non-Asian" group
reflects, e.g., white such
as Caucasian patients), health status (otherwise healthy patients with
influenza, or patients without
influenza) and food conditions (dosing 4 hours before and a. 4 hours after
food intake [fasted],
dosing within 2 to 4 hours before or 2 to 4 hours after food intake
[intermediate], or dosing <2
hours before or < 2 hours after food intake [fed]) as categorical data.
Background data at baseline
were obtained from observations prior to or on the first day of dosing or at
screening if this value
was not available. The eGFR was calculated by Schwartz formula (Schwartz,
Pediatric Clinics of
North America. 1987; 34: 571-90). CLcr for pediatrics was calculated from eGFR
and body surface
area (BSA). The BSA was calculated using the following equation reported by
Mostellar (Mosteller,
N Eng J Med. 1987;317:1098).
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SSA (m2) = [height (cm) x body weight (kg)/3600r2
The following equations were used to calculate eGFR and CLcr.
Parameter Age
Equation
eGFR 2 to 11 wars &FR= 0.55 x [height
(cm)]/Sci-
(mlimin/1.73 m2)
Birth to 1 year eGFR. = 0.45 x [height (cm)]/Scr
(Full-tain
masts)
CLcr (mLizain) <12 wars CLer = eGFR x
BSA/1.73
BSA = body suite area Ser = semi ereamiine aitedL)
1.2 Base Model
A 2-compartment model with first-order absorption and lag time was initially
tested for describing
plasma concentration of baloxavir (S-033447), because it is the same
structural model that was
previously selected to describe the data in pediatric patients (Ishibashi T.
Population
Pharrnacokinetics of S-033188 (Pediatric Patient). Study Report (Final, Study
No.: S-033188-CB-
273-N). Shionogi & Co., Ltd.; 2017). The 2-compartment model includes the
following parameters:
apparent total clearance (CUF), apparent volume of central and peripheral
compartments (Vc/F
and Vp/F), apparent inter-compartmental clearance (Q/F), first-order rate of
absorption (Ka), and
absorption lag time (ALAG). The difference of systemic exposure among
formulations was
incorporated in the model as the difference of relative bioavailability (F). F
is 1 for to-be-marketed
20-mg tablet and 0.88 for to-be-marketed 10-mg tablet (A Phase 1 Study to
Evaluate the
Bioequivalence of 5-033188 10-mg and 20-mg Tablets and Effect of Food on the
Pharmacokinetics in Healthy Adults. Clinical Study Report (Study No.
1622T081F). Shionogi & Co.,
Ltd.; 2017). F was set to 1 for 2% granule in this study because 2% granule
and 20-mg tablet is
bioequivalent (Study No. 1703T081G) (A Phase 1 Study to Evaluate the
Bioequivalence of 5-
033188 20-mg Tablet and 6-033188 Granules 2%. Clinical Study Report (Study No.
1703T081G).
Shionogi & Co., Ltd.; 2018).
Individual model parameters were estimated based on a fixed effect parameter
(PKP) and an inter-
individual variability (IIV) for certain PK parameters which are assumed to
follow a log-normal
distribution and exponential error model as described in Equation (1):
PKP = PKP x exp (npkRi)
(1)
where PKP; represents the i-th individual value of PK parameters, PKP
represents the typical value
of population PK parameters, and npicp,, denotes the difference between the i-
th individual and
typical PK parameter. The limp is a random variable of the I IV parameters and
normally distributed
with a mean of 0 and a variance of wwp2.
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After model building, the covariance between pairs of random IIV parameters
were examined
graphically by plotting ripip,i in different PK parameters and covariance
might be added as
appropriate to account for observed correlations. Decisions regarding the
inclusion of covariance of
IIV were based on the numerical stability of the resulting model or on the
goodness-of-fit (GOF)
plots as described in Section 1.5.
Shrinkage in each npki. (sh_ripip) was computed in NONMEM.
The additive error model, the proportional error model and/or the combination
error model (the
additive error + the proportional error model) were tested as an intra-
individual (residual) variability.
The additive error model, the proportional error model and the combination
error model are given
in the following equations.
Cu = Cu (pred) +
: additive error model (2)
Cu = C (pred) x (1 + Etg) : proportional error model (3)
+
Cu = Cu (pred) x (1 + F 2.
combination error model (4)
where Cu represents the observed j-th concentration in the i-th individual, Cu
(pred) represents the
j-th concentration predicted from the i-th individual PK parameters and e
(ei,i, Ey]) denotes the
difference between the j-th observed and predicted concentration in the i-th
individual. The (Elio
2,0 is a random variable of the intra-individual variability parameters from
population mean and
normally distributed with a mean of 0 and a variance of cr2 (012, 022).
Shrinkage in 6 (sh_c) was computed in NONMEM.
Error model for intra-individual variability was selected by the diagnostic
plots described in Section
1.5 and/or the value of objective function value (OBJ) at the statistical
significance level of 0.05 (p
< 0.05) based on x2 test, that is, difference in 0I3J (AOBJ) of less than -
3.84 for one degree of
freedom represents a statistically significant model improvement.
The structure of the base model with error models was expanded as necessary to
best reflect the
characteristic shape of the observations over time. When IIV could not be
estimated appropriately,
removal of its IIV term was considered.
1.3 Covadate Model
After building a base model with selection of an error model for intra-
individual variability, the
influence of background data was assessed to build a covariate model.
Covariate model was
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constructed by means of combination of screening for covariates, forward
selection, and stepwise
backward deletion. The significance level of 0.05 based on x2 test (p < 0.05)
was used for the
screening (AOBJ was less than -3.84 for one degree of freedom). The
significant covariates at
screening were tested in the forward selection at the significance level of
0.05 based on x2 test to
construct a full model (AOBJ was less than -3.84 for one degree of freedom).
The significance
level of 0.01 based on x2 test was used for the stepwise backward deletion to
construct a final
model (AOBJ was more than 6.63 for one degree of freedom).
As the first covariate assessment, body weight was tested on CL/F and Vc/F
because body weight
is considered to be the most significant covariate in pediatrics. Body weight
was tested as a
covariate on the other PK parameters (e.g., Vp/F, Q/F etc.).
For body weight, a power model as shown in Equation (5) was used.
PKP = 01 x (COV/median of COVr
(5)
where COV is a values of the covariate and 61, 02 are the typical values of
model parameters to be
estimated in equation. The typical allometric exponents of 0.75 on CUF and
Q/F, and 1 on Vc/F
and Vp/F (Ho!ford, Cl/n. Pharrnacokinet. 1996; 30: 329-32; Anderson, Annu Rev
Phatrnacol
Toxicol. 2008; 48: 303-32) were tested for 02 for the effect of body weight on
clearance and volume
of distribution. Also, exponents of 0.632 on CUF and Q/F, and 1.03 on Vc/F and
Vp/F, which were
estimated in the previous pediatric population PK model for baloxavir (8-
033447) (Ishibashi T.
Population Pharmacokinetics of S-033188 (Pediatric Patient). Study Report
(Final, Study No.: 5-
033188-C6-273-N). Shionogi & Co., Ltd.; 2017; published (Koshimichi, Journal
of Pharmaceutical
Sciences (2019) 1-6, https://doi.org/10.1016/jAphs.2019.04.010), were tested
for 82 for the effect
of body weight on clearance and volume of distribution.
In addition to body weight, age (weeks), BMI, gender, AST, ALT, Tbil, eGFR,
CLcr, and health
status were tested as a covariate on CUF; age (weeks), BMI, gender, and health
status were
tested as a covariate on Vc/F; age (weeks), gender, health status and food
conditions were tested
as a covariate on Ka; and food conditions was tested as a covariate on F.
Background data was
tested as a covariate on the other PK parameters (e.g., Vp/F, 0/F etc.).
Prior to building covariate models, plots for relationships between covariates
and PK parameters
were generated for visual inspection of covariates based on the base model.
For continuous covariates, a power model as shown in Equation (6) was used.
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PKP = el x (GOV/median of COV) 2
(6)
where COV is a values of the covariate and E, 132 are the typical values of
model parameters to be
estimated in equation.
For binary and categorical covariates, a multiplicative model as shown in
Equation (7) was used.
PKP = OCAT=0 (OCATOATJ
(7)
where CAT i is a series of indicator variables with a value of either 0 or 1
assigned (CAT 1,
CAT_2, CAT_n representing the n levels of CAT; e.g.,
CAT_1 = 0 for male and CAT_1 = 1 for
female), and
0CAT=0 is the typical values of model parameters to be estimated when the
individual
categorical covariate index variable is equal to zero and Acm- is the i-th
relative influence of model
parameters to be estimated for categorical covariate index variable when CAT_i
is equal to one.
After building the final model, for a simulation purpose for younger children
aged < 2 years, a
sigmoid hyperbolic model was incorporated in the model (simulation model) to
describe the
maturation of CUF. Maturation factor (ME) is described in Equation (8), and
CUE is multiplied by
M F.
MF = PMA/(PMA Y + TM5,,Y)
(8)
where PMA is postmenstrual age (weeks), TM5c, is maturation half-life (weeks),
and y is hill
coefficient. PMA was calculated as 40 + age (weeks), assuming that all
patients were full-term
delivery. The values of TM 50 and y for baloxavir (8-033447) were estimated
from data. Also, the
values of TM 50 = 54.2 weeks and y = 3.92 for morphine, which is metabolized
by uridine
diphosphate glucuronosyl transferase (UGT) (Anderson, Paediatr Armee!). 2011;
21: 222-37),
were tested. The model with the smallest OBJ was selected as the simulation
model.
Alternative expressions might be considered for continuous covariates based on
trends that were
observed in covariate plots and alternative expressions might be considered
for categorical
covariates to facilitate the interpretation of the typical parameter estimates
with respect to specific
patient categories.
Highly correlated covariates might be tested in separate models in order to
avoid confounding in
the estimation of covariate effects.
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A covariate might be retained in the final model, despite not meeting the
criteria above, if there is a
strong pharmacological or physiological rationale for its inclusion.
1.4 Parameter Estimation
The population PK parameters were estimated for the plasma baloxavir (5-
033447) concentration
data by NONMEM. The first-order conditional estimation method with interaction
(FOCE-I) was
used for the analysis.
1.5 Model Evaluation
The base and final model were evaluated by using the point estimates of PK
parameters and their
relative standard error. Also, the following GOF plots with reference lines
(identity, zero line, etc.)
were generated for model diagnostics.
