Note: Descriptions are shown in the official language in which they were submitted.
WO 2012/011917 CA 02806362 2013-01-23PCT/US2010/043003
Administration of Rifalazil to Immunocompromised Patients
Field of the Invention
The invention is generally in the area of treating a bacterial infection or
disorder associated with a bacterial infection, in a patient being treated for
another
disorder with a drug which is metabolized by CYP450. The treatment involves
administering to the patient a therapeutically effective amount of a
composition
comprising rifalazil, 3'-hydroxy-5'-(4-
methylpiperazinyl)benzoxazinorifamycin), or
other rifalazil analogs that does not modulate CYP450. In particular, the
bacterial
infection may be caused by a bacteria with an active and inactive, latent
form, and the
rifalazil is administered in an amount and for a duration sufficient to treat
both the
active and the inactive, latent form of the bacterial infection, which
duration is longer
than is needed to treat the active form of the bacterial infection. One such
bacterial
infection is tuberculosis, and the treatment is particularly useful for
treating
tuberculosis patients who are immunocompromised.
Background of the Invention
There are a variety of disorders, including HIV, HCV, HBV, and cancer,
where the disorder and/or treatments for the disorder result in a patient that
is
immunocompromised. Many of these patients also suffer from tuberculosis
("TB"),
often as a result of having one or more of these disorders and being
immunocompromised.
Additionally, patients having pre-existent chronic liver disease can also
develop tuberculosis. Patients undergoing conventional treatment for
tuberculosis can
develop hepatotoxicity as an adverse reaction to the drugs, and/or can develop
fresh
liver diseases like acute viral hepatitis. Hepatic dysfunction can also alter
absorption
and distribution of drugs that are metabolized or excreted in the liver.
Accordingly,
the presence of co-existent hepatic disease, such as that caused by HCV and
HBV,
poses a significant challenge in the treatment of tuberculosis.
Rifampicin, pyrazinamide, isoniazid, ethionamide and PAS are all hepatotoxic
drugs. Slow acetylators of isoniazid are at a higher risk of hepatotoxicity.
The
hepatotoxic effects of rifampicin and isoniazide are believed to be additive,
whereas
the hepatic damage due to pyrazinamide is related to dose and duration.
Accordingly,
patients with liver disease and who are treated with these agents are at risk
of liver
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damage. If that were not bad enough, patients being treated for viral liver
diseases
such as HCV and HBV are at a higher risk, as several of these agents are not
only
hepatotoxic, they are also modulators (primarily inducers) of CYP450, which
adversely affects the metabolism of several anti-HCV and anti-HBV agents.
As an example, the ability of isoniazid (INH) to elevate the concentrations in
plasma and/or toxicity of co-administered drugs, including those of narrow
therapeutic range (e.g., phenytoin), has been well-documented in humans. Based
on
studies on the inhibitory effect of INH on the activity of common drug-
metabolizing
human cytochrome P450 (CYP450) isoforms, it has been determined that INH
potently inhibits CYP2C19 and CYP3A in a concentration-dependent manner (Desta
et al., "Inhibition of Cytochrome P450 (CYP450) Isoforms by Isoniazid: Potent
Inhibition of CYP2C19 and CYP3A," Antimicrob Agents Chemother., 45(2): 382-
392 (2001)).
Inhibition of one or both CYP2C19 and CYP3A isoforms is the likely
mechanism by which INH slows the elimination of certain co-administered drugs,
including phenytoin, carbamazepine, diazepam, triazolam, and primidone. Slow
acetylators of INH (i.e., patients with certain single nucleotide
polymorphisms of the
CYP450 gene) may be at greater risk for adverse drug interactions, as the
degree of
inhibition was concentration dependent.
Tuberculosis and HIV/AIDS
The World Health Organization has recently doubled its estimate of the
ravages tuberculosis (TB) is causing among HIV/AIDS patients. Over nine
million
people contracted TB in 2007, including around 1.4 million people with
HIV/AIDS.
More than one death in four of the 1.75 million tuberculosis deaths recorded
in 2007
is thought to involve an HIV/AIDS patient.
It has been estimated that one-third of the more than 40 million people living
with HIV/AIDS are also infected with tuberculosis. TB is the leading
infectious killer
of people with HIV/AIDS. TB-HIV co-infections are on the rise in sub-Saharan
Africa and other areas of the world, particularly Asia and Eastern Europe. In
2005, 2.7
million people were newly infected with HIV/AIDS. As long as HIV/AIDS
continues
to spread, TB will remain a constant and deadly threat.
It has been estimated that patients living with HIV have a twenty-fold
increase
in the risk of developing tuberculosis relative to HIV negative people. The
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combination of poor diagnosis, rising drug resistance, and the impact on
HIV/AIDS
patients has heightened alarm among health experts. Drug-resistant strains are
believed to have infected an estimated 500,000 people, of whom around 150,000
of
which die from the disease, according to the World Health Organization
("WHO").
Furthermore, around 10 percent of the drug resistant strains are almost
incurable
extra-resistant strains (XDR-TB), and these extra-resistant strains are now
found in at
least 55 countries.
It is difficult to treat HIV-infected patients, because of the patient's
immunologic status, the need for highly active antiretroviral therapy (HAART),
and
potential drug reactions.
Accordingly, there is an urgent need to find, prevent and treat tuberculosis
in
people living with HIV and to test for HIV in all patients with TB in order to
provide
prevention, treatment and care. However, there are severe shortcomings in
tackling
tuberculosis in HIV/AIDS patients.
Highly active anti-retroviral therapy (HAART) is today's most effective,
available treatment option for controlling the progression of HIV, the virus
that causes
AIDS. Unfortunately, drug-drug interactions between the current first-line TB
regimen and certain commonly used anti-retrovirals complicate treatment for co-
infected patients. Rifampin, a cornerstone of the current TB regimen, induces
the
enzyme cytochrome P450. Cytochrome P450 causes some AIDS drugs to be
metabolized too quickly, inhibiting effective HAART therapy. People with
HIV/AIDS who contract TB must sometimes change their HAART regimens to avoid
this dangerous interaction, or delay needed HAART treatment until their TB is
under
control.
Widely used antiretroviral drugs available in the United States include
protease inhibitors (saquinavir, indinavir, ritonavir, nelfinavir, invirase,
Norvir,
viracept, and agenerase) and nonnucleoside reverse transcriptase inhibitors
(NNRTIs)
(nevirapine, delavirdine, efavirenz, and virammune). Protease inhibitors and
NNRTIs
have substantive interactions with the rifamycins (rifampin, rifabutin, and
rifapentine)
used to treat mycobacterial infections. These drug interactions principally
result from
changes in the metabolism of the antiretroviral agents and the rifamycins
secondary to
induction or inhibition of the hepatic cytochrome CYP450 enzyme system.
Rifamycin-related CYP450 induction decreases the blood levels of drugs
metabolized
by CYP450. For example, if protease inhibitors are administered with rifampin
(a
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potent CYP450 inducer), blood concentrations of the protease inhibitors (all
of which
are metabolized by CYP450) decrease markedly, and most likely the
antiretroviral
activity of these agents declines as well. Conversely, if ritonavir (a potent
CYP450
inhibitor) is administered with rifabutin, blood concentrations of rifabutin
increase
markedly, and most likely rifabutin toxicity increases as well.
Of the available rifamycins, rifampin is the most potent CYP450 inducer;
rifabutin has substantially less activity as an inducer; and rifapentine, a
newer
rifamycin, has intermediate activity as an inducer. The four currently
approved
protease inhibitors and amprenavir (141W94, an investigational agent in Phase
III
clinical trials) are all, in differing degrees, inhibitors of CYP450. The rank
order of
the agents in terms of potency in inhibiting CYP450 is ritonavir (the most
potent);
amprenavir, indinavir, and nelfinavir (with approximately equal potencies);
and
saquinavir (the least potent). The three approved NNRTIs have diverse effects
on
CYP450: nevirapine is an inducer, delavirdine is an inhibitor, and efavirenz
is both an
inducer and an inhibitor.
In contrast to the protease inhibitors and the NNRTIs, the other class of
antiretroviral agents available, nucleoside reverse transcriptase inhibitors
(NRTIs)
(zidovudine, didanosine, zalcitabine, stavudine, and lamivudine) are not
metabolized
by CYP450. Rifampin (and to a lesser degree, rifabutin) increases the
glucuronidation
of zidovudine and thus slightly decreases the serum concentration of
zidovudine. The
effect of this interaction probably is not clinically important, and the
concurrent use of
NRTIs and rifamycins is not contraindicated.
Because current treatment regimens frequently include two NRTIs combined
with a potent protease inhibitor (or, as an alternative, combined with an
NNRTI), and
the protease inhibitors and NNRTIs are adversely affected by conventional anti-
TB
agents, the patients receiving dual treatment with these regimens are at risk
for
developing resistant mutations of HIV. Accordingly, the use of rifampin to
treat
active TB in a patient who is taking a protease inhibitor or an NNRTI is
always
contraindicated. Rifabutin is a less potent inducer of the CPY450 cytochrome
enzymes than rifampin, and, in modified doses, might not be associated with a
clinically significant reduction of protease inhibitors or nevirapine.
Rifapentine is not
recommended as a substitute for rifampin because its safety and effectiveness
have
not been established for treating patients with HIV-related TB.
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Efavirenz is one example of an anti-HIV agent that is incompatible with
conventional TB antibiotics. Efavirenz (brand names Sustiva and Stocrin) is a
non-
nucleoside reverse transcriptase inhibitor (NNRTI) and is used as part of
highly active
antiretroviral therapy (HAART) for the treatment of a human immunodeficiency
virus
(HIV) type 1. Efavirenz is also used in combination with other antiretroviral
agents
as part of an expanded postexposure prophylaxis regimen to reduce the risk of
HIV
infection in people exposed to a significant risk (e.g. needlestick injuries,
certain types
of unprotected sex etc.).
Cytochrome P450 2B6 (CYP2B6) is the main catalyst of efavirenz primary
and secondary metabolism. Accordingly, the administration of CYP450 inducers
to
treat TB has implications for HIV/AIDS therapy Ward et al., J Pharmacol Exp
Ther.;306(1):287-300 (2003).
TB treatment regimens that contain no rifamycins, for example, TB treatment
regimens consisting of streptomycin, isoniazid, have been proposed as an
alternative
for patients who take protease inhibitors or NNRTIs. However, these TB
regimens
have not been studied among patients with HIV infection.
In addition to the risk that conventional anti-TB agents are incompatible with
certain anti-HIV agents, resistance to antituberculosis drugs is an important
consideration for some HIV-infected persons with TB. According to the results
of a
study of TB cases reported to CDC from 1993 through 1996, the risk of drug-
resistant
TB was higher among persons with known HIV infection compared with others. HIV-
positive serostatus is a risk factor for resistance to at least isoniazid, for
both isoniazid
and rifampin resistance (multidrug-resistant (MDR} TB) and for rifampin
monoresistance (TB resistant to rifampin only). The use of rifabutin as
prophylaxis
for Mycobacterium avium complex may also be associated with the development of
rifamycin resistance.
New TB drugs, developed to avoid interactions with anti-retroviral agents, are
essential to treat the growing number of people dually infected with TB and
HIV.
HCV and Tuberculosis
Estimates by the Centers for Disease Control and Prevention indicate that
1.8% of the U.S. population (approximately 4 million Americans) is currently
infected
with HCV. The current standard of therapy for hepatitis C is a combination of
ribavirin and interferon alfa-2b, but this treatment results in a number of
side effects.
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A number of patients infected with hepatitis C virus (HCV) are also co-
infected with
TB, and HCV treatment is typically not recommended while taking medications
for
TB. One reason is that anti-infectives used to treat TB can be hard on the
liver, and
anti-infectives used to treat HCV can cause liver failure. In combination, the
risk of
liver damage is higher.
To further complicate matters, if a patient's liver enzymes increase, which is
a
sign of liver damage, a treating physician might not be able to determine
whether the
liver damage was due to the treatment for HCV, TB, or both. Further, some
treatments for HCV result in immunosuppression, making it more difficult to
treat TB.
As mentioned above with respect to HIV, some anti-TB drugs, such as
rifampicin,
rifabutin, and isoniazid, up-regulate the cytochrome P450 function, causing an
increase in the metabolism of immunosuppressants and (in this case, serine)
protease
inhibitors, thus decreasing their levels in the blood, and, subsequently,
decreasing the
efficacy of the anti-HCV therapy.
Accordingly, there remains a need for effective anti-TB therapy that does not
adversely impact anti-HCV treatments.
HBV and Tuberculosis
Therapy is currently recommended for patients with evidence of chronic active
hepatitis B (HBV) disease (i.e, high aminotransferase levels, positive HBV DNA
findings, HBeAg). In general, for the HBeAg-positive patient population that
is
identified with evidence of chronic hepatitis B virus (HBV) disease, treatment
is
advised to be administered when the HBV DNA level is >20,000 IU/mL (105
copies/mL) and when serum ALT is elevated for 3-6 months.
Elevated hepatitis B (as well as hepatitis C) viral load is believed to
predispose
tuberculosis patients to both drug- and virus-induced hepatotoxicity during
anti-
tuberculosis treatments. Further, as with the treatment of HIV, HBV infections
are
commonly treated with nucleoside and non-nucleoside reverse transcriptase
inhibitors
(NRTIs and NNRTIs) and protease inhibitors (PIs), and both PIs and NNRTIs are
metabolized by CYP450.