= Observed concentrations (OBS) versus population predicted concentrations
(PRED) in both
linear and log scale with a line of identity and a trend line
= OBS versus Bayesian-predicted individual concentrations (IPRED) in both
linear and log scale
with a line of identity and a trend line
= Conditional weighted residuals (CWRES) or conditional weighted residuals
with interaction
(CWRESI) versus PRED with a zero line and a trend line
= 'Individual weighted residuals (IWRES)I versus IPRED with a trend line
= CWRES or CWRESI versus time after reference dose (TARD)
= Histogram (optionally 00 plot) of CWRES or CWRESI and IWRES
= Plots of empirical Bayesian estimate (EBE) of parameters (only base
model) and ETAs versus
the potential covariates
= A scatter plot matrix of EBE of ETAs (only final model)
= Distributions (e.g., histograms) of EBE of ETAs (only final model)
= OBS, IPRED and PRED concentrations versus time overlaid by individual for
representative
subjects (secondary any given subjects) (only final model)
The PRED, IPRED, CWRES, CWRESI and IWRES are the reserved terms in NONMEM.
The final model should meet the following criteria:
= A "minimization successful" statement is indicated by NONMEM.
= A covariance step is completed without warning messages by NONMEM.
= The number of significant digits is I- 3 for all estimated a
= Final estimates of 0 are not close to boundaries.
= GOF plots do not indicate unexplained trends.
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A final model that did not meet these criteria might be accepted only after
careful consideration of
the modeling strategy and study objectives.
The predictive performance of a final model was evaluated by prediction-
corrected visual predictive
check (pcVPC) (Bergstand, AAPS J. 2011; 13: 143-51) and calculating the
percentage of the
observations outside the 90% prediction intervals (PI). In addition to the
pcVPC, the final model
was also evaluated by bootstrapping technique (Ette, Journal of clinical
pharmacology. 1997, 37
(6): 486-95). At least 200 bootstrap replications were performed and the
associated mean
parameter estimates and their corresponding 95% confidence interval (Cl) were
derived from the
replicates.
1.6 Individual post-hoc Pharmacokinetic parameters
The individual systemic exposures of baloxavir (8-033447), such as Cr.õ the
area under the
plasma concentration-time curve from time zero to infinity (AUC040), and C24
after a single dose of
baloxavir marboxil (S-033188) were calculated using individual post-hoc PK
parameters with
empirical Bayesian estimations of the final model. Also, these exposures were
calculated using
individual post-hoc PK parameters with empirical Bayesian estimations of the
simulation model.
The formulae needed to calculate the exposure metrics depends on the model
structure.
1.7 Monte-Carlo Simulation
Monte-Carlo simulation was employed with the final model to assess the
relationship between
body weight and PK parameters (Cmax, AUCo-inr, and C24). A thousand virtual
pediatric patients were
generated for every 5 kg by simulating the body weight (10 to <60 kg) based on
the final model to
be assumed as a uniform distribution for body weight.
Also, Monte-Carlo simulation was employed with the simulation model to assess
the relationships
between age (0 months to <2 years old) and PK parameters (C.., AUC, and C24. A
thousand
virtual pediatric patients were generated for every month old by simulating
the age based on the
simulation model. The relationship between age and body weight for Japanese
pediatrics followed
the database by Ministry of Health, Labour and Welfare ( Ministry of Health,
Labour and Welfare.
Research for growth of babies
(2010). URL: http://www.e-
statgo.jp/SG1/estat/Xlsdl.do?sinfid=000012673573). To generate virtual
pediatric patients, log-
normal distribution was assumed for body weight and geometric mean and its
coefficient of
variance were set for each month (Table 3), and 1:1 proportion was assumed for
gender. MF was
calculated for each month by equation 8 assuming that all pediatric patients
are full-term delivery
and their ages are middle in the age range. For example, a pediatric patient
with 6 months old,
his/her PMA is 40 weeks + 6.5 months = 68.2 weeks.
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Table 3: The Relationships between Age and Body Weight for Birth to <2 Years
Old
Pediatrics
(a) Boys
Percentile
I Assumed Maturation
Age (moots) 1 10 25 , 50 , 75 SO
97 , Geomeixic Mean CV% Factor
0 to 1 2.53 2.91 3_23 3.57 3.89
4.17 4_47 3_57 17.8 0.551
1 to 2 153 /94 4.35 4.79 5..22
5.59 5.96 4.79 16.3 0.620
2 to 3 4.41 - 4.88 5.34 584 6.33 636
7.18 5,84 14.9 0679
3 to 4 5.12 5.61 6.10 6.63 7.16
7_62 8.07 6.63 13.8 0128
4 to 5 5.67 - 6.17 6.67 7.22 7.76
8.25 8_72 7.22 12.8 0.770
to 6 6.10 6.60 7.10 7.66 8.21 8.71
9.20 7_66 12.1 0.804
6 to? 6.44 6_94 7.44 8.00 8.56
9.07 937 8.00 11.5 0832
7 to 8 6.73 7.21 7.71 8.27 814 936
927 8.27 11.0 0.856
8 to 9 6.96 - 744 7.94 8.50 908
9_61 10.14 2.50 10.7 0.875
9 to 10 716 7.64 8.13 8.70 9.31
9.83 10.37 8.70 10.4 0.892
to 11 7.34 - 7.81 8.31 8.82 948 10.03
10.59 8.88 10.1 0.905
11 to 12 7.51 7.98 8.43 9.06 9.67
1a23 10.82 9.06 10.0 (1917
12 to 13 7.68 8.15 8.65 9.24 926
10.44 11.04- 9.24 9.8 0.927
13 to 14 7_85 . 832 813 942 1005
10_65 ti 2R 9_47 93 0_935
14 to 15 11.02 8.49 9.00 9.60 10.25
10.86 11.51 9.60 9.6 0.942
to 16 it 19 8.67 9_18 9.79 10.44
11.08 11.75 9.79 93 0.949
16 to 17 8.36 = 8.84 9.35 9.97 10.64
11.31 11.98 9.97 9.4 (1954
17 to 18 8.53 ' 9_01 9.53 10.16 10_84
11.51 12.23 10.16 93 0.958
18 to 19 8.70 9.18 9.71 10.35 11.04
11.73 12.47 10.35 92 0.963
19 to 20 8.86 935 9.89 10.53 11.25
11.95 12.71 10.53 9.2 0.966
to 21 9.03 . 9.52 10_06 10.72 11.45 1117
12.96 10.72 9.1 0.969
21 to 22 9.19 9_69 10.24 10_91 11_65
12.39 13.20 1091 9_1 0.972
2 2 to 23 9.36 9_86 1G_41 11.09 1115
1161 13.45 11.09 9_1 0.974
23 to M 9.52 10.03 11159 11.28 12.06
12.83 13.69 11.28 9.0 0.977
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(b) Girls
Pert mole
Assumed. Matwatino
Age (montlis)
, 3 ID 1 25 51:1 75 90
97 Geometric Mean CV% , Factor
0 to 1 2.52 282 3.10 3.41 3.71 198
4.25 3.41 16+2 0.551
,1 to 2 139 , 173 4.08 447 486
5.20 154- 447 14.8 0.620
2 to 3 4.19 458 4.97 5.42 5.86
6_27 6_67 142 13.7 0.679
3 to 4 484 5_25 5.67 6.15 6.64
7,08 7.53 6.15 12.8 0.728
4 to 5 5.35 5.77 6.21 6.71 7.23
7.70 8.18 6.71 111 0.770
to 6 5_74 -617 6.62 7_14 7_57 8_17
8_67 7_14 11_6 0_804
6 to 7 6.06 4_49 6.95 7.47 8.02
8.53 9.05 7.47 11.2 0.832
7 to 3 632 45_75 7.21 735 3.31
8.83 9_37 7_75 101 0156
8 to 9 6_53 6_97 743 797 8_54 908
9_63 7_97 10 6 0R75
9 to 10 6.71 7.15 7.2 8.17 8.74
9.29 9.85 8.17 1O5 0.892
to 11 6.86 7_31 7.78 8.34 8.93 9.49
10.06 8.34 10.3 0.905
11 to 12 7.02 7_46 7.95 831 9.11
9_63 10.27 8.51 10.3 0.917
12 to 13 7.16 7_62 8.11 8.68 9.
9.g7 10.48 8.68 10.2 0.927
13 to 14 7.31 7.77 8.27 8.85 9.47
10.07 10.69 8.85 10.2 0.935
14 to 15 7.46 ' 7.93 8.43 9.03 9.66
10.27 10.90 9.03 10.1 0.942
to 16 7.61 LOB 8.60 9.20 9.83 10.47
11.12 9_20 10.1 0.949
16 to 17 7.75 8.24 3.76 9.38 10.04
10.67 11.33 9.38 10.1 0.954
17 to 18 7.90 8.39 3.93 935 10_23
1017 11.55 9.55 10.1 0.958
18 to 19 8.05 8_55 9.09 9.73 10_42
11_08 11_77 9.73 10.1 0.963
19 to 20 3.20 8.71 9.26 9.91 10.61
11.28 11.99 9.91 10.1 0.966
to 21 8.34 8.86 9.43 10.09 10.81 11.49
12.21 10.09 101 0.969
21 to 22 8.49 9.02 9.59 10.27 11.00
11.70 12.44 10_27 10.2 0.972
22 to 23 3.64 9_18 9.76 1a46 11.20
11.92 1167 10_46 10.2 0.974
23 to 24 8.78 9.34 9.93 . 10.64 11.40
12.13_ 12.90 10.64 10.2 0.977
2. Software
PK calculations were performed by using WinNonlin (Version 6.2.1). SAS
(Version 9.2) was used
for statistical analyses. R (Version 3Ø2) was used for PK/PD analysis.
NONMEM (Version 7.3),
Intel Visual FORTRAN Compiler (version 2010), and Perl-speaks-NONMEM (version
4.2) were
used for population PK analysis.
Example 2: Population pharmacokinetic parameters
A population PK model has been developed to describe baloxavir PK in both
Japanese and non-
Japanese influenza patients (adults and adolescents) who are otherwise healthy
(T0821 and
T0831). The relationship between drug exposure and various covariates has been
explored. The
population PK model parameters are summarised in Table 4. Likewise, a
paediatric population PK
model has been developed to describe the population PK of baloxavir in
Japanese otherwise
healthy patients aged 6 months to < 12 years (Study T0822, also called
1618T0822; and Study
T0833, also called 1705T0833). The population PK model parameters in
paediatrics are
summarised in Table 5.