Currently, interferon alfa (IFN-a) and pegylated versions thereof, lamivudine,
telbivudine, adefovir, adefovir dipivoxil, entecavir, and tenofovir are the
main
treatment drugs approved globally for treating HBV.
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The effectiveness of these therapies is dependent on normal metabolism of
these agents. Accordingly, treatment of TB infection with conventional anti-TB
therapeutics that also function as CYP450 inducers can result in heptatoxicity
while
treating the infection, and also reduce the efficacy of the anti-HBV
therapeutics
and/or result in even higher incidences of side effects.
Accordingly, there remains a need for effective anti-TB therapy that does not
adversely impact anti-HBV treatments.
Cancer and Tuberculosis
Patients with cancer are immunocompromised. Because of the cancer and the
cancer treatment, the immune system does not function normally, which
decreases its
ability to fight off infection and disease. Patients with latent, or inactive,
TB, are at
risk for active TB.
Further, there is an association between lung cancer and TB. The incidence of
tuberculous lesions in autopsies unassociated with tumor is around 7%, as
compared
to around 25 % incidence of association with carcinoma; which is significant.
(Dacosta and Kinare, Association of lung carcinoma and tuberculosis, J
Postgrad Med,
37:185 (1991)). Often, lung cancer is diagnosed long after a patient has been
infected
with tuberculosis, and a patient must be treated for both diseases.
The association of tuberculosis and cancer has been recorded in most of the
organs. Pandey et al., "Tuberculosis and metastatic carcinoma coexistence in
axillary
lymph node: A case report," World Journal of Surgical Oncology, Volume 1:1-3
(2003)). In one review, 58,245 cancer patients with cancer were evaluated, and
201
cases of coexisting tuberculosis were identified (Kaplan et al., "Tuberculosis
complicating neoplastic disease. A review of 201 cases," Cancer. 33(3):850-858
(1974)). The highest prevalence was seen in patients with Hodgkin's disease
(96/10,000 cases) followed by lung cancer (92/10,000), lymphosarcoma
(88/10,000)
and reticulum cell sarcoma (78/10,000). These rates are approximately 1% of
all
patients, which is a significant correlation.
Patients with hematologic malignancies (leukemias and lymphomas, such as
Hogkin's lymphoma) are at increased risk of developing tuberculosis, because
of the
T-cell immunodeficiency associated with the disease and/or its treatment. For
example, in a study of 917 patients observed between 1990 and 2000, 24 cases
of
tuberculosis (2.6% of patients) were found, and the mortality of the patients
was
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around 70% (Silva et al., "Risk factors for and attributable mortality from
tuberculosis
in patients with hematologic malignances," Haematologica; 90:1110-1115
(2005)).
Patients at risk include those with
Non-Hodgkin's lymphoma, Hodgkin's disease, multiple myeloma, acute myeloid
leukemia, acute lymphoid leukemia, chronic lymphoid leukemia, myelodysplasia,
and
chronic myeloid leukemia.
Cancer patients with TB are difficult to treat, as conventional TB treatments
can alter CYP450 metabolism of anti-cancer agents. This alteration of CYP450
metabolism is detrimental for several reasons.
When treating cancer, there is frequently a narrow window between drug
toxicity and suboptimal therapy, and inter-individual variation in drug
metabolism
complicates therapy. Genetic polymorphisms in enzymes such as those in the
cytochrome P450 superfamily are at least partially responsible for the
observed inter-
individual variation in pharmacokinetics and pharmacodynamics of anticancer
drugs.
For example, there is potential clinically relevant application of CYP450
pharmacogenetics for anticancer therapy, for example, between CYP1A2 and
flutamide, CYP2A6 and tegafur, CYP2B6 and cyclophosphamide, CYP2C8 and
paclitaxel, CYP2D6 and tamoxifen, and CYP3A5 (van Schaik, "Cancer treatment
and
pharmacogenetics of cytochrome P450 enzymes," Journal Investigational New
Drugs
(Springer Netherlands), 23(6): 513-522 (December, 2005), the contents of which
are
hereby incorporated by reference). In addition to genetic polymorphisms, drugs
which modulate CYP450 also have an impact on chemotherapy.
Further, chemical entities which induce cytochrome P450 may be further
undesirable, since P450 induction is linked to tumor formation which may
further
compromise the cancer patient.
Accordingly, there remains a need for effective anti-TB therapy that does not
adversely impact cancer treatments.
Patients with Liver Disease
Frequently, patients having pre-existent chronic liver disease also develop
tuberculosis. Additionally, patients undergoing treatment for tuberculosis may
develop hepatotoxicity as an adverse reaction to the drugs, and/or can develop
fresh
liver diseases like acute viral hepatitis. Hepatic dysfunction can also alter
absorption
and distribution of drugs that are metabolized or excreted in the liver.
Accordingly,
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the presence of co-existent hepatic disease, such as that caused by HCV and
HBV,
poses a challenge in the treatment of tuberculosis.
Rifampicin, pyrazinamide, isoniazid, ethionamide and PAS are all hepatotoxic
drugs. Slow acetylators of isoniazid are at a higher risk of hepatotoxicity.
The
hepatotoxic effects of rifampicin and isoniazide are believed to be additive,
whereas
the hepatic damage due to pyrazinamide is related to dose and duration.
Accordingly,
patients with liver disease and who are treated with these agents are at risk
of liver
damage. If that were not bad enough, patients being treated for viral liver
diseases
such as HCV and HBV are at a higher risk, as several of these agents are not
only
hepatotoxic, they are also modulators (primarily inducers) of CYP450, which
adversely affects the metabolism of several anti-HCV and anti-HBV agents.
Summary of the Invention
In its broadest sense, the invention is directed to a method for treating
bacterial
infections is patients who are also being treated for a disorder other than
the bacterial
infection using agents that are metabolized by CYP450. The bacterial infection
is
treated with rifalazil or a rifalazil analog that is not a CYP450 modulator,
so that the
antibacterial treatment does not adversely interfere with the other treatments
that the
patient is undergoing. In this case, rifalazil is quite different than
rifampicin and
rifabutin, which are modulators of CYP450, and which can be contraindicated
for
patients taking medications that are metabolized by CYP450.
Compositions and methods for treating tuberculosis ("TB") patients, in
particular, immunocompromised patients, are also disclosed. The compositions
include rifalazil, derivatives of rifalazil in which the sec-butyl group on
the piperidine
ring is replaced with methyl (i.e., 3'-hydroxy-5'-(4-
methylpiperazinyl)benzoxazinorifamycin), and other rifamycin analogs that do
not
incude CYP450. The compositions optionally include other antimicrobial agents
that
do not induce CYP450, particularly the CYP3A4 and CYP2C9 isoforms.
The compositions can be used to treat tuberculosis in patients suffering from
cancer, and/or from infection from one or more of HIV, HBV, and HCV.
Accordingly, in one embodiment, the compositions include a combination of
rifalazil
and one or more anticancer, anti-HIV, anti-HBV, and/or anti-HCV agents. In
another
embodiment, the compositions are administered in alternation with therapy for
cancer,
HIV, HBV, and/or HCV.
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In one embodiment, the methods involve administering to a patient suffering
from cancer and from a concomitant TB infection one or more anti-cancer
compounds
that would be detrimental, or suffer from decreased or lack of efficacy, if an
inducer
or other modulator of CYP450 (cytochrome P450) were administered. The method
further involves administering a composition comprising rifalazil or a
derivative
thereof to treat the TB infection, alone or in combination with another
antimicrobial
agent. The administration of rifalazil is continued until such time as the TB
infection
is effectively treated.
Representative anti-cancer agents that are metabolized by CYP450 include,
but are not limited to, cyclophosphamide, docetaxel, doxorubicin, etoposide,
ifosfamide, paclitaxel, tamoxifen, anastrazole, teniposide, vinblastine,
vindesine, and
gefitinib.
In a second embodiment, the methods involve administering to a patient
suffering from HIV and from a concomitant TB infection one or more anti-cancer
compounds that would be detrimental, or suffer from decreased or lack of
efficacy, if
an inducer or other modulator of CYP450 (cytochrome P450) were administered.
The
method further involves administering a composition comprising rifalazil to
treat the
TB infection, alone or in combination with another antimicrobial agent. The
administration of rifalazil is continued until such time as the TB infection
is
effectively treated.
Representative anti-HIV agents that are metabolized by CYP450 include, but
are not limited to, non-nucleoside reverse transcriptase inhibitors and
protease
inhibitors.
In a third embodiment, the methods involve administering to a patient
suffering from HBV and from a concomitant TB infection one or more anti-cancer
compounds that would be detrimental, or suffer from decreased or lack of
efficacy, if
an inducer or other modulator of CYP450 (cytochrome P450) were administered.
The
method further involves administering a composition comprising rifalazil to
treat the
TB infection, alone or in combination with another antimicrobial agent. The
administration of rifalazil is continued until such time as the TB infection
is
effectively treated.
Representative anti-HBV agents that are metabolized by CYP450 include, but
are not limited to, protease inhibitors and NNRTI.
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In a fourth embodiment, the methods involve administering to a patient
suffering from HCV and from a concomitant TB infection one or more anti-cancer
compounds that would be detrimental, or suffer from decreased or lack of
efficacy, if
an inducer or other modulator of CYP450 (cytochrome P450) is administered. The
method further involves administering a composition comprising rifalazil to
treat the
TB infection, alone or in combination with another antimicrobial agent. The
administration of rifalazil is continued until such time as the TB infection
is
effectively treated.
Representative anti-HCV agents that are metabolized by CYP450 include, but
are not limited to, a combination of Pegylated interferon (Pegasys) and
ribavirin,
polymerase inhibitors such as IDX-375 and IDX-184 (Idenix), PSI-7851 and PSI-
7977 (Pharmas s et) danoprevir (InterMune/Genentech), RG7128
(Pharmas s et/Genentech) , I ANA598 (Anadys Pharmaceuticals), TMN- 191
(R7227),
combinations of RG7128 and RG7227 (Genentech, Pharmas set and Intermune), ABT-
072 (Abbott), VX-916, VX-759, VX-222, and VX-500 (Vertex), Filibuvir (PF-
00868554) (Pfizer), GS 9190 (Gilead), alone or with boosters such as
ritonavir, and
serine protease inhibitors such as Boceprevir (SCH 503034) (Schering Plough),
BILN-2061, Telaprevir (Vertex), ACH-1625 (Achillion), GS-9256 (Gilead), BI
201335 (Boehringer Ingelheim Pharma), Vaniprevir (MK-7009) (Merck),
SCH900518 (Narlaprevir) (Schering / Merck), TMC435 (Medivir/Tibotec).
Additional examples of serine protease inhibitors are provided, for example,
in Reiser
and Timm, "Serine protease inhibitors as anti-hepatitis C virus agents,"
Expert
Review of Anti-infective Therapy, 7(5):537-547 (June 2009), the contents of
which
are hereby incorporated by reference.
Rifalazil and the rifalazil derivatives described herein are not inducers of
cytochrome P450, and in this respect, they differ significantly from other
rifamycin
derivatives such as rifampicin and rifabutin.
The rifalazil and/or rifalazil derivatives can be administered in conjunction,
or
in alternation, with other anti-TB compounds, such as pyrazinamide, isoniazid,
ethionamide and PAS. Ideally, due to the co-administration of rifalazil and/or
rifalazil
derivatives, the dosage of these agents can be decreased, which can result in
lower
incidences of side effects. Additionally, the co-administration of rifalazil
and/or
rifalazil derivatives can reduce the duration of treatment.
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In another embodiment, a patient suffering from a bacterial infection caused
by a bacteria with an active form as well as an inactive, latent form, and who
is also
being treated for another disorder with an agent that is metabolized by
CYP450, is
treated for the bacterial infection by administering rifalazil or a rifalazil
analog that
does not modulate CYP450. Ideally, the rifalazil or a rifalazil analog is
administered
for a longer period of time than would be required to treat the active
bacteria, so that it
can accumulate in the patient's cells, and the drug's persistence will enable
it to be
present to treat the latent form of the bacteria, when it transitions into the
active form.
In this manner, one can prevent a relapse of a bacterial infection.
The present invention will be better understood with reference to the
following
detailed description.
Detailed Description
The invention described herein relates to the discovery that rifalazil, and
certain rifalazil derivatives, administered alone or in combination with one
or more
additional antibiotics suitable for treating tuberculosis (TB) infections and
which do
not modulate, for example, do not induce CYP450, can be effective to treat a
subject
suffering from tuberculosis, which patient is also administered one or more
active
agents which are metabolized by CYP450 in the treatment of another disorder.
Examples of such other disorders include, but are not limited to, cancer, HIV,
HBV,
HCV, and liver disorders.
The use of anti-tuberculosis agents which do not induce or otherwise modulate
CYP450 can be useful for patients who might otherwise have to put therapies
for
treating other disorders on hold until the tuberculosis treatment is
completed.
The present invention will be better understood with reference to the
following
detailed description, and with respect to the following definitions.
Definitions
The term "an effective amount" refers to the amount of rifalazil, alone or in
combination with one or more additional antibiotics, needed to eradicate
tuberculosis
or other bacterial infection from the subject, or to prevent an infection of
tuberculosis
or other bacterial infection, as determined by a diagnostic test that detects
tuberculosis
or other infection.