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Table 4: Population PharmacokInetIc Parameters in Adults (report S-033188-CB-
272-N)
Pharrinacokineti
c parameter Units Estimate
RS E (%) IIV (%)
CUF Uhr 5.40
1.5 38.7
Vc/F L 333
2.7 54.8
Cl/F Uhr 6.27
4.5
Vp/F L 212
2.3 22.2
Ka 1/hr 1.10
6.5 111.8
ALAG hr 0.32
3.6
CUF (Uhr) = 5.40 x (body weight/64.8) "4 x1.72 Non-Asian x (ALT/17) -6116,
where Non-Asian
= 1 for Non-Asian and Non-Asian = 0 for Asian
Vc/F (L) = 333 x (body weight/64.8) 1.76 x 1.36 Non-Asian
Q/F (L/hr) = 6.27 x (body weight/64.8) (1473
Vp/F (L) = 212 x (body weight/64.8) 0.642
Ka (hi) = 1.10 x 0.613 gender, where gender = 1 for female and gender = 0 for
male
Effect of food on bioavailability = 0.869 fel where fed = 1 when dosing <2
hours before or after
food intake and fed = 0 when dosing 2 hours before or after food intake
Abbreviations: ALAG, absorption lag time; CL/F, apparent total clearance; Ka,
first-order rate of
absorption; 0/F, apparent inter-compartmental clearance; Vc/F, apparent volume
of central
compartment; Vp/F, apparent volume of peripheral compartment.
Table 5: Population Pharmacokinetic Parameters in Japanese paediatrics-
studiesT0822
(161810822) and 10833 (170510833)
Pharrnacokinetic
parameter Units Estimate
RSE (%) IIV (%)
CUF Uhr 2.72
5.4 22.7
Vc/F L 117
11.9
Q/F Uhr 1.06
36.7
Vp/F L 67.1
34.4
Ka 1/hr 0.702
17.9 128.1
ALAG hr 0.47
4.1
CUF (Uhr) = 2.72 x (body weight/20.7) 77
VdF (L) = 117 x(body weight/20.7) 1.07
0/F (Uhr) = 1.06 x (body weight/20.7)1177
Vp/F (L) = 67.1 x(body weight/20.7) 1+07
Relative bioavailability for 10-mg tablet = 0.88 (fixed)
Abbreviations: ALAG, absorption lag time; CL/F, apparent total clearance; Ka,
First-order rate of
absorption; Off,apparent inter-compartmental clearance; Vc/F, apparent volume
of central
compartment; Vp/F. apparent volume of peripheral compartment.
Balcixavir PK was found to be linear with respect to dose in both adults and
paediatrics. PK was
found to be well described using a two-compartment model with first-order
absorption with a lag-
time and first order elimination from the central compartment. In adults,
baloxavir demonstrated low
oral clearance of 5.4 1./hr (Japanese). Both bodyweight and race (Asian versus
non-Asian) were
found to be significant covariates on CL/F. At the same bodyweight, CUF was on
average 1.7 fold
higher in non-Japanese. Interestingly, a similar but slightly lower ethnic
effect was seen on volume
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(V/F), suggesting the covariate may not solely reflect a difference in
absolute bio-availability (F). In
Japanese paediatrics, bodyweight was a significant covariate on both clearance
and volume.
Population median oral clearance was about 3 L/h for a Japanese child weighing
24 kg. Oral drug
clearance and inter-compartmental clearance scaled to bodyweight with an
allometric exponent of
0.632, whereas both central and peripheral volume terms scaled with their
typical exponent
approaching 1. Based on these allometric relationships, bodyweight-adjusted
oral drug clearance
(Uhr/kg) decreases with increasing bodyweight and can be estimated to be about
2-fold lower in a
10-kg child compared to an adult of 70 kg. Furthermore, because volume of
distribution scaled
roughly proportional to bodyweight (i.e., approximately constant on a per kg
basis), disposition half-
life increases with increasing bodyweight.
Example 3: Dose finding for non-Asian (e.g. white) paediatric patients
A single dose administration will be used, as supported by adult and
adolescent phase 2/3 studies
as well as phase 3 Japanese paediatric studies, where a single oral dose
administration was
confirmed to provide rapid and sustained relief of influenza symptoms.
Optimal doses for two non-Asian paediatric patient groups (patient group 1:
birth to <1 year, and
patient group 2: 1 to <12 years) were simulated. The optimal doses were
simulated to match adult
exposures in terms of total drug exposure (AUCir,f), C24 and CT2, while not
exceeding adult Crnax. In
the Japanese phase 2, global phase 3 studies and Japanese paediatric studies,
baloxavir marboxil
has shown a consistent and substantial drop in viral titres within 24 hours
post dose. This supports
the selection of C24 as the primary PK metric for acute viral killing and use
of this metric to inform
exposure-matching to adults. However, because an adequate level of drug
exposure beyond 24
hours may play a role to sustain inhibition of viral replication, model
simulations also ensured the
selected doses would adequately match adult exposure in terms of overall drug
exposure (e.g.,
AUCini and C72). A link between viral rebound and less sustained drug exposure
over time (shorter
T1/2 relative to adults) cannot be ruled out at this point.
Simulations of the anticipated drug exposure in non-Japanese paediatric
subjects were obtained
from the Japanese population PK model (Section 1.2, Table 5) with the
following two optimizations:
(1) The disposition parameters CUF and VdF obtained in Japanese paediatric
patients were
scaled by respectively 1.72 and 1.36, to account for the anticipated ethnic
effect in these
parameters as estimated from the global adult population PK model (Section
1.2, Table 4). A
more detailed explanation of the factors 1.72 and 1.36 for accounting for the
ethnic effect in
pharrnacokinetics of baloxavir marboxil can be found in Koshimichi, Hiroki, et
at. 'Population
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Pharmacokinetic and Exposure-Response Analyses of Baloxavir Marboxil in Adults
and
Adolescents Including Patients With Influenza." Journal of pharmaceutical
sciences (2018).
(2) A literature-based maturation factor (MF) was used to reduce CL/F
parameter in an attempt to
mimic ontogeny and select conservative doses in neonates and infants. MF was
expressed as
MF = PMAy / (PMAy + TM50y), where PMA is postmenstrual age (weeks), TM50 is
maturation
half-life (54.2 weeks) until 50% maturation, and y is Hill coefficient (3.92).
The maturation
factor (MF) is described, e.g. in Anderson, Paediatr Anaesth. 2011; 21: 222-
37.
Model-based simulations (accounting for ethnic effect as well as bodyweight)
indicated a regimen
of 2 mg/kg up to 20 kg and 40 mg above 20 kg can be expected to mimic adult
drug exposure
adequately in terms of AUCmi, C24 and C72 and was selected in paediatrics
older than 3 months for
studies CP40559 (Study 1) and CP40563 (Study 2). Furthermore, simulations
confirm that this
regimen can contain C. below the current upper limit of exposure achieved and
confirmed to be
safe in humans so far. For younger infants (<3 months), where incomplete
enzyme maturation
cannot fully be ruled out to slightly reduce overall drug clearance,
simulations are supportive that
baloxavir marboxil dosing at 1 mg/kg is sufficient for adequate matching of
drug exposure to adults.
Further details on the simulations which led to optimal doses for non-Asian
(e.g. white such as
Caucasian) paediatric patients are given in Examples 4 and 5, below.
Example 4: Simulations for optimal doses for non-Asian pediatric patients (1-
12 years old)
The three dosing regimens explored were based on patient weight:
(1) 1 mg/kg < 40 kg, 40 mg flat 40 kg (previously proposed regimen),
(2) 1.5 mg/kg < 25 kg, 40 mg fiat 25 kg, and
(3) 2.0 mg/kg < 20 kg, 40 mg flat 20 kg.
Of note, each regimen is tailored to the weight at which body weight (BW)-
based dosing will stop,
thereby managing risk to exceed 40 mg (adult reference dose). The projected
pediatric drug
exposure for various BW groups in terms of total drug exposure (AUCo_ia), peak
drug exposure
(C.), and drug concentration at 24 hours and 72 hours after dosing is depicted
in Figure 1,
Figure 2, Figure 3, and Figure 4, respectively. Adult reference exposure
distributions for efficacy
are shown for adults globally, and separated out for Caucasians and Asians.
The thorough QT
(TQT) study in Asians provides the current safe upper limit of exposure
achieved in humans so far.
In this regard, Q and T are two peaks in an electrocardiogram and if the
distance between the two
peaks changes during a clinical study it can indicate a drug's cardiac
liability. In other words ¶TQT"
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measures side effects of the drug investigated on the heart (see, e.g.,
(3renier, Drug, healthcare
and patient safety 10 (2018): 27).
As shown in previous studies, oral drug clearance of baloxavir is
characterized to scale
allometrically with an exponent of 0.632 on BW in Asian Pediatrics. Based on
this relationship, BW-
adjusted oral drug clearance (L/hr/kg) was estimated to be about 2-fold lower
in a 10-kg child
compared to an adult of 70 kg. In agreement with these calculations, the
herewith provided
simulation confirms that regimen three (i.e. regimen (3) shown above) matches
adult exposure
optimally in terms of both total drug exposure (Figure 1) as well as drug
levels up to 72 hours after
dosing (Figure 4), particularly in pediatrics with a BW less than 25 kg. In
light of the higher drug
clearance and, hence, a faster disposition in children, a higher dose per BW
(compared to adults)
can also sustain drug exposure until at least 72 hours after dosing at similar
levels as seen in
adults. It can, however, be appreciated from Figure 4 that the improved
exposure matching of
regimen three (relative to regimen one) on AUCainf and C72 comes at the
expense of an increase
in C. (Figure 2) and C24 (Figure 3) of about 2-fold (relative to regimen one).
Nonetheless,
average peak drug levels will remain below the levels measured in the adult
thorough QT (TQT)
study.
The optimal regimen should present the highest benefit-risk profile based on
available data, and
thus balances risks of compromised efficacy and safety. A single dose of
baloxavir marboxil has
been well tolerated in both adults and Asian pediatrics, and a substantial and
consistent reduction
in viral titers has been seen over a wide dose range, indicating a wide
therapeutic window. In line
with this wide window, no clear relationship has been found between drug
exposure and
occurrence of adverse events. Moreover, as baloxavir was well tolerated in the
TOT study (with
highest peak and total drug exposures so far achieved in human), it appears
reasonable to
consider the exposure data of this study as the best estimate of a safe upper
limit of exposure in
humans.
In the recently completed study using 1 mg/kg of baloxavir marboxil was used
in Asian pediatrics
weighing less than 20 kg. Our simulations support that more adequate exposure
matching to adults
can be achieved in terms of both total (AUCo_ir,f) and sustained (C72) drug
exposure using either
regimen two or three (i.e. regimen (2) or (3) specified above). Regimen three
however mimics adult
exposure better than regimen two, while both regimens can contain exposure
with sufficient
confidence within a reliable benchmark shown to be safe in adults.
Of note, in addition to our simulations, the available sparse PK data in the
recently completed
Asian pediatric study 1602T0833 (enrolling pediatrics weighing less than 20
kg) confirms drug
concentrations briefly after dosing to fluctuate at about the mean of 100
ng/na (1 ring/kg). Since PK
is known to be linear with dose, a dose of 2 mg/kg can be expected to increase
exposure by a
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factor of 2. It appears reasonable therefore to propose regimen three (i.e.
regimen (3) specified
above): 2 mg/kg for patients weighing up to 20 kg (and 40 mg flat for patients
weighing more than
20 kg).
Example 5: Simulations for optimal doses for non-Asian pediatric patients (0-1
year old)
The three dosing regimens explored were:
(1) 1 mg/kg (previously proposed regimen),
(2) 1.5 mg/kg, and
(3) 2.0 mg/kg.
Simulation of pediatric drug exposure distribution in terms of AUC0_,,th
Crnax, C24, and 072 are
depicted in Figure 5, Figure 6, Figure 7, and Figure 8 respectively.
In agreement with the simulations for 1-12 year old children, regimen three
(i.e. regimen (3)
specified above) matches adult exposure most optimally in terms of total drug
exposure (AUC0411)
and 072, at least for infants aged 3 months and older. For the younger infants
(<3 months), where
incomplete enzyme maturation might slightly reduce overall drug clearance,
simulations are
supportive that baloxavir marboxil dosing at 1 mg/kg is sufficient for
adequate matching of AUCoi
to adults. In infants older than 3 months, the overall increase in AUCo_inr
using regimen three is
also expected to improve matching of drug exposure to adults in terms of C72
(Figure 8), but with
an approximate 2-fold increase in terms of Galax compared to regimen one
(Figure 6). Of note,
since baloxavir has low oral drug clearance, in addition to a demonstrated age-
independent
absolute bio-availability (similar C.ax in adults and children seen in Asian
patients at 1 mg/kg), C..
predictions can be made with fairly high confidence across age-groups (note
also that the volume
of distribution is demonstrated to be proportional to BW).
Taken together, these simulations support the ability to improve benefit-risk
assessment for infants
of 3 months and older with a regimen of 2 mg/kg, while the reduced dose of 1
mg/kg is considered
sufficient for younger infants (4 weeks-3 months) as well as for newborns (0-4
weeks).
Example 6: Preparation of granules comprising the compound of the invention
A. Preparation of granule. compositions
A compound II can be produced, e.g., by a method disclosed in International
Publication No. WO
2016/175224.
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Manufacturing Method for Compound 1
0
OHO
.-----
Me0A0 0 0
Y. LN-Th
., Nrm
-..-N.,....1.40õ..0
-1.-- -.-.. 0%.õ..y.
N.õN...ecr0
14
=
F
S F
F S
F
II I
Potassium carbonate (1483.4 mg, 10.7 mmol), potassium iodide (549.5 mg, 3.3
mmol),
tetrahydrofuran (33.1 g), N,N-dimethylacetamide (3.8 g) and water (80.3 mg)
were added to the
compound 11 (4.0 g, 8.3 mmol), followed by stirring. The resultant mixture was
heated to 60 C, to
which chloromethyl methyl carbonate (1758.9 mg, 14.2 num!) was added. The
resultant was
stirred at 60 C for 9 hours, and then cooled to 20 C. Acetic acid (822.0 mg),
2-propanol (3.1 g)
and water (20.0 g) were added thereto, and the resultant was extracted twice
with tetrahydrofuran
(1.8 g, 8.9 g). The solvent was distilled off through vacuum concentration to
a liquid weight of
about 32 g. The resultant was heated to 45 C, 2-propanol (1.6 g) was added
thereto, and the
resultant was cooled to 20 C. A sodium acetate aqueous solution prepared from
sodium acetate
(339.0 mg) and water (46.0 g) was added thereto, followed by cooling to 5 C.
After the resultant
was stirred at 5 C for 3 hours, a pale yellow precipitate was filtered off.
The thus obtained solid
was washed with a mixture of 2-propanol (4.7 g) and water (6.0 g), and the
solid was then washed
again with 2-propanol (6.3 g). To the thus obtained pale yellow solid,
dimethyl sulfoxide (30.9 g)
was added, followed by stirring. The resultant was heated to 60 C, to which a
mixture of dimethyl
sulfoxide (2.2 g) and water (4.8 g) was added. A mixture of dimethyl sulfoxide
(19.9 g) and water
(28.4 g) was further added thereto, followed by cooling to 20 C. After the
resultant was stirred at
20 C for 3 hours, a generated white precipitate was filtered off. The thus
obtained solid was
washed with a mixture of dimethyl sulfoxide (8.0 g) and water (4.8 g), and the
solid was washed
again with water (12.0 g). The thus obtained solid was dried to give a
compound I (4.21 g) as
white crystal.
1H-NMR (DMSO-D6) 6: 2.91-2.98 (1H, m), 3.24-3.31 (1H, m), 3.44 (1H, t, J =
10.4 Hz), 3.69 (1H,
dd, J = 11.5, 2.8 Hz), 3.73 (3H, s), 4.00 (1H, dd, J = 10.8, 2.9 Hz), 4.06
(1H, d, J = 14.3 Hz), 4.40
(1H, d, J = 11.8 Hz), 4.45 (1H, dd, J = 9.9, 2.9 Hz), 5.42 (1H, dd, J = 14.4,
1.8 Hz), 5.67 (1H, d, J =
6.5 Hz), 5.72-5.75 (3H, m), 6.83-6.87 (1H, m), 7.01 (1H, d, J = 6.9 Hz), 7.09
(1H, dd, J = 8.0, 1.1
Hz), 7.14-7.18 (1H, m), 7.23 (1H, d, J = 7.8 Hz), 7.37-7.44 (2H, in)
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Powder X-ray Diffraction: 28 (a): Characteristic peaks are present at 8.6 0.2
, 14.1 0.2 ,
17.4 0.2 , 20.00 0.20, 24.0 0.2 , 263 0.2 , 29.6 0.2 and 35.4 0.2 .
The powder X-ray diffraction pattern of the crystal of compound I is shown in
Figure 10.
(1) Study on Stabilizer
In order to study a stabilizer, a stabilizer shown in each of Tables 7 to 9
and a compound
represented by formula (I) were wet-granulated, and the amount of increase in
the compound
represented by formula (II), which is a related substance, were evaluated
after a temporal stability
test of the produced granule. A preparation having a formulation shown in
Table 6 was produced
by the stirring granulation method.
[Table 6]
Content (mg)
Compound represented by Formula (I)
2.0
Purified White Sugar
488.0
Hydrogenated Maltose Starch Syrup (Maltitol)
500.0
Stabilizer
30.0
Hydroxypropyl Cellulose
10.0
Total
1030.0
(Method for Manufacturing Preparation)
A compound represented by formula (I), purified white sugar, powdered
hydrogenated maltose
starch syrup (maltitol), a stabilizer and hydroxypropyl cellulose shown in
Table 6 were mixed using
a high-speed mixer (FS-GS SJT 10 high-speed mixer, Fukae Powiec Co., Ltd.),
and water was
added to the mixture, followed by stirring granulation. Then, the granulation
product was subjected
to size selection in a power mill (model P-3S, Showa Kagakukikai Co., Ltd.),
and the resultant was
dried at 65 to 70 C in a fluidized bed granulator (WSG2&5 fluid bed dryer
granulator, Okawara
Mfg. Co., Ltd.). After drying, a granule was obtained by size selection in a
power mill (model P-35,
Showa Kagakukikai Co., Ltd.). Granulation conditions in the high-speed mixer
were as follows:
(Granula(ion Conditions)
- Granulator: FS-GS SJT 10 high-speed mixer
- Rotational Speed of Agitator: 250 rpm
- Rotational Speed of Chopper: 2500 mm
- Acceleration in Solution Injection: 21 2 gimin
- Moisture: 4 to 6.5% by weight
- Mashing time: 1 min 5 sec
(Temporal Stability Test of Preparation)
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The produced preparation was stored at 60 C for 2 weeks, and the amount of
increase in the
compound represented by formula (II), which is a related substance, was
measured.
(Stabilizer)
As shown in Tables 7 to 9, sodium chloride (Kanto Chemical Co., Inc.),
potassium chloride (Wako
Pure Chemical Industries, Ltd.), ascorbic acid (Nacalai Tesque, Inc.), fumaric
acid (Merck KGaA),
medium-chain fatty acid triglyceride Miglyol (Mitsuba Trading Co., Ltd.),
triethyl citrate (Merck
KGaA), sodium nitrite (Nacalai Tesque, Inc.), glycerin (Kanto Chemical Co.,
Inc.), and vitamin E
(Merck KGaA) were used as the stabilizer.
[Table 7]
Example 7-1 Example 7-2
Example 7-3 Example 7-4
Potassium
Stabilizer Sodium Chloride
Ascorbic Acid Fumaric Acid
Chloride
[Table 8]
Example 7-5 Example 7-6
Comparative Comparative
Example 7-1
Example 7-2
Medium-Chain Fatty Acid Triethyl
Stabilizer
Sodium Nitrite Glycerin
Triglyceride Miglyol Citrate
[Table 9]
Comparative
Comparative
Example 7-3
Example 7-4
Stabilizer Vitamin E
None
(Method for Measuring Compound represented by Formula (I1))
The amount of the compound represented by formula (II) was measured by liquid
chromatography
by employing the following method and conditions:
- Detector: ultraviolet absorptiometer (measurement wavelength: 260 nm)
- Column: XBridge C18, 3.5 pm, 3.0 x 150 mm
- Column temperature: constant temperature around 35 C
- Mobile Phase A: 0.1% trifluoroacetic acid/0.2 mM EDTA solution, Mobile
Phase B:
acetonitrile
- Delivery of mobile phase: controlled for a concentration gradient with a
mixing ratio
between the mobile phase A and the mobile phase B changed as shown in Table
10.