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Disorders commonly treated with rifampicin and rifabutin include
Mycobacterium infections, including tuberculosis and leprosy, as well as
inactive
meningitis. These agents are typically administered in conjunction with
isoniazid,
ethambutol, pyrazinamide and/or streptomycin. When used to treat TB, these
agents
are commonly administered daily for several months without a break in
treatment, to
minimize the risk of drug-resistant tuberculosis is greatly increased. Drug
resistance is
one of the main reasons that rifabutin is administered in tandem with the
three
aforementioned drugs, particularly isoniazid.
When used to treat leprosy, rifampicin is typically used in combination with
dapsone and clofazimine to avoid eliciting drug resistance.
Rifampicin has also been used to treat methicillin-resistant Staphylococcus
aureus (MRSA) in combination with fusidic acid, and in prophylactic therapy
against
Neisseria meningitidis (meningococcal) infection. It is also used to treat
infection by
Listeria species, Neisseria gonorrhoeae, Haemophilus influenzae and Legionella
pneumophila.
Rifampicin is an effective liver enzyme-inducer, promoting the upregulation
of hepatic cytochrome P450 enzymes (such as CYP2C9 and CYP3A4), increasing the
rate of metabolism of many other drugs that are cleared by the liver through
these
enzymes. As a consequence, rifampicin can cause a range of adverse reactions
when
taken concurrently with other drugs. For instance, patients undergoing long
term
anticoagulation therapy with warfarin have to be especially cautious and
increase their
dosage of warfarin accordingly. Failure to do so could lead to under-treating
with
anticoagulation resulting in serious consequences of thromboembolism.
Rifabutin is now recommended as first-line treatment for tuberculosis.
Rifampicin is
more widely used because of its cheaper cost.
Rifabutin is used to treat mycobacterium avium complex disease, a bacterial
infection most commonly encountered in late-stage AIDS patients. Rifabutin is
also
used in trials for treating Crohn's Disease as part of the anti-MAP therapy.
Its main
usefulness lies in the fact that it has lesser drug interactions than
rifampicin. It has
also found to be useful in the treatment of (Chlamydia) pneumoniae (Cpn)
Infection.
An "effective amount" of rifalazil or rifalazil derivatives, alone or in
combination with one or more additional antibiotics that do not induce or
otherwise
modulate CYP450, in particular, the CYP3A4 and CYP2C9 isoforms.
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WO 2012/011917 CA 02806362 2013-01-23 PCT/US2010/043003
As used herein, tuberculosis is a disorder caused by mycobacterium
tuberculosis, but the compositions and methods described herein can also be
used to
treat mycobacterial non-tuberculosis, and mycobacterium para-tuberculosis, as
well as
other disorders caused by these bacteria.
Chlamydia trachomatis is a bacteria, and methods for treating the bacterial
infection are described. Chlamydia trachomatis, and other Chlamydial
infections, are
also known to cause various disorders. For example, Chlamydia trachomatis can
cause urogenital infections, trachoma, conjunctivitis, pneumonia and
lymphogranuloma venereum (LGV). Chlamydophila pneumoniae can cause
bronchitis, sinusitis, pneumonia and atherosclerosis, and Chlamydophila
psittaci can
cause pneumonia (psittacosis). The treatment of the infections, as well as the
underlying disorders, is within the scope of the invention described herein.
I. Rifalazil
As used herein, "Rifalazil" refers to 3'-hydroxy-5'-(4-isobuty1-1-piperazinyl)
benzoxazinorifamycin, also known as KRM-1648 or ABI1648. Methods of making
rifalazil and microgranulated formulations thereof are described in U.S. Pat.
Nos.
4,983,602 and 5,547,683, respectively. The invention as previously discussed
contemplates the use of Rifalazil derivatives that are similar or superior in
therapeutic
effect to Rifalazil, for example, 3'-hydroxy-5'-(4-
methylpiperazinyl)benzoxazinorifamycin.
Rifalazil is a synthetic antibiotic designed to modify the parent compound,
rifamycin. Compared to other antibiotics in the rifamycin class, it has
extremely high
antibacterial activity. However, while it has a broad spectrum of
antibacterial action
covering Gram-positive and Gram-negative organisms, both aerobes and
anaerobes, it
is not an inducer of CYP450, like rifabutin and rifampicin.
II. Rifalazil Analogs
There are a variety of rifalazil analogs that can be used in addition to or in
place of rifalazil. Principal among these is 3'-hydroxy-5'-(4-
methylpiperazinyl)benzoxazinorifamycin. Other rifalazil analogs include those
described in U.S. Patent No. 7,078,399, U.S. Patent No. 7,342,011, U.S. Patent
No.
7,220,738, U.S. Patent No. 7,271,165, U.S. Patent No. 7,488,726, U.S. Patent
No.
7,547,692, and U.S. Patent No. 11/638738, the contents of each of which are
hereby
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WO 2012/011917 CA 02806362 2013-01-23PCT/US2010/043003
incorporated by reference. Those rifalazil derivatives in these patents and
pending
applications that induce CYP450, such as the CYP3A4 and CYP2C9 isoforms, can
be
identified using no more than routine experimentation using routine assays.
One such
assay is described in Burczynski et al., "Cytochrome P450 Induction in Rat
Hepatocytes Assessed by Quantitative Real-Time Reverse-Transcription
Polymerase
Chain Reaction and the RNA Invasive Cleavage Assay," DMD 29(9): 1243-1250
(September 1, 2001).
III. Pharmaceutical Compositions
The pharmaceutical compositions described herein include rifalazil, and,
optionally, one or more other anti-TB agents that do not induce or otherwise
modulate
CYP450. The compositions can also include, or be administered in combination
or
alternation with, agents useful for treating the patient for cancer, HIV, HBV,
HCV,
liver disease, and the like.
Rifalazil Formulations
The rifalazil used in the invention described herein can be in any suitable
form
that provides suitable bioavailability. Acceptable forms include
microgranulated
crystals, and combinations of rifalazil with micelle-forming surfactants, and,
optionally, lipophilic antioxidants. Such formulations are described, for
example, in
U.S. Serial No. 10/950,917 and 11/784,051, the contents of which are hereby
incorporated by reference in their entireties.
The formulations in U.S. Serial No. 10/950,917 generally fall within the
following description. The pharmaceutical compositions are intended for oral
administration in unit dosage form, and include rifalazil and an amount of
micelle-
forming excipient sufficient to produce, upon administration to fasted
patients, a
coefficient of variation in Cmax of less than 60%, a coefficient of variation
in
AUCinfinity of less than 40%, and/or a mean bioavailability of greater than
30%. The
composition can be in the form of a liquid-filled capsule, which capsule
includes
rifalazil and a micelle-forming excipient.
Examples of micelle-forming excipients include, but are not limited to,
polyethoxylated fatty acids, PEG-fatty acid diesters, PEG-fatty acid mono-
ester and
di-ester mixtures, polyethylene glycol glycerol fatty acid esters, alcohol-oil
transesterification products, polyglycerized fatty acids, propylene glycol
fatty acid
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WO 2012/011917 CA 02806362 2013-01-23PCT/US2010/043003
esters, mixtures of propylene glycol esters-glycerol esters, mono- and
diglycerides,
sterol and sterol derivatives, polyethylene glycol sorbitan fatty acid esters,
polyethylene glycol alkyl ethers, sugar esters, polyethylene glycol alkyl
phenols,
sorbitan fatty acid esters, lower alcohol fatty acid esters, and ionic
surfactants.
The micelle-forming excipients can also be selected from sodium lauryl
sulfate, polyoxy1-40 stearate, PEG-3 castor oil, PEG-5, 9, and 16 castor oil,
PEG-20
castor oil, PEG-23 castor oil, PEG-30 castor oil, PEG-35 castor oil, PEG-38
castor oil,
PEG-40 castor oil, PEG-50 castor oil, PEG-60 castor oil, PEG-100 castor oil,
PEG-
200 castor oil, PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castor oil,
PEG-
hydrogenated castor oil, PEG-20 hydrogenated castor oil, PEG-25 hydrogenated
castor oil, PEG-30 hydrogenated castor oil, PEG-40 hydrogenated castor oil,
PEG-45
hydrogenated castor oil, PEG-50 hydrogenated castor oil, PEG-60 hydrogenated
castor oil, PEG-80 hydrogenated castor oil, and PEG-100 hydrogenated castor
oil.
PEG-35 castor oil can be preferred.
The capsules can also include a hydrophilic polymer, such as PEG 300, PEG
400, and PEG 600, and a gelling agent, such as a polyoxyethylene-
polyoxypropylene
block copolymer. The capsules can also include between 0.5% and 10% (w/w)
water,
and, optionally, a liquid that is 65% to 85% (w/w) PEG-35 castor oil, 8% to
25% PEG
400, 4% to 6% (w/w) water, and 0.2% to 1.5% Pluronic F68. The capsules can be
hard capsules or soft capsules.
The pharmaceutical compositions typically include between around 0.1 and
around 100 mg of rifalazil, for example, between 0.1 and 25 mg of rifalazil,
and can
include, for example, between about 20% and about 90% (w/w) micelle-forming
excipient.
The formulations described in U.S. Serial No. 11/784,051 are also intended for
oral administration in unit dosage form, and also include rifalazil and one or
more
surfactants. They also include a lipophilic antioxidant. The surfactants are
typically
from about 20% to about 99% (w/w) of the composition, for example, between 75%
to 95% (w/w) of the composition. Examplary lipophilic antioxidants include
carotenoids, tocopherols and esters thereof, tocotrienols and esters thereof,
retinol and
esters thereof, ascorbyl esters, butylhydroxyanisole (BHA),
butylhydroxytoluene
(BHT), propyl gallate, and mixtures thereof. The lipophilic antioxidant can be
an
antioxidant surfactant, for example, retinyl palmitate, ascorbyl palmitate, or
tocopheryl- PEG- 1000- succinate.
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The pharmaceutical composition can include from 1 to 50 % (w/w) of a first
lipophilic antioxidant selected from retinol, retinyl palmitate, ascorbyl
palmitate,
tocopherol, tocotrienol and tocopheryl-PEG-1000-succinate and less than 0.1%
(w/w)
of a second lipophilic antioxidant selected from tocopherol, tocopherol
acetate,
tocopherol nicotinoate, tocopherol succinate, tocotrienol, tocotrienol
acetate,
tocotrienol nicotinoate, tocotrienol succinate, carotenoids, BHT, BHA, and
propylgallate. The composition can also include from 1 to 20 % (w/w) of said
first
lipophilic antioxidant, and can also include a hydrophilic co-solvent selected
from
alcohols, polyethylene glycols, and mixtures thereof, such as ethanol,
propylene
glycol, glycerol, and mixtures thereof. One type of hydrophilic co-solvent is
a
polyethylene glycol with a molecular weight of between 200 and 10,000 Da. The
compositions can also include PEG-35 castor oil.
One representative formulation includes from 0.2 to 2.5% (w/w) rifalazil, from
75 to 85% (w/w) PEG-35 castor oil, from 0.5 to 1.5% (w/w) pluronic F68, from 8
to
15% PEG-400, from 1.5 to 2.5% (w/w) ascorbyl palmitate, from 0.01 to 0.05%
(w/w)
BHT, and from 1.5 to 2.5% (w/w) water.
In one embodiment, the compositions include PEG-35 castor oil, PEG-8
caprylic/capric glycerides, and PEG-6 apricot kernel oil, and in one aspect of
this
embodiment, the composition includes from 0.2 to 2.5% (w/w) rifalazil, from 22
to
28% (w/w) PEG-35 castor oil, from 45 to 50% (w/w) PEG-6 apricot kernel oil,
from
20 to 25% PEG-8 caprylic/capric glycerides, from 1.5 to 2.5% (w/w) ascorbyl
palmitate, and from 0.01 to 0.05% (w/w) BHT.
Ideally, in both formulations (i.e., with and without the lipophilic
antioxidant),
the solubility of the rifalazil or rifalazil derivative in the one or more
surfactants is
greater than 16 mg/mL, for example, greater than 20 mg/mL.
In one embodiment, the pharmaceutical compositions include between 0.1 and
100 mg of rifalazil, more particularly between 1 and 30 mg of rifalazil.
The presence of the lipophilic antioxidant can be useful in inhibiting the
conversion of rifalazil to rifalazil N-oxide.
Various salt forms of Rifalazil also can be used in the broad practice of the
present invention.
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Ideally, the rifalazil is administered in a composition that is administered
orally, but the rifalazil can alternatively be administered parenterally, for
example,
intraveneously.
The dosage of Rifalazil in various specific embodiments can range from about
0.01 to 1000 mg., although any specific dosage that is advantageous in a given
application can be employed. The dosage of Rifalazil in various emobodiments
can be
any suitable amount, e.g., about 1 to 1000 mg (desirably about 1 to 100 mg,
more
desirably about 1 to 50 mg, and even more desirably about 1 to 25 mg). The
Rifalazil
may be given daily (e.g., once, or twice daily) or less frequently (e.g., once
every
other day, once or twice weekly, or twice monthly), or in any other dosing
regimen
that provides therapeutic benefit. The administration of rifalazil can be by
any suitable
means that results in an effective amount of the compound reaching the target
region.