[Table 10]
Time after Injection (min) Mobile Phase A (vol%)
Mobile Phase B (vor/o)
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0 - 5 70
30
5-40 70 ¨> 20
30 ¨> 80
40 - 40.1 20 ¨> 70
80 ¨> 30
- Flow rate: about 0.6 mL/min
- Injection amount: 5 pL
- Sample cooler temperature: about 5 C
- Washing solution for autoinjector: acetonitrile/methanol mixture (1:3)
- Range of area measurement: 50 minutes after injection of sample solution
- Equation for calculating amount of compound represented by formula (II):
Amount of compound represented by formula (II) (%) = (ATII / ZAT) x 100
ATII: peak area of compound represented by formula (II) in sample solution
EAT: Sum of peak areas of sample solution (excluding blank and system peaks)
(Results)
The amount of increase (To) in the compound represented by formula (II) in the
temporal stability
test of the preparations of Examples 7-1 to 7-6 and Comparative Examples 7-1
to 7-4 is shown in
Tables 11 to 13. As a result, the amount of increase (%) in the compound
represented by formula
(II) in the granules of Examples 7-1 to 7-6 was lower than that in the granule
containing no
stabilizer of Comparative Example 7-4. Particularly, the amount of increase in
the compound
represented by formula (II) in the granules containing sodium chloride of
Example 7-1, ascorbic
acid of Example 7-3, fumaric acid of Example 7-4 and medium-chain fatty acid
triglyceride Miglyol
of Example 7-5 was much smaller than that in the granule containing no
stabilizer of Comparative
Example 7-4.
[Table 11]
Example 7-1 Example
7-2 Example 7-3 Example 7-4
Potassium
Stabilizer Sodium Chloride
Ascorbic Acid Fumaric Acid
Chloride
Amount of Increase
(%) in Compound
0.70 1.31
0.28 0.30
represented by
Formula (II)
[Table 12]
Example 7-5
Example 7-6 Comparative
Comparative
Example 7-1
Example 7-2
Medium-Chain Fatty
Triethyl
Stabilizer
Sodium Nitrite Glycerin
Acid Triglyceride
Citrate
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Miglyol
Amount of Increase
(%) in Compound
0.34 1.24
6.63 9.95
represented by
Formula (II)
[Table 13]
Comparative
Comparative
Example 7-3
Example 7-4
Stabilizer
Vitamin E None
Amount of Increase (%) in Compound
3.56
1.35
represented by Formula (II)
(2) Study on Excipient
In order to study an excipient, an excipient shown in each of Tables 14 to 16
and a compound
represented by formula (I) were wet-granulated, and the amount of increase in
the compound
represented by formula (II), which is a related substance, was evaluated after
a temporal stability
test of the produced granule.
(Method for Producing Preparation)
An excipient shown in each of Tables 14 to 16 and a compound represented by
formula (I) were
mixed in a bag at a ratio of 1:1, and then, the mixture was sieved through a
30-mesh sieve (wire
diameter: 0.22 mm). The sieved mixed powder was mixed in a mortar, and then,
purified water
was gradually added such that moisture in granulation was about 5% by weight
based on the
charged amount of the materials, and the resultant was kneaded using a pestle.
The kneaded
product was subjected to wet size selection while pressed by hand through 16-
mesh wires (wire
diameter: 0.65 mm). The granulation product after the size selection was dried
in a vented dryer,
and a granule was prepared while pressed by hand through 20-mesh wires (wire
diameter: 0.40
mm).
(Temporal Stability Test of Preparation)
The produced preparation was stored at 60 C for 2 weeks, and the amount of
increase in the
compound represented by formula (II), which is a related substance, was
measured.
(ExciDient)
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As shown in Tables 14 to 16, purified while sugar (Merck KGaA), hydrogenated
maltose starch
syrup (maltitol, ROQUETTE), D-mannitol (ROQUETTE), lactose hydrate (DMV-
Fonterra Excipients
GmbH & Co. KG), sorbitol (Merck KGaA), erythritol (ROQUETTE), xylitol
(ROQUETTE), and
isonnalt (Beneo-Palatinit GmbH) were used as the excipient
[Table 14]
Example 7-7 Example 7-8
Example 7-9
Hydrogenated
Maltose
Excipient Purified White Sugar
D-Mannitol
Starch Syrup (Maltitol)
[Table 15]
Reference Example 7-1 Reference
Example 7-2 Reference Example 7-3
Excipient Lactose Hydrate Sorbitol
Erythritol
[Table 16]
Reference Example 7-4
Reference Example 7-5
Excipient Xylitol
lsomalt
(Results)
The amount of increase (%) in the compound represented by formula (II) in the
temporal stability
test of the preparations of Examples 7-7 to 7-9 and Reference Examples 7-1 to
7-5, and the
melting point of each excipient are shown in Tables 17 to 19. As a result, the
amount of increase
(%) in the compound represented by formula (II) in the granules of Examples 7-
7 to 7-9 was
slightly lower than that in the granules of Reference Examples 7-1, 7-2 and 7-
5. The amount of
increase (%) in the compound represented by formula (II) in the granules of
Reference Examples
7-3 and 7-4 was almost the same as that in the granules of Examples 7-7 to 7-
9, whereas the
melting point was lower as compared with Examples 7-7 to 7-9 and thus, there
was a possibility of
sticking. Accordingly, it was regarded that purified white sugar, hydrogenated
maltose starch syrup
(maltitol) and D-mannitol are preferred as the excipient.
[Table 17]
Example 7-7
Example 7-8 Example 7-9
Excipient Purified White Sugar
Hydrogenated D-Mannitol
Maltose
Starch
Syrup (Maltitol)
Melting point (aC) 160- 186
145 166 - 168
Amount of Increase (%)
0.08
0.06 0.11
in Compound
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represented by Formula
(II)
[Table 18]
Reference Example Reference
Reference
7-1
Example 7-2 Example 7-3
Excipient Lactose Hydrate
Sorbitol Erythritol
Melting point ( C) 201 - 202 95
121
Amount of Increase (%)
in Compound
0.17
0.15 0.08
represented by Formula
(II)
[Table 19]
Reference Example Reference
7-4
Example 7-5
Excipient Xylitol
Isomalt
Melting point ( C) 92 - 96
141 - 161
Amount of Increase (%) in
Compound represented by 0.04
0.38
Formula (II)
(3) Study on Combination of Excipients
Although purified white sugar, hydrogenated maltose starch syrup (rnaltitol)
and D-mannitol were
selected as a preferable excipient, in order to study a combination of these
excipients, a
combination of excipients shown in each of Tables 20 and 21 and a compound
represented by
formula (I) were wet-granulated, and the produced granule was evaluated for
(a) the amount of
increase in the compound represented by formula (II), which is a related
substance, (b)
suspensibility in water, (c) container adherenoe,(d) a fine granule yield, and
(e) a bulk density. A
preparation having a formulation shown in each of Tables 20 and 21 was
produced by the stirring
granulation method.
!Table 201
Example 7-10
Example 7-11 Example 7-12
(weight mg)
(weight mg) (weight mg)
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Compound
represented by 10.0 20.0
10.0
Formula (I)
Maltitol 300.0 350.0
490.0
D-Mannitol 614.0 554.0
490.0
Purified White Sugar - -
-
Sodium Chloride 30.0 30.0
-
Polyvinyl Pyrrolidone
10.0 10.0
10.0
k25
Total 964.0 964.0
1000.0
Weight Ratio of Sugar Maltitol:
Maltitol: Maltitol:
or Sugar Alcohol D-Mannitol = D-
Mannitol = D-Mannitol =
32.8:67.2
38.7:61.3 50.0:50.0
JTable 211
Comparative
Comparative
Example 7-5
Example 7-6
(weight mg)
(weight mg)
Compound represented by
10.0
10.0
Formula (I)
Maltitol 500.0
-
D-Mannitol -
500.0
Purified White Sugar 480.0
480.0
Sodium Chloride -
-
Polyvinyl Pyrrolidone k25 10.0
10.0
Total 1000.0
1000.0
Weight Ratio of Sugar or Maltitol:
D-Mannitol:
Sugar Alcohol Purified White
Sugar = Purified White Sugar =
51.0:49.0
51.0:49.0
(Method for Producing Preparation)
A compound represented by forrnula (I), an excipient and polyvinyl pyrrolidone
shown in each of
Tables 20 and 21 were mixed using a high-speed mixer (LFS-GS-2.1 high-speed
mixer, Fukae
Powtec Co., Ltd.), and water was added to the mixture, followed by stirring
granulation. Then, the
granulation product was subjected to size selection in a power mill (model P-
3S, Showa
Kagakukikai Co., Ltd.), and the resultant was dried at 65 to 70 C in a
fluidized bed granulator (MP-
01 Fluid bed dryer granulator, Powrex Corp.). After drying, a granule was
obtained by size
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selection in a power mill (model P-3S, Showa Kagakukikai Co., Ltd.).
Granulation conditions in the
high-speed mixer were as follows:
(Granula(ion Conditions)
- Granulator: LFS-GS-2J high-speed mixer
- Rotational Speed of Agitator: 333 rpm
- Rotational Speed of Chopper: 2500 rpm
- Acceleration in Solution Injection: 20 3.5 g/min
- Moisture: 3 to 7.5% by weight
- Mashing time: 1 to 2 min 5 sec
(Suspensibility Test of Preparation in Water)
The number of times of mix by inversion required for preparing a visually
uniform suspension when
9.5 mL of water was added to about 1 g of the present preparation was
recorded.
(Container Adherence of Preparation)
In the production of the present preparation, the amount of a granulation
product adhering to the
interior wall of a stirring granulator after granulation was visually
confirmed. The presence or
absence of adhesion after scraping off was evaluated as an index for container
adherence.
(Fine Granule Yield Measurement of Preparation)
100 g of the present preparation was sieved through Nos. 30 and 140 sieves,
and the ratio of the
amount of a granule passing through the No. 30 sieve and remaining on the No.
40 sieve to the
total amount of the sieved granule was calculated.
(Bulk Density Measurement of Preparation)
The present preparation was injected to a container (capacity: 100 mL) until
overflowing, and the
preparation was carefully leveled off to remove an excess from the upper
surface of the container.
The value of a preparation weight in the container was obtained from a
container weight tared in
advance, and a bulk density was determined according to the following
equation:
Bulk density = Preparation weight in container /100
(Ercipient)
As shown in Tables 20 and 21, purified white sugar (Merck KGaA), hydrogenated
maltose starch
syrup (maltitol. ROQUETTE), and D-mannitol (ROQUETTE) were used in combination
as the
excipient.
(Results)
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The suspensibility in water, container adherence, fine granule yield and bulk
density of the
preparations of Examples 7-10 to 7-12 and Comparative Examples 7-5 and 7-6 are
shown in
Tables 22 and 23. As a result, the preparations of Examples 7-10 to 7-12
containing a mixture of
hydrogenated maltose starch syrup (maltitol) and D-mannitol as an excipient
had excellent
suspensibility in water, small adherence to a container, and a bulk density of
0.5 g/mL or larger.
Particularly, in Examples 7-10 and 7-11, the fine granule yield was also as
high as 90% or more.
On the other hand, the preparations of Comparative Examples 7-5 and 7-6
containing a mixture of
purified white sugar and hydrogenated maltose starch syrup (maltitol) or
purified white sugar and
D-mannitol as an excipient were inferior in suspensibility in water to
Examples and also had large
container adherence. Particularly, in Comparative Example 7-6, the fine
granule yield was also
low.
[Table 22]
Example 7-10
Example 7-11 Example 7-12
Suspensibility in Water Uniformly
Uniformly Uniformly
suspended by 15 suspended by 10 suspended by
times
times 10 times
Container Adherence Small
Small Small
Fine Granule Yield (%) 92
90 72
Bulk Density (g/mL) 0.67
0.67 0_59
[Table 23]
Comparative
Comparative
Example 7-5
Example 7-6
Suspensibility in Water Uniformly suspended
by 25 Uniformly suspended by
Limes
30 times
Container Adherence Large
Large
Fine Granule Yield (%) 89
66
Bulk Density (g/mL) 0.76
0.65
(4) Study on Binder
In order to study a binder, a binder shown in Table 24 and a compound
represented by formula (I)
were wet-granulated, and the produced preparation was evaluated for (a) the
amount of increase
in the compound represented by formula (II), which is a related substance,
after a temporal stability
test and (b) a bulk density. A preparation having a formulation shown in Table
24 was produced by
the stirring granulation method. Polyvinyl pyrrolidone K25 (BASF) and
hydroxypropyl cellulose SL
(Shin-Etsu Chemical Ca, Ltd.) were used as the binder_
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[Table 24]
Example 7-13 Example 7-14
Reference
(weight mg)
(weight mg) Example 7-6
(weight mg)
Compound represented by Formula (I) 10.0
10_0 10.0
Purified White Sugar 480.0
460.0 480.0
Hydrogenated Maltose Starch syrup
500.0
500.0 500.0
(Ma Ititol)
Polyvinyl Pyrrolidone K25 10.0
30.0 -
Hydroxypropyl Cellulose SL -
- 10.0
Total 1000.0
1000.0 1000.0
(Method for Producing Preparation)
A compound represented by formula (I), purified white sugar, hydrogenated
maltose starch syrup
(maltitol), and hydroxypropyl cellulose SL (Nippon Soda Co., Ltd.) or
polyvinyl pyrrolidone K25 as a
binder shown in Table 24 were mixed using a high-speed mixer (LFS-GS-2J high-
speed mixer,
Fukae Powtec Co., Ltd.), and water was added to the mixture, followed by
stirring granulation.
Then, the granulation product was subjected to size selection in a power mill
(model P-35, Showa
Kagakukikai Co., Ltd.), and the resultant was dried at 65 to 70 C in a
fluidized bed granulator (MP-
01 Fluid bed dryer granulator, Powrex Corp.). After drying, a granule was
obtained by size
selection in a power mill (model P-35, Showa Kagakukikai Co., Ltd.).
Granulation conditions in the
high-speed mixer were as follows:
(Granulation Conditions)
- Granulator: LFS-GS-2J high-speed mixer
- Rotational Speed of Agitator: 333 rpm
- Rotational Speed of Chopper: 2500 rpm
- Acceleration in Solution Injection: 20 3.5 gimin
- Moisture: 3 to 7.5% by weight
- Mashing time: 1 to 2 min 1 5 sec
(Temporal Stability Test of Preparation)
The produced preparation was stored at 60 C for 2 weeks, and the amount of
increase in the
compound represented by formula (II), which is a related substance, was
measured.
(Bulk Density Measurement of Preparation)
The present preparation was injected to a container (capacity: 100 mL) until
overflowing, and the
preparation was carefully leveled off to remove an excess from the upper
surface of the container.
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The value of a preparation weight in the container was obtained from a
container weight tared in
advance, and a bulk density was determined according to the following
equation:
Bulk density = Preparation weight in container /100
(Results)
The amount of increase (%) in the compound represented by formula (II) in the
temporal stability
test of the preparations of Examples 7-13 and 7-14 and Reference Example 7-6,
and the bulk
density are shown in Table 25. As a result, the amount of increase (To) in the
compound
represented by formula (II) in the preparations of Examples 7-12 and 7-13
containing polyvinyl
pyrrolidone was lower than that in the preparation of Reference Example 7-6
containing
hydroxypropyl cellulose. The amount of increase (%) in the compound
represented by formula (II)
in the temporal stability test and the bulk density in the preparation of
Example 7-12 in which the
amount of polyvinyl pyrrolidone was 1% by weight were lower than those in the
preparation of
Example 7-13 in which the amount of polyvinyl pyrrolidone was 3% by weight.
[Table 25]
Example 7-13 Example 7-14
Reference
Example 7-6
Amount of Increase (%) in Compound
0.12
0.15 0.20
represented by Formula (II)
Bulk Density (g/mL) 0.72
0.77
(5) Study on Fluidizing Agent
In order to study a fluidizing agent, (a) the amount of related substances
after temporal storage of
a preparation and (b) stickiness between preparations were evaluated. A
preparation having a
formulation shown in each of Tables 26 and 27 was produced by the stirring
granulation method.
1% and 3% light anhydrous silicic add (Cab-o-sil, Cabot Corp.), 1% and 3%
hydrated silicon
dioxide (RxCIPIENTS) and 1% and 3% sodium stearyl fumarate (PRUV, JRS Pharma)
were used
as the fluidizing agent.
[Table 26]
Example 7-15 Example 7-16 Example 7-17
(weight mg)
(weight mg) (weight mg)
Compound represented by Formula (I) 10.0
10.0 10.0
Hydrogenated Maltose Starch Syrup
490.0
490.0 490.0
(Ma Ititol)
D-Mannitol 490.0
490.0 490.0
Polyvinyl Pyrrolidone k25 10.0
10.0 10.0
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Sucralose 5.0
5.0 5.0
Light Anhydrous Silicic Acid 10.0
30.0 -
Hydrated Silicon Dioxide -
- 10.0
Sodium Stearyl Fumarate -
- -
Strawberry Flavor 1.0
1.0 1.0
Total 1016.0
1036.0 1016.0
[Table 27]
Example 7-18 Comparative
Comparative
(weight mg)
Example 7-7 Example 7-8
(weight mg)
(weight mg)
Compound represented by Formula
10.0
10.0 10.0
(I)
Hydrogenated Maltose Starch Syrup
490_0
490_0 490_0
(Maltitol)
D-Mannitol 490.0
490.0 490.0
Polyvinyl Pyrrolidone k25 10.0
10.0 10.0
Sucralose 5.0
5.0 5.0
Light Anhydrous Silicic Acid -
- 10.0
Hydrated Silicon Dioxide 30.0
- -
Sodium Stearyl Fumarate -
10.0 30.0
Strawberry Flavor 1.0
1.0 1.0
Total 1036.0
1016.0 1036.0
(Method for Producing Preparation)
A compound represented by formula (I), hydrogenated maltose starch syrup
(nnaltitol), D-mannitol,
polyvinyl pyrrolidone K25, sucralose, a fluidizing agent (any of light
anhydrous silicic acid, hydrated
silicon dioxide, and sodium stearyl fumarate) and strawberry flavor shown in
each of Tables 26 and
27 were mixed using a high-speed mixer (LFS-GS-2J high-speed mixer, Fukae
Powtec Co., Ltd.),
and water was added to the mixture, followed by stirring granulation. Then,
the granulation product
was subjected to size selection in a power mill (model P-35, Showa Kagakukikai
Co., Ltd.), and the
resultant was dried at 65 to 70 C in a fluidized bed granulator (MP-01 Fluid
bed dryer granulator,
Powrex Corp.). After drying, a granule was obtained by size selection in a
power mill (model P-35,
Showa Kagakukikai Co., Ltd.). Granulation conditions in the high-speed mixer
were as follows:
(Granulation Conditions)
- Granulator: LFS-GS-2J high-speed mixer
- Rotational Speed of Agitator: 333 rpm
- Rotational Speed of Chopper: 2500 rpm
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- Acceleration in Solution Injection: 20 3.5 g/rnin
- Moisture: 3 to 7.5% by weight
- Mashing time: 1 to 2 min 5 sec
(Temporal Stability Test of Preparation)
The produced present preparation was stored at 60 C for 2 weeks, and the
amount of increase in
the compound represented by formula (II), which is a related substance, was
measured.
IStickiness Test of Preparation)
1 g of the preparation was charged into a 4 mL brown bottle, and evaluation
was made as follows:
good (indicated by circle), the preparation present at the bottom fluidized
when the bottle was
inverted three times; fair (indicated by triangle), the preparation present in
an upper part fluidized
when the bottle was inverted three times; and poor (indicated by x-mark), the
preparation did not
fluidize when the bottle was inverted three times.
(Results)
The amount of increase (%) in the compound represented by formula (II) in the
temporal stability
test of the preparations of Examples 7-15 to 7-18 and Comparative Examples 7-7
and 7-8, and the
stickiness between preparations are shown in Tables 28 and 29. As a result,
the amount of
increase (%) in the compound represented by formula (II) in the preparations
of Examples 7-15 to
7-18 was almost the same as that in the preparations of Comparative Examples 7-
7 and 7-8
containing sodium stearyl fumarate, and was almost the same even when the
amount of the
fluidizing agent was changed.