The compound may be contained in any appropriate amount in any suitable
carrier substance, and is generally present in an amount of 1-95% by weight of
the
total weight of the composition. In one embodiment, the composition is
provided in a
dosage form that is suitable for oral administration, e.g., a tablet, capsule,
pill, powder,
granulate, suspension, emulsion, solution, or gel.
The pharmaceutical composition can generally be formulated according to
conventional pharmaceutical practice (see, e.g., Remington: The Science and
Practice
of Pharmacy (20th ed.), ed. A. R. Gennaro, 2000, Lippincott Williams &
Wilkins,
Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick
and
J. C. Boylan, 1988-1999, Marcel Dekker, N.Y.).
The pharmaceutical compositions used to deliver the rifalazil can be
formulated to release rifalazil at a predetermined time period, or set of
criteria (i.e.,
upon reaching a certain pH).
Solid Dosage Forms for Oral Use
Formulations for oral use include tablets containing the active ingredient(s)
in
a mixture with non-toxic pharmaceutically acceptable excipients. These
excipients
may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol,
sugar, mannitol,
microcrystalline cellulose, starches including potato starch, calcium
carbonate,
sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium
phosphate);
granulating and disintegrating agents (e.g., cellulose derivatives including
microcrystalline cellulose, starches including potato starch, croscarmellose
sodium,
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WO 2012/011917 CA 02806362 2013-01-23PCT/US2010/043003
alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol,
acacia,
alginic acid, sodium alginate, gelatin, starch, pregelatinized starch,
microcrystalline
cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium,
methylcellulose, hydroxypropyl methylcellulose, ethylcellulose,
polyvinylpyrrolidone,
or polyethylene glycol); and lubricating agents, glidants, and antiadhesives
(e.g.,
magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated
vegetable oils, or
talc). Other pharmaceutically acceptable excipients can be colorants,
flavoring agents,
plasticizers, humectants, buffering agents, and the like.
The tablets may be uncoated or they may be coated by known techniques,
preferably to delay disintegration and absorption in the gastrointestinal
tract until the
tablets reach the colon. The coating can be adapted to not release the
rifalazil until
after passage through the stomach, for example, by using an enteric coating
(e.g., a
pH-sensitive enteric polymer).
The coating may be a sugar coating, a film coating (e.g., based on
hydroxypropyl methylcellulose, methylcellulose, methyl hydroxyethylcellulose,
hydroxypropylcellulose, carboxymethylcellulose, acrylate copolymers,
polyethylene
glycols and/or polyvinylpyrrolidone), or a coating based on methacrylic acid
copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose
phthalate,
hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate,
shellac,
and/or ethylcellulose. Furthermore, a time delay material such as, for
example,
glyceryl monostearate or glyceryl distearate, may be employed.
The solid tablet compositions may include a coating adapted to protect the
composition from unwanted chemical changes (e.g., chemical degradation prior
to the
release of the active drug substance). The coating may be applied on the solid
dosage
form in a similar manner as that described in Encyclopedia of Pharmaceutical
Technology.
Formulations for oral use may also be presented as hard gelatin capsules
wherein the active ingredient is mixed with an inert solid diluent (e.g.,
potato starch,
lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or
kaolin).
Powders and granulates may be prepared using the ingredients mentioned above
under tablets and capsules in a conventional manner using, e.g., a mixer, a
fluid bed
apparatus or a spray drying equipment.
Controlled Release Oral Dosage Forms
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Controlled release compositions for oral use may be constructed to release the
active drug by controlling the dissolution and/or the diffusion of the active
drug
substance.
Any of a number of strategies can be pursued in order to obtain controlled
release in which the rate of release outweighs the rate of metabolism of the
compound
in question. In one example, controlled release is obtained by appropriate
selection of
various formulation parameters and ingredients, including, e.g., various types
of
controlled release compositions and coatings. Thus, the drug is formulated
with
appropriate excipients into a pharmaceutical composition that, upon
administration,
releases the drug in a controlled manner. Examples include single or multiple
unit
tablet or capsule compositions, oil solutions, suspensions, emulsions,
microcapsules,
micro spheres , nanoparticles, patches, and liposomes.
Dissolution or diffusion controlled release can be achieved by appropriate
coating of a tablet, capsule, pellet, or granulate formulation of compounds,
or by
incorporating the compound into an appropriate matrix. A controlled release
coating
may include one or more of the coating substances mentioned above and/or,
e.g.,
shellac, beeswax, glycowax, castor wax, camauba wax, stearyl alcohol, glyceryl
monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose,
acrylic
resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride,
polyvinyl
acetate, vinyl pyrrolidone, polyethylene, polymethacrylate,
methylmethacrylate, 2-
hydroxymethacrylate, methacrylate hydrogels, 1,3 butylene glycol, ethylene
glycol
methacrylate, and/or polyethylene glycols. In a controlled release matrix
formulation,
the matrix material may also include, e.g., hydrated metylcellulose, carnauba
wax and
stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-
methyl
inethacrylate, polyvinyl chloride, polyethylene, and/or halogenated
fluorocarbon.
Combination or Alternation Therapy
In addition, the rifalazil or rifalazil derivative described herein can be
administered in combination or alternation with one or more anti-retrovirus,
anti-HBV,
interferon, anti-cancer or antibacterial agents, including but not limited to
other
compounds of the present invention.
For example, when used to treat or prevent tuberculosis infection in an HIV,
HBV, or HCV-positive patient, the rifalazil, rifalazil derivative, or
pharmaceutically
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WO 2012/011917 CA 02806362 2013-01-23PCT/US2010/043003
acceptable salt can be administered in combination or alternation with an
antiviral
agent, such as anti-HIV, anti-HBV, or anti-HCV agent, including, but not
limited to,
those of the formulae below.
In general, in combination therapy, effective dosages of two or more agents
are
administered together, whereas during alternation therapy, an effective dosage
of each
agent is administered serially. The dosage will depend on absorption,
inactivation and
excretion rates of the drug, as well as other factors known to those of skill
in the art. It
is to be noted that dosage values will also vary with the severity of the
condition to be
alleviated. It is to be further understood that for any particular subject,
specific dosage
regimens and schedules should be adjusted over time according to the
individual need
and the professional judgment of the person administering or supervising the
administration of the compositions.
Certain compounds described herein may be effective for enhancing the
biological activity of certain agents according to the present invention by
reducing the
metabolism, catabolism or inactivation of other compounds, and as such, are co-
administered for this intended effect. For example, the rifalazil, rifalazil
derivative, or
pharmaceutically-acceptable salt thereof is administered because it does not
impact the
metabolism of anti-HIV, HBV, HCV, or cancer agents that are metabolized by
CYP450.
The combination therapy may be administered as (a) a single pharmaceutical
composition which comprises rifalazil (or a rifalazil derivative), at least
one additional
pharmaceutical agent described herein, and a pharmaceutically acceptable
excipient,
diluent, or carrier; or (b) two separate pharmaceutical compositions
comprising (i) a
first composition comprising rifalazil (or a rifalazil derivative) as
described herein and
a pharmaceutically acceptable excipient, diluent, or carrier, and (ii) a
second
composition comprising at least one additional pharmaceutical agent described
herein
and a pharmaceutically acceptable excipient, diluent, or carrier. The
pharmaceutical
compositions can be administered simultaneously or sequentially and in any
order.
Combination Anti-TB Therapy
For combination anti-TB therapy, the rifalazil and/or rifalazil derivative can
be
combined with an additional antibiotic that is effective at treating TB, and
which does
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CA 02806362 2013-01-23
WO 2012/011917
PCT/US2010/043003
not induce or otherwise modulate CYP450. Examples include one or more of
isoniazid, streptomycin, pyrazinamide, and ethambutol.
The rifalazil and the other antibiotic can be administered simultaneously or
sequentially. For sequential administration, the rifalazil can be administered
before,
during, or after administration of the additional antibiotic, or any
combination thereof.
For combination therapy, the dosage and the frequency of administration of
each component of the combination can be controlled independently. For
example,
one of the compounds (i.e., rifalazil or the additional antibiotic) may be
administered
three times per day, while the second compound may be administered once per
day.
The compounds may also be formulated together such that one administration
delivers
both compounds.
Combination Therapy For Treating HIV and Tuberculosis
The rifalazil can be administered in combination or alternation with one or
more anti-HIV agents, one of which is ideally an NNRTI or a protease
inhibitor, or
other anti-HIV agent that is metabolized by CYP450 or a subtype thereof.
HIV Therapies: Protease Inhibitors (PIs)
:i
Brand
Pharmaceutical
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Abbreviation Experimental Code
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141W94 or VX-478 GlaxoSmithKline
lopinavir
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22
CA 02806362 2013-01-23
WO 2012/011917
PCT/US2010/043003
HIV Therapies: Nucleoside/Nucleotide Reverse
Transcriptase Inhibitors (NRTIs)
1Generic
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ii
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Company
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lamivudine i
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abacavir
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.._
...............+
::
.==
=
.
El vucitabine i L-FD4C
ilACH-126443, Achillion
:==============================================================================
======
=====:,
-4
==================================================:!
i KP-1461
i SN 1461,
Koronis
23
CA 02806362 2013-01-23
WO 2012/011917
PCT/US2010/043003
i GenericExperimental Pharmaceutical
Brand Name
Name
: Abbreviation
Code
Company
_
ISN1212
i Racivir
i RCV
Pharmasset
:
i:
i Dexelvuecitabine Reverset
i D-D4FC
i DPC 817
Pharmasset
i GS9148 and
:
.
=
prodrugs
Gilead Sciences
.
:
:
thereof
......_
"
HIV Therapies: Non-Nucleoside Reverse
Transcriptase Inhibitors (NNRTIs)
,
iez
Brand
Pharmaceutical
Generic Name Abbreviation' Experimental
Name
Code
i Company
:
V iramune Inevirapine
NVP
i BI-RG-587
Boehringer Ingelheim
: Rescriptor Idelavirdine
DLV
i U-90152S/T
!Pfizer
;
......................
: Sustiva0 Iefavirenz
EFV
DM P-266
i Bristol-Myers Squibb
,
1(+)-calanolide
Sarawak Medichem
IA
:
i
capravirine
CPV
AG-1549 or S-1153 131-1zer
'
I
DPC-083
Bristol-Myers Squibb
:.%
TMC-125
Tibotec-Virco Group
TMC-278
Tibotec-Virco Group
!
IDX12899
!Idenix
!r
....._
IDX12989
idenix
HIV Therapies: Other Classes of Drugs
,
........
.............
Brand
GenericExperimental Pharmaceutical
Abbreviation
Name
Name
Code
Company
,
:
tenofovir
:
TDF
or
:
:
i
disoproxil VireadTm
Bis(POC)
Gilead Sciences
fumarate
PMPA
i
(DF)
Cellular Inhibitors
¨
................:,õõ...
¨,i
Brand
Generic1
Experimental Pharmaceutical Abbreviation
Name
Name
Code
Company
Bristol-Myers
Droxia hydroxyurea HU
, Squibb
Entry Inhibitors (including Fusion Inhibitors)
Brand
GenericExperimental Pharmaceutical
: Abbreviation
Name
Name
Code
Company
24
CA 02806362 2013-01-23
WO 2012/011917
PCT/US2010/043003
Brand GenericExperimental Pharmaceutical
Abbreviation
: Name Name
Code
Company
Fuzeonlm enfuv i aide
T-20
Trimeris
: T-1249 Trimeris
AMD-3100 AnorMED. Inc.
Progenics
CD4-IgG2
PRO-542
Pharmaceuticals
BMS-488043 Bristol-Myers
Squibb
,r----
aplavu-oc
GSK-873,140¨ GlaxoSmithKline
- r
: Advanced
Peptide T
Immuni T, Inc.
TNX-355 Tanox, Inc.
maraviroc
UK-427,857 Pfizer
CXCR4 Inhibitor
AMD070
AMD11070 AnorMED, Inc.
CCR5 antagonist
vicriroc
SCH-D SCH-417690
Schering-Plough
HIV Therapies: Immune-Based Therapies
,
1BrandExperimental !Pharmaceutical
:
Generic Name Abbreviation
=
1Name
i Code
1Company :
:
:i
, aldesleukin, or
1
Proleukin
IL-2
Chiron Corporation
, Interleukin-2
1
:
HIV-1
I.
The Immune
1Remune Immunogen, or
i AG1661
,Response Corporation
, Salk vaccine
,,
HollisEden
,
' HE2000
:
,
Pharmaceuticals
,
Combination Therapy For Treating HBV and Tuberculosis
Non-limiting examples of antiviral agents that can be used in combination
with the compounds disclosed herein include those in the tables below.
Hepatitis B Therapies
Drug Name Drug Class Company
!:
Int ron
A interferon Schering-Plough
(interferon alfa-2b)
:.==
¨ :- ,......,
!:
Pegasys , interferon Roche
25
CA 02806362 2013-01-23
WO 2012/011917
PCT/US2010/043003
Drug Name
Drug Class Company
:
.
:
: (Peginterferon alfa-
2a)
:
Epivir-HBV
nucleoside
GlaxoSmithKline
(lamivudine; 3TC)
analogue
.:
Hepsera (Adefovir nucleotide
Gilead Sciences
Dipivoxil)"
analogue
.:
Gilead
Emtriva
nucleoside
Scienceshttp://www.hivandhepatitis.com/advertis i
(emtricitabine; FTC) . analogue
ement/triangle.html
:¨
¨
: nucleoside
Entecavir
Bristol-Myers Squibb
analogue
:.==
=
Clevudine (CLV, L- nucleoside
Pharmasset
FMAU)
analogue
:.==
=
,1
ACH 126 443 (L- nucleoside
Achillion Pharmaceuticals
Fd4C)
analogue
:.==
=
_............................:
,
nucleoside
I AM 365
Amrad
.
: analogue
.:
=
Amdoxovir
nucleoside
RFS Pharma LLC
.
(AMDX, DAPD) : analogue
:.
:
------
::
:
nucleoside
LdT (telbivudine) : analogue
Idenix
.
=
:
¨
=
nucleoside Emory University
CS-1220
=
i
analogue
..
::
Immune
TheradigmEpimmune
:
stimulant
.:
:
Zadaxin (thymosin) Immune
SciClone
stimulant
.:
EHT 899
i viral protein Enzo Biochem
Dexelvuecitabine/Reve nucleoside i Pharmasset
rset/D-D4FC
analogue
:
i RFS Phamm APD
nucleoside
,
:
analogue
HBV DNA vaccine Immune
. stimulant
PowderJect (UK)
.
i
. :
.
=
:
Eli Lilly
MCC 478
nucleoside
.
: analogue
=
i valLdC
:
: nucleoside Idenix
:.
(valtorcitabine)
: analogue
=
..._
..........._
:;
:
IICN 2001
: nucleoside ICN
.
analogue
:
26
CA 02806362 2013-01-23
WO 2012/011917
PCT/US2010/043003
: Drug Name
; Drug Class Company
.
:
nucleoside
1Racivir
Pharmasset
=
:
:
. analogue
:
nucleoside
Robustaflavone
Advanced Life Sciences
.
. analogue
:
i LM-019c
Emory University
:
:
nucleoside 1
Penciclovir
=
. analogue
: :.
=
:
: Famciclovir
:
! DXG
; nucleoside ;
=
: analogue
: ara-AMP prodrugs i
i HBV/MF59
...................:......
¨:
:;
nucleoside i
HDP-P-acyclovir
:
: analogue
.:
: Hammerhead
:
:..
ribozymes
=
.
.
Glycosidase
.
:
=
:.
Inhibitors
.
;
=
Pegylated
Interferon
=
Human
Monoclonal
.==
: Antibodies
:i
:
......
Combination Therapy For Treating HCV and Tuberculosis
Antiviral agents suitable for treating the HCV infection include, but are not
limited to, NRTI, NNRTI, protease inhibitors, such as serine protease
inhibitors,
interferons, pegylated interferons, IMPDH (inosine monophosphate
dehydrogenase)
inhibitors, vaccines, monoclonal and polyclonal antibodies, such as anti-CD20
monoclonal antibodies. immunomodulators, antisense therapeutics, caspase
inhibitors,
anti-fibrotics, and polymerase inhibitors. Specific anti-HCV compounds include
the
following.
Table of anti-Hepatitis C Compounds in Current Clinical Development
Pharmaceutical
!Drug Name
1Drug Category
Company
¨
ITGASYS
Long acting interferon
1 licoche
27
CA 02806362 2013-01-23
WO 2012/011917
PCT/US2010/043003
4:0egy1ated interferon
ialfa-2a
41NIFERGEN
Interferon, Long acting interferon InterMune
interferon alfacon-1
õ
!OMNIFERON
lInterferon, Long acting interferon Viragen
4-iatural interferon
.
Human Genome
, LBUFERON Longer acting interferon
Sciences
l' EBIF
Interferon i res-Serono
i nterferon beta-1a
' =
Omega Interferon Interferon I: ioMedicine
..)
!Oral Interferon alpha Ki:oral Interferon !Amarillo
Biosciences
jnterferon gamma-.
Anti-fibrotic InterMune
lb .
41)-501 Anti-fibrotic Interneuron
IMPDH inhibitor (inosine
Merimebodib VX-497
Vertexmonophosphate dehydrogenase)
iAMANTADINE Endo Labs
Broad Antiviral Agent
i(Symmetrel) Solvay
JDN-6556 tApotosis regulation Idun Pharma.
NTL-002 Monclonal Antibody XTL
4-1CV/1VIF59 Vaccine 'Chiron
iCIVACIR Wolyclonal Antibody NABI
.
..
I ITherapeutic vaccine 4nno genetic s
'VIRAMIDINE Nucleoside Analogue iICN
i.
ZADAXIN (thymosin Immunomodulator
Sci Clone
ialfa-1)
,
!CEPLENE .
4iistamine !Immunomodulator I axim
klihydrochloride
=
AIX 950 /
Protease Inhibitor Vertex/ Eli Lilly
tY 570310
' Isis Pharmaceutical /
ISIS 14803 lAntisense
Elan
Idun Pharmaceuticals,
IIDN-6556 Caspase inhibitor Inc.
I tt = ://www.idun.com
. .
TK 003 Polymerase Inhibitor i KROS Pharma
,
!Tarvacin Anti-Phospholipid Therapy Peregrine
> ,
OCV-796 1Polymerase Inhibitor ViroPharma
/Wye
!CH-6 ISerine Protease Schering
IANA971 Isatoribine IANADYS
.
' NA245 Isatoribine i NADYS
..)
!CPG 10101 (Actilon) Immunomodulator Coley
28
CA 02806362 2013-01-23
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Rituximab (Rituxam) Anti-CD20 Monoclonal Antibody enetech/IDEC
NM283 Polymerase Inhibitor Idenix Pharmaceuticals
(Valopicitabine)
HepXTM-C Monclonal Antibody NTL
IC41 Therapeutic Vaccine :antercell
Medusa Interferon Longer acting interferon klamel Technologies
E-1 Therapeutic Vaccine Inno genetic s
Multiferon Long Acting Interferon friragen
I I ILN 2061 Serine Protease i oehringer - Ingelheim
Interferon beta-1a Interferon Ares-Serono
(REBIF)
Combination Therapy For Treating Cancer and Tuberculosis
In use in treating or preventing cancer, the rifalazil or rifalazil derivative
described herein can be administered together with at least one
chemotherapeutic
agent as part of a unitary pharmaceutical composition. Alternatively, the
rifalazil or
rifalazil derivative can be administered apart from the anticancer
chemotherapeutic
agent. In this embodiment, the rifalazil or rifalazil derivative and the at
least one
anticancer chemotherapeutic agent are administered substantially
simultaneously, i.e.
the compounds are administered at the same time or one after the other, so
long as the
compounds reach therapeutic levels for a period of time in the blood.
Combination therapy involves administering the rifalazil or rifalazil
derivative,
as described herein, or a pharmaceutically acceptable salt or prodrug of a
compound
described herein, in combination with at least one anti-cancer
chemotherapeutic agent
(i.e., VEGF inhibitors, alkylating agents, and the like).
Examples of known anticancer agents which can be used for combination
therapy include, but are not limited to alkylating agents, such as busulfan,
cis-platin,
mitomycin C, and carboplatin; antimitotic agents, such as colchicine,
vinblastine,
paclitaxel, and docetaxel; topo I inhibitors, such as camptothecin and
topotecan; topo
II inhibitors, such as doxorubicin and etoposide; RNA/DNA antimetabolites,
such as
5-azacytidine, 5-fluorouracil and methotrexate; DNA antimetabolites, such as 5-
fluoro-2'-deoxy-uridine, ara-C, hydroxyurea and thioguanine; and antibodies,
such as
Herceptin and Rituxan . Other known anti-cancer agents, which can be used for
combination therapy, include arsenic trioxide, gamcitabine, melphalan,
chlorambucil,
cyclophosamide, ifosfamide, vincristine, mitoguazone, epirubicin, aclarubicin,
bleomycin, mitoxantrone, elliptinium, fludarabine, octreotide, retinoic acid,
tamoxifen
29
WO 2012/011917 CA 02806362 2013-01-23PCT/US2010/043003
and alanosine. Other classes of anti-cancer compounds that can be used in
combination with the rifalazil or rifalazil derivatives are described below.
The rifalazil or rifalazil derivatives can be combined with alpha-1-
adrenoceptor antagonists, such as doxazosin, terazosin, and tamsulosin., which
can
inhibit the growth of prostate cancer cell via induction of apoptosis
(Kyprianou, N., et
al., Cancer Res 60:4550 4555, (2000)).
Sigma-2 receptors are expressed in high densities in a variety of tumor cell
types (Vilner, B. J., et al., Cancer Res. 55: 408 413 (1995)) and sigma-2
receptor
agonists, such as CB-64D, CB-184 and haloperidol, activate a novel apoptotic
pathway and potentiate antineoplastic drugs in breast tumor cell lines.
(Kyprianou, N.,
et al., Cancer Res. 62:313 322 (2002)). Accordingly, the rifalazil or
rifalazil
derivatives can be combined with at least one known sigma-2 receptor agonists,
or a
pharmaceutically acceptable salt of said agent.
The rifalazil or rifalazil derivatives can be combined with lovastatin, a HMG-
CoA reductase inhibitor, and butyrate, an inducer of apoptosis in the Lewis
lung
carcinoma model in mice, can potentiate antitumor effects (Giermasz, A., et
al., Int. J.
Cancer 97:746 750 (2002)). Examples of known HMG-CoA reductase inhibitors,
which can be used for combination therapy include, but are not limited to,
lovastatin,
simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin, and
pharmaceutically acceptable salts thereof.
Certain HIV protease inhibitors, such as indinavir or saquinavir, have potent
anti-angiogenic activities and promote regression of Kaposi sarcoma (Sgadari,
C., et
al., Nat. Med. 8:225 232 (2002)). Accordingly, the rifalazil or rifalazil
derivatives can
be combined with HIV protease inhibitors, or a pharmaceutically acceptable
salt of
said agent. Representative HIV protease inhibitors include, but are not
limited to,
amprenavir, abacavir, CGP-73547, CGP-61755, DMP-450, indinavir, nelfinavir,
tipranavir, ritonavir, saquinavir, ABT-378, AG 1776, and BMS-232,632.
Synthetic retinoids, such as fenretinide (N-(4-hydroxyphenyl)retinamide,
4HPR), can have good activity in combination with other chemotherapeutic
agents,
such as cisplatin, etoposide or paclitaxel in small-cell lung cancer cell
lines
(Kalemkerian, G. P., et al., Cancer Chemother. Pharmacol. 43:145 150 (1999)).
4HPR
also was reported to have good activity in combination with gamma-radiation on
bladder cancer cell lines (Zou, C., et al., Int. J. Oncol. 13:1037 1041
(1998)).
Representative retinoids and synthetic retinoids include, but are not limited
to,
30
WO 2012/011917 CA 02806362 2013-01-23PCT/US2010/043003
bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, alpha-
difluoromethylornithine, ILX23-7553, fenretinide, and N-4-carboxyphenyl
retinamide.
Proteasome inhibitors, such as lactacystin, exert anti-tumor activity in vivo
and
in tumor cells in vitro, including those resistant to conventional
chemotherapeutic
agents. By inhibiting NF-kappaB transcriptional activity, proteasome
inhibitors may
also prevent angiogenesis and metastasis in vivo and further increase the
sensitivity of
cancer cells to apoptosis (Almond, J. B., et al., Leukemia 16:433 443 (2002)).
Representative proteasome inhibitors include, but are not limited to,
lactacystin, MG-
132, and PS-341.
Tyrosine kinase inhibitors, such as STI571 (Imatinib mesilate, Gleevec ),
have potent synergetic effects in combination with other anti-leukemic agents,
such as
etoposide (Liu, W. M., et al. Br. J. Cancer 86:1472 1478 (2002)).
Representative
tyrosine kinase inhibitors include, but are not limited to, Gleevec , ZD1839
(Iressal0),
SH268, genistein, CEP2563, SU6668, SU11248, and EMD121974.
Prenyl-protein transferase inhibitors, such as farnesyl protein transferase
inhibitor R115777, possess antitumor activity against human breast cancer
(Kelland,
L. R., et. al., Clin. Cancer Res. 7:3544 3550 (2001)). Synergy of the protein
farnesyltransferase inhibitor 5CH66336 and cisplatin in human cancer cell
lines also
has been reported (Adjei, A. A., et al., Clin. Cancer. Res. 7:1438 1445
(2001)).
Prenyl-protein transferase inhibitors, including farnesyl protein transferase
inhibitor,
inhibitors of geranylgeranyl-protein transferase type I (GGPTase-I) and
geranylgeranyl-protein transferase type-II, or a pharmaceutically acceptable
salt of
said agent, can be used in combination with rifalazil or the rifalazil analogs
described
herein. Examples of known prenylprotein transferase inhibitors include, but
are not
limited to, R115777, 5CH66336, L-778,123, BAL9611 and TAN-1813.
Cyclin-dependent kinase (CDK) inhibitors, such as flavopiridol, have potent,
often synergetic, effects in combination with other anticancer agents, such as
CPT-11,
a DNA topoisomerase I inhibitor in human colon cancer cells (Motwani, M., et
al.,
Clin. Cancer Res. 7:4209 4219, (2001)). Representative cyclin-dependent kinase
inhibitors include, but are not limited to, flavopiridol, UCN-01, roscovitine
and
olomoucine.
Certain COX-2 inhibitors are known to block angiogenesis, suppress solid
tumor metastases, and slow the growth of implanted gastrointestinal cancer
cells
31
WO 2012/011917 CA 02806362 2013-01-23PCT/US2010/043003
(Blanke, C. D., Oncology (Hunting) 16(No. 4 Suppl. 3):17 21 (2002)).