Meanwhile, as a result of studying the stickiness of the preparations of
Examples 7-15 to 7-18 and
Comparative Examples 7-7 and 7-8, the preparations of Examples 7-15 to 7-18
had smaller
stickiness than that of the preparations of Comparative Examples 7-7 and 7-8.
[Table 28]
Example 7-15 Example 7-16 Example 7-17
Amount of Increase (%) in Compound
0.64
0.51 0.34
represented by Formula (10
Stickiness A
0 0
[Table 29]
Comparative
Comparative
Example 7-18
Example 7-7
Example 7-8
Amount of Increase (%) in Compound
0.58
0.51 0.45
represented by Formula (II)
Stickiness 0
x x
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(6) Study on Suspending Agent
In order to study a suspending agent, the suspensibility of a preparation in
water was evaluated.
The present preparabon having a formulation shown in Table 30 was produced by
the stirring
granulation method. Hypromellose (TC-5, Shin-Etsu Chemical Co., Ltd.),
hydroxypropyl cellulose
(HPC-L, Nippon Soda Co., Ltd.), and methyl cellulose (SM-4, Shin-Etsu Chemical
Co., Ltd.) were
used as the suspending agent.
[Table 30]
Example 7-19 Reference
Reference Comparative
(weight mg) Example 7-
7 Example 7-8 Example 7-9
(weight mg)
(weight mg) (weight mg)
Compound
represented by 20.0 20.0
20.0 20.0
Formula (I)
D-Mannitol 564.0 564.0
564.0 564.0
Hydrogenated Maltose
350.0 350.0
350.0 353.0
Starch Syrup (Maltitol)
Sodium Chloride 30.0 30.0
30.0 30.0
Polyvinyl Pyrrolidone 10.0 10.0
10.0 10.0
Hypromellose 3.0
Hydroxypropyl
3.0
Cellulose
Methyl Cellulose
3.0
Sucralose 5.0 5.0
5.0 5.0
Light Anhydrous Silicic
20.0 20.0
20.0 20.0
Acid
Strawberry Flavor 1.0 1.0
1.0 1.0
Total 1003.0 1003.0
1003.0 1003.0
(Method for Producing Preparation)
A compound represented by formula (I), D-mannitol, hydrogenated maltose starch
syrup (maltitol),
sodium chloride and polyvinyl pyrrolidone K25 shown in Table 30 were mixed
using a vertical
granulator (model VG-50, Powrex Corp.), and water was added to the mixture,
followed by stirring
granulation. Then, the granulation product was subjected to size selection in
a power mill (model
P-3S, Showa Kagakukikai Co., Ltd.), and the resultant was dried at 65 to 70 C
in a fluidized bed
granulator (GPGC-158130 fluid bed dryer granulator, Powrex Corp.). After
drying, size selection
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was performed in a power mill (model P-3S, Showa Kagakukikai Co., Ltd.). The
granulation
product after the size selection was mixed with sucralose, a suspending agent
(any of
hypromellose, hydroxypropyl cellulose, and methyl cellulose), light anhydrous
silicic acid and
strawberry flavor using a V-shaped mixer (130 L V type blender, manufactured
by Tokuju Corp.) to
obtain a granule.
(Granulation Conditions)
- Granulator: vertical granulator VG-50
- Rotational Speed of Agitator: 200 rpm
- Rotational Speed of Chopper: 2500 rpm
- Acceleration in Solution Injection: 105 3 g/min
- Moisture: 4.5 to 7.5% by weight
- Mashing time: 1 to 3 min 1 5 sec
(Suspensibi(ity Test of Preparation in Water)
1 g of the present preparation was added into a stoppered container containing
9.5 mL of water,
and the stoppered container was reciprocally inverted 40 times, and
immediately thereafter, a
liquid was collected from upper and lower parts of the container. After the
completion of container
inversion, the container was left at room temperature for 10 minutes, and a
liquid was collected
from a central part of the container. The concentration of the compound
represented by formula (I)
in the collected liquids was measured.
(Method for Measuring Compound represented by Formula (I))
The amount of the compound represented by formula (I) was measured by liquid
chromatography
by employing the following method and conditions:
- Detector: ultraviolet absorptiometer (measurement wavelength: 260 nm)
- Column: ACQUITY UPLC BEH C18 1.7 pm, 2.1 x 50 mm (Waters Corp.)
- Column temperature: constant temperature around 35 C
- Mobile Phase A: 0.1% trifluoroacetic acid/0.2 mM EDTA solution, Mobile
Phase B:
acetonitrile
- Delivery of mobile phase: controlled for a concentration gradient with a
mixing ratio
between the mobile phase A and the mobile phase B changed as shown in Table 31
[Table 31]
Time after Injection (min) Mobile Phase A
(vol%) Mobile Phase B (vol%)
0 - 2_3 62
38
2.3 - 3 62-2O
38 ¨> 80
3 - 4 20
80
- Flow rate: about 0.6 mL/min
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- Injection amount: 4 pL
- Sample cooler temperature: about 5 C
- Washing solution for autoinjector: acetonitrile
- Range of area measurement 8 minutes after injection of sample solution
- Equation for calculating amount of compound represented by formula (I):
Amount of compound represented by formula (I) (%) = MS / C xAT / As x 100
MS: weighed amount (mg)
C: labeled amount in preparation (mg/mL)
As: peak area obtained from standard solution
AT: peak area obtained from sample solution
(Evaluation of Suspensibility in Water)
The suspensibility of the preparation was evaluated according to the following
equation:
Ratio (%) of amount of compound represented by formula (I) in suspension at
central position of
container after 10 minutes from container inversion = (Concentration of
compound represented by
formula (I) in suspension at central position of container after 10 minutes
from container inversion /
Concentration of compound represented by formula (I) in suspension at central
position of
container immediately after container inversion) x 100 (%)
(Results)
The suspensibility in water of the preparations of Example 7-19, Reference
Examples 7-7 and 7-8
and Comparative Example 7-9 is shown in Table 32. As a result, the ratio of
the amount of the
compound represented by formula (I) in the suspensions of Example 7-19 and
Reference
Examples 7-7 and 7-8 was higher than that in the suspension of Comparative
Example 7-9
containing no suspending agent Particularly, the preparation of Example 7-19
containing
hypromellose had a high ratio of the amount of the compound represented by
formula (I) in the
suspension and had good suspensibility in water.
[Table 32]
Example 7-19 Reference
Reference Comparative
Example 7-7 Example 7-8 Example 7-9
Ratio (%) of amount of 95.1 93.0
92.9 65.8
compound represented by
formula (I) in suspension at
central position of
container after 10 minutes
from container inversion
(7) Study on Lubricant
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In order to study a lubricant, an angle of repose was evaluated as an index
for fluidity of a
preparation. A preparation having a formulation shown in Table 33 was produced
by the stirring
granulation method. Talc (Merck KGaA, LUB) was used as the lubricant.
[Table 33]
Example 7-20
Comparative
(weight mg)
Example 7-10
(weight mg)
Compound represented by Formula
20.0
20.0
(I)
D-Mannitol 560.0
561.0
Powdered Hydrogenated Maltose
350.0
350.0
Starch Syrup (Maltitol)
Sodium Chloride 30.0
30.0
Polyvinyl Pyrrolidone 10.0
10.0
Hypromellose 3.0
3.0
Sucralose 5.0
5.0
Light Anhydrous Silicic Acid 20.0
20.0
Talc 1.0
Strawberry Flavor 1.0
1.0
Total 1000.0
1000.0
(Method for Producing Preparation)
A compound represented by formula (I), D-mannitol, hydrogenated maltose starch
syrup (maltitol),
sodium chloride, polyvinyl pyrrolidone K25, and hypronnellose shown in Table
33 were mixed using
a vertical granulator (model FM-VG50, Powrex Corp.), and water was added to
the mixture,
followed by stirring granulation. Then, the granulation product was subjected
to size selection in a
power mill (model P-3S, Showa Kagakukikai Co., Ltd.), and the resultant was
dried at 65 to 70 C in
a fluidized bed granulator (GPGC-158c30 fluid bed dryer granulator, Powrex
Corp.). After drying,
size selection was performed in a power mill (model P-3S, Showa Kagakukikai
Co., Ltd.). The
granulation product after the size selection was mixed with talc, sucralose,
light anhydrous silicic
acid and strawberry flavor using a V-shaped mixer (130 L V type blender,
Tokuju Corp.) to obtain a
granule.
(Granulation Conditions)
- Granulator: vertical granulator VG-50
- Rotational Speed of Agitator: 200 rpm
- Rotational Speed of Chopper: 2500 rpm
- Acceleration in Solution Injection: 105 3 ginnin
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- Moisture: 4.5 to 7.5% by weight
- Mashing time: 1 to 3 min 5 sec
(Measurement of Angle of Repose of Preparation)
The angle of repose of the produced preparation was measured using a powder
tester (Hosokawa
Micron Group) under the following conditions:
Operation time: 170 sec, Slow down: 10 sec, Amplitude: 1.5 mm
(Results)
The angle of repose of the preparations of Example 7-20 and Comparative
Example 7-10 is shown
in Table 34. As a result, the preparation of Example 7-20 containing talc had
a smaller angle of
repose than that of the preparation of Comparative Example 7-10 containing no
talc, demonstrating
that the fluidity of the preparation can be enhanced by containing talc.
[Table 34]
Example 7-20
Comparative
Example 7-10
Angle of Repose ( ) 33/
36.2
(8) Measurement of Release Rate
The preparation of Example 7-20 shown in Table 33 was stored at 60 C for 2
weeks and at 40 C
and 75% relative humidity for 2 weeks, and the release rate of the compound
represented by
formula (I) was measured.
(Dissolution Property Test of Preparation)
The produced preparation was stored at 60 C for 2 weeks and at 40 C and 75%
relative humidity
for 2 weeks, and the release rate of the compound represented by formula (I)
was measured by
the second method of Dissolution Test described in the Japanese Pharmacopoeia
(paddle
method). The fluid used in the method of Dissolution Test was the dissolution
test second fluid
(containing 1% Tween 20), and the rotational speed of the paddle was set to 50
rpm.
(Results)
As shown in Figure 2, the release rate from the preparation of Example 7-20
after storage at 60 C
for 2 weeks and after storage at 40 C and 75% relative humidity for 2 weeks
hardly differed from
the release rate from the preparation immediately after preparation.