Representative
COX-2 inhibitors include, but are not limited to, celecoxib, valecoxib, and
rofecoxib.
IKB-a phosphorylation inhibitors, such as BAY-11-7082 (an irreversible
inhibitor of IKB-a phosphorylation) are also known to induce apoptosis, or to
enhance
the effectiveness of other agents at inducing apoptosis. These inhibitors can
also be
used in combination with the compounds described herein.
Among the anti-cancer agents are therapeutics specifically being pursued for
treating liver cancer, which can be important given the co-incidence of liver
cancer
and tuberculosis, and the hepatotoxicity of existing anti-TB and cancer
treatments.
Examples include ALN-VSP, an RNAi therapeutic (Alnylam), PV-10 (Provectus),
ZIO-101 (Arsenic) (ZIOPHARM), 4SC-201 (Resminostat), an HDAC inhibitor (4SC
AG), PI-88 (Progen Industries), GV1001 (Heptovax) (Pharmexa), Doxorubicin,
including Doxorubicin Transdrug , a treatment presented in the form of
nanoparticles
delivered via hepatic intra-arterial route, and Doxorubicin (ThermoDox)
Celsion), a
heat-activated liposome therapy, Nexavar (sorafenib) Onyx Pharmaceuticals
(Bayer
and Onyx), alone or in combination with Tarceva (Genentech).
Any of the above-mentioned compounds can be used in combination therapy
with the rifalazil or rifalazil derivatives.
The compounds can also be administered in conjunction with surgical tumor
removal, by administering the compounds before and/or after surgery, and in
conjunction with radiation therapy, by administering the compounds before,
during,
and/or after radiation therapy.
The appropriate dose of the compound is that amount effective to prevent
occurrence of the symptoms of the disorder or to treat some symptoms of the
disorder
from which the patient suffers. By "effective amount", "therapeutic amount" or
"effective dose" is meant that amount sufficient to elicit the desired
pharmacological
or therapeutic effects, thus resulting in effective prevention or treatment of
the
disorder.
When treating cancers, an effective amount of the anticancer agent is an
amount sufficient to suppress the growth of the tumor(s), shrink the tumor,
and, more
ideally, to destroy the tumor. Cancer can be prevented, either initially, or
from re-
occurring, by administering the compounds described herein in a prophylactic
manner. Preferably, the effective amount is sufficient to obtain the desired
result, but
32
WO 2012/011917 CA 02806362 2013-01-23PCT/US2010/043003
insufficient to cause appreciable side effects.
The effective dose can vary, depending upon factors such as the condition of
the patient, the severity of the cancer, and the manner in which the
pharmaceutical
composition is administered. The effective dose of compounds will of course
differ
from patient to patient, but in general includes amounts starting where
desired
therapeutic effects occur but below the amount where significant side effects
are
observed.
The compounds, when employed in effective amounts in accordance with the
method described herein, are selective to certain cancer cells, but do not
significantly
affect normal cells.
For human patients, the effective dose of typical compounds generally
requires administering the compound in an amount of at least about 1, often at
least
about 10, and frequently at least about 25 jig/ 24 hr/ patient. The effective
dose
generally does not exceed about 500, often does not exceed about 400, and
frequently
does not exceed about 300 pg/ 24 hr/ patient. In addition, administration of
the
effective dose is such that the concentration of the compound within the
plasma of the
patient normally does not exceed 500 ng/mL and frequently does not exceed 100
ng/mL.
V. Methods of Treating Immunocompromised Patients Suffering from
Tuberculosis Infection
The compositions described herein can be used to treat immunocompromised
patients, including cancer patients, HIV-positive patients, HBV patients, and
HCV
patients, suffering from a tuberculosis infection or at risk for being
infected with
tuberculosis.
When the immunocompromised patients have an HIV, HBV, and/or HCV
infection, and are co-infected with tuberculosis, by using the compositions
described
herein, the patients can continue their existing HIV, HBV, and/or HCV
treatments
without fear of complications resulting from induction of CYP450.
Treatment of HIV-Positive Patients
Ideally, the management of TB among HIV-infected patients taking
antiretroviral drugs includes directly observed therapy, and the availability
of
experienced and coordinated TB/HIV care givers (CDC, Recommendations and
33
WO 2012/011917 CA 02806362 2013-01-23 PCT/US2010/043003
Reports, October 30, 1998 / 47(RR20);1-51, Prevention and Treatment of
Tuberculosis Among Patients Infected with Human Immunodeficiency Virus:
Principles of Therapy and Revised Recommendations). As described herein, the
management of TB also includes the use of a TB treatment regimen that includes
rifalazil instead of rifampin The same holds true for patients with cancer,
HBV, HCV,
and various liver disorders.
Because the use of rifalazil as an alternative to the use of rifampin or
rifabutin
for antituberculosis treatment is now available, the previously recommended
practice
of stopping protease inhibitor therapy to allow the use of rifampin or
rifabutin for TB
treatment is no longer needed for patients with HIV-related TB.
The use of the anti-tuberculosis regimens described herein may further include
an assessment of the patient's response to treatment to decide the appropriate
duration
of therapy (i.e., 6 months or 9 months). Physicians and patients also should
be aware
that paradoxical reactions might occur during the course of TB treatment when
antiretroviral therapy restores immune function.
Short-course (i.e., 2 months) multidrug regimens (e.g., rifalazil or a
rifalazil
derivative, combined with pyrazinamide or other anti-TB agents) can be used to
prevent TB in persons with HIV infection.
The co-treatment of mycobacterium tuberculosis infection and HIV infection
can take into consideration the frequency of co-existing TB and HIV infection
and
rates of drug-resistant TB among patients infected with HIV; the co-
pathogenicity of
TB and HIV disease; the potential for a poorer outcome of TB therapy and
paradoxical reactions to TB treatment among HIV-infected patients; and
therapies to
prevent TB among HIV-infected persons. Effective treatments for TB patients co-
infected with HIV can not only help reduce new cases of TB in general, but
also help
decrease further transmission of drug-resistant strains and new cases of drug-
resistant
TB.
The Use of Rifalazil in Combination with Anti-Retroviral Agents
Widely used antiretroviral drugs available in the United States include
protease inhibitors (saquinavir, indinavir, ritonavir, and nelfinavir) and
nonnucleoside
reverse transcriptase inhibitors (NNRTIs) (nevirapine, delavirdine, and
efavirenz).
Protease inhibitors and NNRTIs have substantive interactions with certain
rifamycins
(rifampin, rifabutin, and rifapentine) used to treat mycobacterial infections.
These
34
WO 2012/011917 CA 02806362 2013-01-23PCT/US2010/043003
drug interactions principally result from changes in the metabolism of the
antiretroviral agents and the rifamycins secondary to induction or inhibition
of the
hepatic cytochrome CYP450 enzyme system. Rifamycin-related CYP450 induction
decreases the blood levels of drugs metabolized by CYP450. For example, if
protease
inhibitors are administered with rifampin (a potent CYP450 inducer), blood
concentrations of the protease inhibitors (all of which are metabolized by
CYP450)
decrease markedly, and most likely the antiretroviral activity of these agents
declines
as well. Conversely, if ritonavir (a potent CYP450 inhibitor) is administered
with
rifabutin, blood concentrations of rifabutin increase markedly, and most
likely
rifabutin toxicity increases as well. These undesirable side effects are
avoided by
using rifalazil or the other rifamycin analogs described herein, instead of
rifampin,
rifabutin, or rifapentine.
In contrast to the protease inhibitors and the NNRTIs, the other class of
antiretroviral agents available, nucleoside reverse transcriptase inhibitors
(NRTIs)
(zidovudine, didanosine, zalcitabine, stavudine, and lamivudine) are not
metabolized
by CYP450. Rifampin (and to a lesser degree, rifabutin) increases the
glucuronidation
of zidovudine and thus slightly decreases the serum concentration of
zidovudine. The
effect of this interaction probably is not clinically important, and the
concurrent use of
NRTIs and rifamycins is not contraindicated.
Because current treatment regimens frequently include two NRTIs combined
with a potent protease inhibitor (or, as an alternative, combined with an
NNRTI), and
the protease inhibitors and NNRTIs are adversely affected by conventional anti-
TB
agents, the patients receiving dual treatment with these regimens are at risk
for
developing resistant mutations of HIV. Accordingly, the use of rifampin to
treat
active TB in a patient who is taking a protease inhibitor or an NNRTI is
always
contraindicated. Rifabutin is a less potent inducer of the CPY450 cytochrome
enzymes than rifampin, and, in modified doses, might not be associated with a
clinically significant reduction of protease inhibitors or nevirapine.
Rifapentine is not
recommended as a substitute for rifampin because its safety and effectiveness
have
not been established for treating patients with HIV-related TB.
TB treatment regimens that contain no rifamycins, for example, TB treatment
regimens consisting of streptomycin, isoniazid, have been proposed as an
alternative
for patients who take protease inhibitors or NNRTIs. However, these TB
regimens
have not been studied among patients with HIV infection.
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For this reason, the treatment regimens using rifalazil or rifalazil
derivatives
described herein overcome the limitations of the prior TB treatment for HIV-
infected
individuals.
In one embodiment, the initial phase of a 9-month TB regimen consists of
rifalazil or a rifalazil derivative, along with one or more of isoniazid,
streptomycin,
pyrazinamide, and ethambutol administered a) daily for 8 weeks or b) daily for
at
least the first 2 weeks, followed by twice-a-week dosing for 6 weeks, to
complete the
2-month induction phase. The second phase of treatment involves administration
of
rifalazil or a rifalazil derivative, along with one or more of isoniazid,
streptomycin,
and pyrazinamide, 2-3 times a week for 7 months.
Another option is a 6-month regimen that includes rifalazil or a rifalazil
derivative, along with one or more of isoniazid, rifampin, pyrazinamide, and
ethambutol (or streptomycin). These drugs are administered a) daily for 8
weeks or b)
daily for at least the first 2 weeks, followed by 2-3-times-per-week dosing
for 6 weeks,
to complete the 2-month induction phase. The second phase of treatment
includes a)
isoniazid and rifalazil or a rifalazil derivative administered daily or 2-3
times a week
for 4 months. Rifalazil or a rifalazil analog, and one or more of isoniazid,
pyrazinamide, and ethambutol (or streptomycin) also can be administered three
times
a week for 6 months
Pyridoxine (vitamin B6) (25-50 mg daily or 50-100 mg twice weekly) can be
administered to all HIV-infected patients who are undergoing TB treatment with
isoniazid, to reduce the occurrence of isoniazid-induced side effects in the
central and
peripheral nervous system.
The CDC's most recent recommendations for the use of treatment regimens is
6 months, to complete a) at least 180 doses (one dose per day for 6 months) or
b) 14
induction doses (one dose per day for 2 weeks) followed by 12 induction doses
(two
doses per week for 6 weeks) plus 36 continuation doses (two doses per week for
18
weeks). While the use of rifalazil and/or rifalazil derivatives may obviate
the need for
such lengthy treatment, the CDC guidelines can be useful in determining an
appropriate baseline treatment modality, and patient monitoring can be used to
determine whether the treatment duration can be shortened.
The minimum duration of short-course rifampin-containing TB treatment
regimens can be, for example, 6 months, to complete a) at least 180 doses (one
dose
per day for 6 months) or b) 14 induction doses (one dose per day for 2 weeks)
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followed by 12-18 induction doses (two to three doses per week for 6 weeks)
plus 36-
54 continuation doses (two to three doses per week for 18 weeks)
Three-times-per-week rifalazil regimens can include at least 78 doses
administered over 26 weeks.
The final decision on the duration of therapy should consider the patient's
response to treatment. For patients with delayed response to treatment, the
duration of
rifalazil-based regimens should be prolonged from 6 months to 9 months (or to
4
months after culture conversion is documented).
Interruptions in therapy because of drug toxicity or other reasons should be
taken into consideration when calculating the end-of-therapy date for
individual
patients. Completion of therapy is typically based on the total number of
medication
doses administered, rather than on duration of therapy alone.
Reinstitution of therapy for patients with interrupted TB therapy might
require
a continuation of the regimen originally prescribed (as long as needed to
complete the
recommended duration of the particular regimen) or a complete renewal of the
regimen. In either situation, when therapy is resumed after an interruption of
greater
than or equal to 2 months, sputum samples (or other clinical samples as
appropriate)
should be taken for smear, culture, and drug-susceptibility testing.
When caring for persons with HIV infection, clinicians should make
aggressive efforts to identify those who also are infected with M.
tuberculosis.
Because the reliability of the tuberculin skin test (TST) can diminish as the
CD4+ T-
cell count declines, it can be important to screen for TB with TST as soon as
possible
after HIV infection is diagnosed. Because the risk of infection and disease
with M.
tuberculosis is particularly high among HIV-infected contacts of persons with
infectious pulmonary or laryngeal TB, these persons should be evaluated for TB
as
soon as possible after learning of exposure to a patient with infectious TB.
Monthly Monitoring of Patients During TB Preventive Treatment
Patients undergoing preventive treatment for TB can optionally receive a
periodic, for example, a monthly clinical evaluation of their adherence to
treatment
and medication side effects.
In one embodiment, the preventive therapy regimens include the use of a
combination of at least two antituberculosis drugs that the infecting strain
is believed
to be susceptible to (e.g., rifalazil or a rifalazil derivative, in
combination with
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ethambutol pyrazinamide, levofloxacin or ethambutol). The clinician can review
the
drug-susceptibility pattern of the M. tuberculosis strain isolated from the
infecting
source-patient before choosing a preventive therapy regimen.
Follow-up of HIV-Infected Persons Who Have Completed Preventive Therapy
Follow-up care, including chest x-rays and medical evaluations, may not be
necessary for patients who complete a course of TB preventive treatment,
unless they
develop symptoms of active TB disease or are subsequently re-exposed to a
person
with infectious TB disease.
These examples are provided to illustrate two potential combinations for
sequential therapy. They are not intended to limit the invention in any way.
Treatment of Cancer Patients
Where the immunocompromised patients have cancer, the patients can
continue their existing cancer treatments without fear of complications
resulting from
induction of CYP450. The types of cancer treatments that are implicated by
this
treatment modality specifically include the treatment of liver cancers, lung
cancer,
lymphoma and leukemia. However, patients suffering from tuberculosis and which
are inflicted with other cancers can also benefit from this treatment. For
example,
patients with the following cancers can benefit from the treatment described
herein
when they are infected with tuberculosis: human sarcomas and carcinomas, e.g.,
fibro s arc oma, myxo s arc oma, lip o s arc oma, chondro s arc oma, o steo
genic sarcoma,
chordoma, angiosarcoma, endothelio s arc oma, lymphang io s arc oma,
lymphangioendothelio s arc oma, synovioma, mesothelioma, Ewing's tumor,
leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast
cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell
carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma,
papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary
carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct
carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor,
cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma,
bladder
carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma,
craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma,
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oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma;
leukemias, e.g., plasma cell leukemia, acute lymphocytic leukemia, acute
myelocytic
leukemia (myeloblastic, promyelocytic, myelomonocytic, monocytic and
erythroleukemia); chronic leukemia (chronic myelocytic (granulocytic) leukemia
and
chronic lymphocytic leukemia); and polycythemia vera, lymphoma (Hodgkin's
disease and non-Hodgkin's disease), including NF-KB mutant and Velcade
Resistant
lymphoma cells, multiple myeloma, PI3 kinase deficient myeloma, Waldenstrom's
macroglobulinemia, and heavy chain disease, and malignant forms of these
cancers.
When treating cancer, there is frequently a narrow window between drug
toxicity and suboptimal therapy, and inter-individual variation in drug
metabolism
complicates therapy. Genetic polymorphisms in enzymes such as those in the
cytochrome P450 superfamily are at least partially responsible for the
observed inter-
individual variation in pharmacokinetics and pharmacodynamics of anticancer
drugs.
For example, there is potential clinically relevant application of CYP450
pharmacogenetics for anticancer therapy, for example, between CYP1A2 and
flutamide, CYP2A6 and tegafur, CYP2B6 and cyclophosphamide, CYP2C8 and
paclitaxel, CYP2D6 and tamoxifen, and CYP3A5 (van Schaik, "Cancer treatment
and
pharmacogenetics of cytochrome P450 enzymes," Journal Investigational New
Drugs
(Springer Netherlands), 23(6): 513-522 (December, 2005), the contents of which
are
hereby incorporated by reference). In addition to genetic polymorphisms, drugs
which modulate CYP450 also have an impact on chemotherapy.
Representative chemotherapeutic agents metabolized by CYP450 include
cyclophosphamide, docetaxel, doxorubicin, etoposide, ifosfamide, paclitaxel,
tamoxifen, anastrazole, teniposide, vinblastine, vindesine, and gefitinib.
The compositions described herein can be used as therapy for treating
tuberculosis and other bacterial disorders treatable with rifalazil and
rifalazil
derivatives described herein, in any and all of these patients, in combination
or
alternation with existing therapies used to manage the aforementioned types of
cancers, liver disorders, HIV, HBV, and HCV.
VII. Methods of Treating Disorders Other than Tuberculosis
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The compositions described herein can be used to treat bacterial infections
other than tuberculosis, and disorders mediated by such infections, in
immunosuppressed patients.
The compositions can be used to treat immunocompromised patients suffering
from respiratory tract infections, acute bacterial otitis media, bacterial
pneumonia,
urinary tract infections, complicated infections, noncomplicated infections,
pyelonephritis, intra-abdominal infections, deep-seated abcesses, bacterial
sepsis, skin
and skin structure infections, soft tissue infections, bone and joint
infections, central
nervous system infections, bacteremia, wound infections, peritonitis,
meningitis,
infections after burn, urogenital tract infections, gastro-intestinal tract
infections,
pelvic inflammatory disease, endocarditis, and other intravascular infections.
Patients can also be treated for gastrointestinal disorders, such as
inflammatory bowel disease, irritable bowel syndrome, clostridium difficile
infections
and the associated disorder (CDAD), and Crohn's Disease, as well as hepatic
encephalopathy, particularly where such patients are co-infected with another
disease
where the treatment requires the use of the p450 pathway, such as HIV, HBV,
HCV,
and cancer.
The compositions can also be used to treat diseases associated with bacterial
infection. For example, bacterial infections can produce inflammation,
resulting in the
pathogenesis of atherosclerosis, multiple sclerosis, rheumatoid arthritis,
diabetes,
Alzheimer's disease, asthma, cirrhosis of the liver, psoriasis, meningitis,
cystic
fibrosis, cancer, or osteoporosis. Accordingly, the present invention also
features a
method of treating the diseases associated with bacterial infection listed
above.
Immunocompromised patients can be treated for microbial infections cause by
bacterium such as Anaplasma bovis, A. caudatum, A. centrale, A. marginale A.
ovis, A.
phagocytophila, A. platys, Bartonella bacilliforrnis, B. clarridgeiae, B.
elizabethae, B.
henselae, B. henselae phage, B. quintana, B. taylorii, B. vinsonii, Borrelia
afielii, B.
andersonii, B. anserina, B. bissettii, B. burgdorferi, B. crocidurae, B.
garinii, B.
hennsii, B. japonica, B. miyamotoi, B. parkeri, B. recurrentis, B. turdi, B.
turicatae, B.
valaisiana, Brucella abortus, B. melitensis, C. psittaci, C. trachomatis,
Cowdria
ruminantium, Coxiella burnetii, Ehrlichia canis, E. chaffeensis, E. equi, E.
ewingii, E.
muris, E. phagocytophila, E. platys, E. risticii, E. rurninantium, E.
sennetsu,
Haemobartonella canis, H. felis, H. muris, Mycoplasma arthriditis, M. buccale,
M.
faucium, M. fermentans, M. genitalium, M. hominis, M. laidlawii, M.
lipophilum, M.
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orale, M. penetrans, M. pirum, M pneumoniae, M. salivarium, M. spermatophilum,
Rickettsia australis, R. conorii, R. felis, R. helvetica, R. japonica, R.
massiliae, R.
montanensis, R. peacockii, R. prowazekii, R. rhipicephali, R. rickettsii, R.
sibirica,
and R. typhi.
More specifically, bacterial infections such as C. difficile, S. aureus, B.
anthracis, leprosy, MAC, C. pneumoniae, and Chlamydia trachomatis can be
treated.
Immunocompromised patients may also be treated for chronic diseases
associated with a bacterial infection, particularly chronic diseases caused by
bacteria
capable of establishing a cryptic phase. The chronic disease may be an
inflammatory
disease, such as asthma, coronary artery disease, arthritis, conjunctivitis,
lymphogranuloma venerum (LGV), cervicitis, and salpingitis. The chronic
disease can
also be an autoimmune disease (e.g., systemic lupus erythematosus, diabetes
mellitus,
or graft versus host disease).
Immunocompromised patients diagnosed as being infected with a bacterium
having a multiplying form and a non-multiplying form can be treated, for
example, by
administering to the patient (i) rifalazil or a rifalazil derivative as
described herein,
and (ii) a second antibiotic that is effective against the multiplying form of
the
bacterium, wherein the two antibiotics are administered in amounts and for a
duration
that, in combination, effectively treat the patient.
Immunocompromised patients can be treated for persistent intracellular
bacterial infections caused by one of the following: Chlamydia spp. (e.g., C.
trachomatis, C. pneumoniae, C. psittaci, C. suis, C. pecorum, C. abortus, C.
caviae, C.
felis, C. muridarum), N. hartmannellae, W. chondrophila, S. negevensis, or P.
acanthamoeba.
Where a patient is suffering from a bacterial infection caused by one of the
above-listed bacteria, which have an active form as well as an inactive,
latent form,
and is also being treated for another disorder with an agent that is
metabolized by
CYP450, the patient can be treated for the bacterial infection by
administering
rifalazil or a rifalazil analog that does not modulate CYP450. Ideally, the
rifalazil or a
rifalazil analog is administered for a longer period of time than would be
required to
treat the active bacteria, so that it can accumulate in the patient's cells,
and the drug's
persistence in the blood stream and within the cells will enable it to be
present to treat
the latent form of the bacteria, when it transitions into the active form. In
this manner,
one can prevent a relapse of a bacterial infection.
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The compositions can be used to treat drug resistant Gram-positive cocci, such
as methicillin-resistant S. aureus and vancomycin-resistant enterococci, and
are useful
in the treatment of community-acquired pneumonia, upper and lower respiratory
tract
infections, skin and soft tissue infections, hospital-acquired lung
infections, bone and
joint infections, and other bacterial infections.
The compositions can be administered to the ear (e.g., the tympanic membrane
or the external auditory canal of the ear) to treat or prevent bacterial
infections
associated with otitis media (e.g., an infection of H. influenza, M.
catarhalis, or S.
pneumoniae) or otitis externa (e.g., an infection of S. intermedius,
Streptococcus spp.,
Pseudomonas spp., Proteus spp., or E. coli). The compositions can also be used
to
treat infections associated with otic surgical procedures such as
tympanoplasty,
stapedectomy, removal of tumors, or cochlear implant surgery. The compositions
may
also be used prophylactically, prior to therapies or conditions that can cause
ear
infections. In such a use, the compositions can be applied to an area of the
ear to
which the surgical intervention will be performed, within at least seven days
(before
or after) of the surgical intervention.
The time sufficient to treat a bacterial infection ranges from one week to one
year, but it can also be extended over the lifetime of the individual patient,
if
necessary. In more preferable embodiments, the duration of treatment is at
least 30
days, at least 45 days, at least 100 days, or at least 180 days. Ultimately,
it is most
desirable to extend the treatment for such a time that the bacterial infection
is no
longer detected.
VII. Methods of Treating Patients Other Than Immunocompromised Patients
Enzyme induction is the process by which exposure to certain substrates (e.g.,
drugs, environmental pollutants) results in accelerated biotransformation with
a
corresponding reduction in unmetabolized drug. Most drugs can exhibit
decreased
efficacy due to rapid metabolism, but drugs with active metabolites can
display
increased drug effect and/or toxicity due to enzyme induction. Enzyme
inhibition
occurs when 2 drugs sharing metabolism via the same isozyme compete for the
same
enzyme receptor site. The more potent inhibitor will predominate, resulting in
decreased metabolism of the competing drug. For most drugs, this can lead to
increased serum levels of the unmetabolized entity, leading to a greater
potential for
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toxicity. For drugs whose pharmacological activity requires biotransformation
from a
pro-drug form, inhibition can lead to decreased efficacy.
Cytochrome P450 3A (CYP3A) is involved in biotransformation of more than
half of all drugs currently available. Drug interactions by inhibition of
CYP3A are of
major interest in patients receiving combinations of drugs. Some interactions
with
CYP3A inhibitors also involve inhibition of the multidrug export pump, P-
glycoprotein.
Various rifamycin analogs, including rifampicin and rifabutin, are CYP3A
inducers. When patients taking drugs that are metabolized by CYP3A4 also have
bacterial infections commonly treated with rifampicin or rifabutin, it can be
advantageous to use rifalazil or rifalazil derivatives that do not induce
CYP3A4. A
number of adverse drug reactions can be avoided by adopting this approach.
Accordingly, in addition to immunocompromised patients, there are patients
treated for chronic disorders, where the patients have to undergo treatment on
a daily
basis for the rest of their lives. Where the treatment involves administration
of agents
metabolized by CYP450, in particular, the CYP3A4 and CYP2C9 isoforms, and such
patients additionally suffer from one or more of the above-mentioned bacterial
infections and/or disorders associated with these bacterial infections, it is
preferable to
administer rifalazil or a rifalazil derivative that is not an inducer of
CYP450, in
particular CYP3A4 or CYP2C9. Accordingly, the rifalazil or rifalazil-
containing
compositions can be particularly useful for treating patients being treated
for chronic
disorders, such as the following:
Calcium Channel Blockers
Most calcium channel blockers decrease the force of contraction of the
myocardium (muscle of the heart). Calcium channel blockers work by blocking
voltage-gated calcium channels (VGCCs) in cardiac muscle and blood vessels.
This
decreases intracellular calcium leading to a reduction in muscle contraction.
The
decrease in cardiac contractility decreases cardiac output. Since blood
pressure is
determined by cardiac output and peripheral resistance, the result is a
lowering of
blood pressure. Lower blood pressure can help ameliorate symptoms of ischemic
heart disease such as angina pectoris.