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(9) Preparation having different composition ratio
Example 7-21 shown in Tables 34 was prepared in the same manner of Example 7-
20 by the
stirring granulation method.
[Table 35]
Example 7-21
(weight mg)
Compound represented by Formula (I)
40_0
D-Mannitol
540.0
Powdered Hydrogenated Maltose Starch Syrup
350.0
(Maltitol)
Sodium Chloride
30.0
Polyvinyl Pyrrolidone
10_0
Hypromellose
3.0
Sucralose
5.0
Light Anhydrous Silido Acid
20.0
Talc
1.0
Strawberry Flavor
1.0
Total
1000.0
B. Preparation of granules which are optimized for the preparation of an oral
suspension
Granules which are optimized for the preparation of an oral suspension have
been prepared. The
granulated powder was manufactured via a standard wet granulation process. The
detailed
composition of the granules for oral suspension is shown Table 1 and the
rationale for use of the
excipients is provided. The excipients and their amounts are known to be
suitable for the intended
paediatric populations from 0 to < 18 years of age. The granulae can easily be
reconstituted with
water. More specifically, 2 g granulae, which contain 40 mg of baloxavir
marboxil (nominal) can be
reconstituted with 20 mL water, which corresponds to a final concentration of
2 mg of the
compound /mL.
The detailed composition of the granules for oral suspension is shown Table
36.
Table 36: Components and Composition of Baloxavir marbox11 Granules for Oral
Suspension
Component Nominal Concentration
Function Quality Standard
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amount in Granule
(mg/bottle) (%)
Active
Baloxavir Marboxil 40 2
In-house standard
ingredient
Mannitol 1120 56
Diluent Ph. Eur./USP/JP
MaInto! 700 35
Diluent Ph. EuriNF/JPE
Taste
Sodium Chloride 60 3
masking Ph. Eur./USP/JP
agent
Hypromellose 6 0.3
Dispersant Ph. Eur./USP/JP
Povidone (K value: 25) 20 1
Binder Ph. Eur./USP/JP
Silica, Colloidal
40 2
Fluidizer Ph. EuriNF/JP
Anhydrous
Sucralose 10 0.5
Sweetener Ph. Eur./NF/JPE
Talc 2 0.1
Lubricant Ph. Eur./USP/JP
Strawberry Flavour 2 0.1
Flavour In-house standard
Purified Water a
Vehicle Ph. Eur./USP/JP
Total Weight' 2,000 100
a Purified water is removed during manufacturing process.
An overfill of, e.g. 0.13 g of granules is applied to obtain the targeted
maximum extractable
volume of 20 mL after reconstitution; fill weight may be adjusted based on
assay value for bulk
granules.
Bitter taste has been reported in adult clinical studies with baloxavir
marboxil and several
excipients have been included in the formulation to mask the bitter taste and
ensure palatability,
such as sodium chloride, sucralose and strawberry flavour. Thus, the granulae
provided herewith
have the advantages that they are to be administered in the form of an oral
suspension and that
the bitter taste of the active compound is masked. Accordingly, these granulae
improve
acceptance of the compound in paediatric patients, which contributes to the
achievement of the
therapeutic effect.
Example 7: Global phase Ill study investigating one-dose baloxavir marboxil
(XCIFLUZA) in children with the flu
Methods:
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miniSTONE-2 was a phase Ill, global multicenter, randomized, double-blind,
active-
controlled study in otherwise healthy paediatric patients with influenza,
conducted during
the 2018/19 season mainly in the US. The study evaluated the safety (primary
objective),
pharrnacokinetics (PK) and efficacy (secondary objective) of one-dose of
baloxavir
marboxil (granular formulation for suspension) in otherwise healthy children
aged 1 to less
than 12 years with influenza. More specifically, the effect of baloxavir
marboxil was
compared to the effect of oseltamivir. The influenza infection was confirmed
by a rapid
influenza diagnostic test and displaying influenza-like symptoms (a
temperature of 38 C or
over, and one or more respiratory symptoms).
Patients were randomized 2:1 to receive either a weight-based single oral dose
of
baloxavir marboxil or standard oral dose of oseltamivir (twice-daily dosing
for five days).
More specifically, participants enrolled in the study were recruited in
parallel into two
cohorts: patients aged five to less than 12 years and patients aged one to
less than 5
years. Patients in both cohorts were randomly assigned to receive one-dose of
baloxavir
marboxil (2mg/kg for patients under 20kg or 40mg for patients 20kg or over) or
oseltamivir
twice a day over five days (dosing according to body weight).
The primary endpoint was the proportion of patients with adverse events or
severe
adverse events up to study day 29. Secondary endpoints include
pharmacokinetics (PK),
time to alleviation of influenza signs and symptoms, and duration of symptoms,
including
fever and time to cessation of viral shedding by virus titer for virology.
Results in summary:
This study investigated the safety (primary objective), pharmacokinetics and
efficacy of a
single dose of baloxavir marboxil in otherwise healthy children aged 1 to < 12
years with
influenza. The study showed that baloxavir marboxil (XOFLUZA), given as a new
oral
suspension, is a well-tolerated and effective potential treatment for the flu
in otherwise
healthy children aged one to less than 12 years.
The obtained results can be summarized as follows.
= Baloxavir was well tolerated and no new safety signals were identified
0 no SAEs
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= No relevant differences in demographics or clinical baseline
characteristics
were noticed between baloxavir and oseltamivir groups
O median age 6 years; 53% female; 85% Caucasian; no relevant differences
observed between baloxavir and oseltamivir groups
= Pharmacokinetic data
0 initial 'lead in' PK indicated baloxavir exposure to be consistent with
adults
and adolescents
= Baloxavir showed comparable efficacy compared with oseltamivir in Time To
Alleviation of Influenza Signs and Symptoms (TASS) endpoint
O TASS uses cough, nasal symptoms, return to daycare/school/normal
activities (from parent/carer questionnaire) and fever
O TASS: baloxavir 138 hrs (CI 116.6, 163.2); oseltamivir 150 hrs (Cl 115.0,
165.7)
O TASS was an exploratory endpoint and did not undergo statistical testing.
The almost identical confidence intervals indicate comparable efficacy
between treatmennt
= Clear difference in Time To Cessation of Viral Shedding
0 There was a clear difference in the median Time to Cessation of Viral
Shedding between baloxavir (24 hrs) and Oseltarnivir (76 hrs); delta 56 hrs.
These data continue to suggest that baloxavir-treated patients are no longer
infective after a median time of 1 day compared to 3 days in oseltamivir-
treated patients. This may be of significance to the reduction of onward
transmission of influenza.
Results in detail:
The study assessed baloxavir marboxil versus an active comparator
(oseltamivir) in
children aged between one and less than 12 years with the flu.
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Of the 176 paediatric patients recruited, 124 formed the ITTi population
(baloxavir
marboxil, n=81 vs oseltamivir, n=43), 89.7% of which had an influenza A
infection (65.5%
H3N2, 24.1% H1N1). No SAEs, deaths or adverse events of special interest were
observed and the safety profile of baloxavir marboxil was consistent with that
observed in
clinical studies to date. The median time to alleviation of influenza signs
and symptoms
observed in the BXM group (138 hours [95% Cl; 116.6,163.2]) was comparable to
the
oseltamivir group (150 hours [95% CI; 115.0,165.7]). Consistent with previous
phase Ill
studies, there was a clear difference in the median time to cessation of viral
shedding
between baloxavir marboxil (24.2 hours 195% Cl; 23.5,24.6]) and oseltamivir
(75.8 hours
[95% Cl; 68.9,97.8]).
Thus, the phase III miniSTONE-2 study met its primary endpoint, demonstrating
that
baloxavir marboxil (XOFLUZA) is well-tolerated in children with the flu. As
described
above, the study also showed that baloxavir marboxil is comparable to
oseltamivir ¨ a
proven effective treatment for children with the flu ¨ at reducing the
duration of flu
symptoms, including fever.
Conclusion:
A single, oral dose of baloxavir marboxil was well tolerated and effective for
the treatment
of influenza in otherwise healthy paediatric patients aged between 1 and < 12
years. The
MINISTONE-2 study showed that baloxavir marboxil (XOFLUZA), given as a new
oral
suspension, is a well-tolerated and effective potential treatment for the flu
in otherwise
healthy children aged one to less than 12 years.
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The present invention refers to the following nucleotide and amino acid
sequences:
SEQ ID NO:1: Influenza A virus (ANVSN/1933(H1N1)): GenBank: X17336.1,
comprising the 1381
mutation. The I381 mutation is underlined and shown in bold face.
MEDFVRQCFN PMIVELAEKAMKEYGEDLKIETNKFAATCTHLEVCFMYSDFHFIDEQGESIVVELG
DPNALLKHRFEI I EGRDRTIAWIVI NSICNTTGAEKP KFLPD LYDYKKN RFI El GVTRREVHIYYLEKA
NKI KS EKTHI H IFS FTGEEMATKADYTLDEES RARI KTRLFTI RQEMASRGLWDSFRQSERGEETI E
ERFEITGTMRKLADQSLPPNFSSLENFRAYVDGFEPNGYIEGKLSQMSKEVNARIEPFLKSTPRPL
RLPDGPPCSQRSKFLLMDALKLSIEDPSHEGEGIPLYDAIKCMRTFFGWKEPNVVKPHEKGINPNY
LLSWKQVLAELQDI EN EEKI P RTKN MKKTSQ LKVVALGEN MAPEKVDFDDCKDVG DLKQYDSDEP
ELRSLASWIQNEFNKACELTDSSWIELDEIGEDAAPIEHIASMRRNYFTAEVSHCRATEYIMKGVY1
NTALLNASCAAMDDFQLIPMISKCRTKEGRRKTN LYGFI I KGRSH LRNDTDVVN FVSM EFSLTDPR
LEPHKVVEKYCVLEVG DMLLRSAI C HVS RPM FLYVRTNGTSKI KMKWGM EMRRCLLQSLQQ I ES MI
EAESSVKEKDMTKEFFENKSETWPVGESPKGVEEGSIGKVCRTLLAKSVFNSLYASPQLEGFSAE
SRKLLLIVQALRDNLEPGTFDLGGLYEAIEECLI NDPVVVLLNASWFNSFLTHALR
SEQ ID NO:2: Sequence fraction of the influenza A virus (ANVSN/1933(H1N1 )):
GenBank:
X17336.1, comprising the I38T mutation. The I38T mutation is underlined and
shown in bold face.
FAATCTH
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