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Representative calcium channel blockers include diltiazem, nifedipine,
felodipine, amlodipine, verapamil, There are two main classes of calcium
channel
blockers, dihydropyridines and non-dihydropyridines.
Dihydropyridines
Dihydropyridine calcium channel blockers are often used to reduce systemic
vascular resistance and arterial pressure, but are not used to treat angina
(with the
exception of amlodipine and nifedipine, which carry an indication to treat
chronic
stable angina as well as vasospastic angina) because the vasodilation and
hypotension
can lead to reflex tachycardia. This CCB class is easily identified by the
suffix "-
dipine".
Representative dihydropyridines include Amlodipine (Norvasc), Aranidipine
(Sapresta), Azelnidipine (Calblock), Barnidipine (HypoCa), Benidipine (Coniel)
,
Cilnidipine (Atelec, Cinalong, Siscard), Clevidipine (Cleviprex), Efonidipine
(Landel),
Felodipine (Plendil), Lacidipine (Motens, Lacipil), Lercanidipine (Zanidip),
Manidipine (Calslot, Madipine), Nicardipine (Cardene, Carden SR), Nifedipine
(Procardia, Adalat), Nilvadipine (Nivadil), Nimodipine (Nimotop), Nisoldipine
(Baymycard, Sular, Syscor), Nitrendipine (Cardif, Nitrepin, Baylotensin), and
Pranidipine (Acalas)
Non-Dihydropyridines
Among non-dihydropyridines, there are two main classes, phenylalkylamines
and benzothiazepines.
(Phenylalkylamines)
Phenylalkylamine calcium channel blockers are relatively selective for
myocardium, reduce myocardial oxygen demand and reverse coronary vasospasm,
and are often used to treat angina. They have minimal vasodilatory effects
compared
with dihydropyridines, and therefore cause less reflex tachycardia, making it
appealing for treatment of angina, where tachycardia can be the most
significant
contributor to the heart's need for oxygen. Representative phenylalkylamines
include
Verapamil (Calan, Isoptin) and Gallopamil (Procorum, D600).
Benzothiazepines
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Benzothiazepine calcium channel blockers are an intermediate class between
phenylalkylamine and dihydropyridines in their selectivity for vascular
calcium
channels. By having both cardiac depressant and vasodilator actions,
benzothiazepines are able to reduce arterial pressure without producing the
same
degree of reflex cardiac stimulation caused by dihydropyridines. Diltiazem is
a
representative benzothiazepine.
Many of the estimated 50 million Americans with high blood pressure receive
medications for hypertension and for other conditions, placing them at risk
for
adverse drug interactions. The risk for hypertension and for adverse drug
reactions is
highest in the elderly, who have the greatest need for pharmacologic therapy.
The
most important class of drug interactions involves the cytochrome P450
microsomal
enzyme system, which handles a variety of xenobiotic substances. Because of
the
potential for interactions with rifampicin and rifabutin, the present
invention provides
an effective alternative for treating bacterial infections in these patients.
In addition to ordinary heart patients, heart disease and high blood pressure
are
major health concerns for people with HIV. Standard treatment for these
illnesses
often includes calcium channel blockers (CCBs). There is already a potential
for
significant drug interactions between CCBs and HIV protease inhibitors (PIs)
that
may influence the dosing, monitoring, and choosing of CCBs and PIs when used
in
people infected with HIV. Additional interactions with rifabutin and
rifampicin can
be avoided when such patients are treated for bacterial infections.
Anti-Fungals
Azole anti-fungals, such as voriconazole, are metabolized by the CYP450
isoenzymes 2C19 and 3A4 and, to a lesser extent, by CYP2C9. Several drug-drug
interactions with voriconazole can be expected, because many other drugs are
also
transformed by these enzymes, leading to a contraindication for co-
administration of
voriconazole with some other drugs. Representative azole antifungals include
ketoconazole, itraconazole, and clotrimazole.
When co-administered with voriconazole, rifampin, a CYP450 inducer,
decreased the Cmax (maximum plasma concentration) and AUCT (area under the
plasma concentration-time curve within a dosing interval) of voriconazole by
93%
and 96%, respectively. Geist, "Induction of Voriconazole Metabolism by
Rifampin in
a Patient with Acute Myeloid Leukemia: Importance of Interdisciplinary
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Communication To Prevent Treatment Errors with Complex Medications,"
Antimicrob Agents Chemother. September; 51(9): 3455-3456 (2007). In this case,
an
immunocompromised patient with acute myeloid leukemia was treated with
voriconazole for antifungal prophylaxis. The patient was also treated with
rifampin,
to treat a Staphylococcus epidermidis infection, without recognizing the
potential for
drug-drug interactions. The result was a loss of effectiveness of voriconazole
caused
by rifampin.
In immunocompromised patients suffering from both fungal and bacterial
infections, co-administration of voriconazole to treat the fungal infection
and rifalazil
to treat the bacterial infection can be useful for maintaining the therapeutic
efficacy of
voriconazole. Unlike co-administration of rifabutin or rifampicin, there will
not be a
massive reduction of systemic voriconazole exposure due to induced metabolism.
The same is true for other azole antifungal agents.
Birth Control
Rifampin (Rifadin , Rimactane(D) is an inducer of CYP3A4, and can cause
clinically significant drug interactions with oral contraceptives. Rifampin
significantly reduces the efficacy of oral contraceptives as a result of
decreased
plasma concentrations of estradiol (a substrate of CYP3A4), which can be
reduced
when rifampin induces CYP3A4 enzymes. The rifalazil and rifalazil derivatives
described herein can avoid these side effects, maintaining the efficacy of
birth control
when women taking such birth control medicines are treated for bacterial
infections.
Representative birth control agents include estradiol (estrogen),
levonorgestrel
(female sex hormone, oral contraceptive), ethinylestradiol (hormonal
contraceptive),
toremifene (SERM), mifepristone (antiprogesterone, anti-implantation agent),
testosterone (androgen), and finasteride (antiandrogen).
Immunosuppres s ants
Immunosuppres sant therapy is critical for transplant recipients.
Representative immunosuppressants include cyclosporine, tacrolimus, and
sirolimus.
All are substrates for CYP450, so it can be important to treat bacterial
infections, such
as those described herein, with rifalazil and the rifalazil derivatives
described herein.
Tricyclic Antidepressants and Selective Serotonin Reuptake Inhibitors (SSRIs)
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Many patients suffering from depression will take antidepressants such as
tricyclic antidepressants and SSRIs for the rest of their lives.
Representative tricyclic
antidepressants include amitriptyline, imipramine, and clomipramine.
Representative
SSRIs include citalopram, escitalopram, fluoxetine, and norfluoxetine,
sertraline,
SNRIs
In addition to SSRIs, serotonin¨norepinephrine reuptake inhibitors (SNRIs)
are a class of antidepressant drugs used in the treatment of major depression
and other
mood disorders. They are sometimes also used to treat anxiety disorders,
obsessive-
compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD),
chronic
neuropathic pain, fibromyalgia syndrome (FMS), and for the relief of
menopausal
symptoms.
SNRIs act upon and increase the levels of two neurotransmitters in the brain
that are known to play an important part in mood, these being serotonin and
norepinephrine. Representative SNRIs include Venlafaxine and Desvenlafaxine
(Pristiq), the active metabolite of Venlafaxine (Wyeth), Duloxetine (Cymbalta,
Yentreve, Eli Lilly and Company), Milnacipran (Dalcipran, Ixel, Save11a) and
Levomilnacipran (F2695), the levo- isomer of milnacipran, Sibutramine
(Meridia,
Reductil), Bicifadine (DOV-220,075, DOV Pharmaceutical), and SEP-227162
(Sepracor).
In addition to these anti-depressants, anxiolytics such as spiperone and
buspirone are often used, and both are metabolized by CYP450. Further, various
antipsychotics, such as haloperidol, risperidone, ziprasidone, and
aripiprazole, are
also metabolized by CYP450. Benzodiazepines are frequently used to treat
patients
suffering from sleep disorders and other CNS disorders. Representative
benzodiazepines include flunitrazepam, midazolam, alprazolam, triazolam, and
clonazepam pimozide.
Additional agents used to treat depression and psychosis, and which are
incompatible with CYP450 inducers, include Mirtazapine (NaSSA), nefazodone
(psychoactive and antidepressant), pimozide (antipsychotic), reboxetine
(antidepressant) and zopiclone (hypnotic).
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All of these patients will benefit from treatment with rifalazil and rifalazil
derivatives that are not inducers of CYP450 when they also suffer from
bacterial
infections.
Opiate Analgesics
Opiates are highly susceptible to changes in CYP3A4 activity, and interact
with other drugs that inhibits or induce CYP3A4. Drugs that increase CYP3A4
activity (enzyme inducers) reduce opiate plasma concentrations.
If a patient is being treated with rifampacin or rifabutin, which are CYP3A4
inducers, they may not respond adequately to opiates such as oxycodone,
alfentanil,
fentanyl, sufentanil, codeine, methadone and tramadol. (See, for example,
Nieminen
et al., "Rifampin greatly reduces the plasma concentrations of intravenous and
oral
oxycodone," Anesthesiology.;110(6):1371-1378) (2009).
In patients undergoing opiate therapy, including oxycodone therapy, it is
preferable to avoid using rifampacin or rifabutin to treat bacterial
infections, and
instead, to use rifalazil or rifalazil derivatives that do not incude CYP450.
Statins
Representative statins include atorvastatin, lovastatin, and simvastatin.
These
agents are administered daily for the life of the patient, and are
incompatible with
CYP450 inducers. Accordingly, when such patients are treated for bacterial
infections, the compositions described herein can be safely used.
Antiarrhythmics
Amiodarone, quinidine, and digoxin are representative antiarrhythmic agents.
Lidocaine, a local anesthetic, also functions as an antiarrhythmic agent.
These agents
are substrates for CYP450, and, as such, patients taking these agents and
suffering
from bacterial infections should be prescribed rifalazil and rifalazil
derivatives that do
not induce CYP450 rather than rifampicin or rifabutin.
Phosphodiesterase Type 5 (PDE5) Inhibitors and Kinins
Kinins and PDE5 inhbitors are frequently used as vasodilators and smooth
muscle contractors, and as such are frequently used to treat erectile
dysfunction.
Sildenafil is a representative PDE5 inhibitor. Patients taking these agents
and
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suffering from bacterial infections should be prescribed rifalazil and
rifalazil
derivatives that do not induce CYP450 rather than rifampicin or rifabutin.
H1 Antagonists
Astemizole is a representative H1 antagonist, and is used as an anti-pruritic.
HI antagonists are frequently incompatible with CYP450 inducers.
Anti-Coagulants
Warfarin is a representative anticoagulant. It is known to be incompatible
with
rifampicin and rifabutin, but is compatible with the rifalazil and rifalazil
derivatives
described herein.
Anticonvulsants
Representative anticonvulsants that are substrates for CYP3A4 include
carbamazepine and valproate.
Proton Pump Inhibitors
Representative proton pump inhibitors include omeprazole and esomeprazole.
These agents are metabolized by CYP450, and as such, are incompatible with
rifampicin and rifabutin, but compatible with rifalazil and rifalazil
derivatives
described herein.
Miscellaneous Agents
Other substrates for CYP3A4 include ergot alkaloids (circulation,
neurotransmission), ivabradine (used to treat angina pectoris), montelukast (a
leukotriene receptor antagonist), ondansetron (a 5-HT3 antagonist),
paracetamol (an
analgesic and antipyretic), quinine (an antipyretic, anti-smallpox agent, and
analgesic),
theophylline (a stimulant), glibenclamide (an antidiabetic), cisapride (a 5-
HT4
receptor agonist), terfenadine (an Hl-receptor antagonist), barbituates such
as
phenobarbital. These agents are metabolized by CYP450, and as such, are
incompatible with rifampicin and rifabutin, but compatible with rifalazil and
rifalazil
derivatives described herein.
VIII. Methods of Treating Patients with Liver Disease
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Frequently, patients having pre-existent chronic liver disease also develop
tuberculosis. Additionally, patients undergoing treatment for tuberculosis may
develop hepatotoxicity as an adverse reaction to the drugs, and/or can develop
fresh
liver diseases like acute viral hepatitis. Hepatic dysfunction can also alter
absorption
and distribution of drugs that are metabolized or excreted in the liver.
Accordingly,
the presence of co-existent hepatic disease, such as that caused by HCV and
HBV,
poses a challenge in the treatment of tuberculosis.
Rifampicin, pyrazinamide, isoniazid, ethionamide and PAS are all hepatotoxic
drugs. Slow acetylators of isoniazid are at a higher risk of hepatotoxicity.
The
hepatotoxic effects of rifampicin and isoniazide are believed to be additive,
whereas
the hepatic damage due to pyrazinamide is related to dose and duration.
Accordingly,
patients with liver disease and who are treated with these agents are at risk
of liver
damage. If that were not bad enough, patients being treated for viral liver
diseases
such as HCV and HBV are at a higher risk, as several of these agents are not
only
hepatotoxic, they are also modulators (primarily inducers) of CYP450, which
adversely affects the metabolism of several anti-HCV and anti-HBV agents.
The present invention is not to be limited in scope by the specific
embodiments described herein. Indeed, various modifications of the invention
in
addition to those described will become apparent to those skilled in the art
from the
foregoing description. Such modifications are intended to fall within the
scope of the
appended claims.
Various publications are cited herein, the disclosures of which are
incorporated by reference in their entireties.
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