Note: Descriptions are shown in the official language in which they were submitted.
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PHARMACEUTICAL COMPOSITION COMPRISING GABOXADOL AND AN INHIBITOR OF PAT1 OR
OAT
FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition comprising
gaboxadol or a
pharmaceutically acceptable salt thereof and one or more inhibitors of PAT1
and/or one or
more inhibitors of OAT. The present invention further relates to a
pharmaceutical
composition comprising from about 0.5 mg to about 50 mg gaboxadol or a
pharmaceutically
acceptable salt thereof, wherein the composition provides an in vivo plasma
profile
comprising a mean Tmax which is longer than about 20 minutes.
BACKGROUND OF THE INVENTION
Gaboxadol (4, 5, 6, 7-tetrahydroisoxazolo [5,4-c] pyridine-3-ol) (THIP) is
described in EP
Patent No. 0000338 and in EP Patent No. 0840601, and has previously shown
great potential
in the treatment of sleep disorders and in pre-clinical models of depression
(W02004112786).
Gaboxadol has the following general formula:
OH
\N
HN
Gaboxadol may be prepared using methods that are well known in the art. For
example as
disclosed in EP Patent No. 0000338 and in W02005023820.
W002094225 discloses a granular preparation containing gaboxadol that can be
used for the
preparation of solid, shaped pharmaceutical unit dosage forms containing
gaboxadol with an
immediate release profile.
W00122941 discloses a melt granulated composition containing gaboxadol and a
modified
release dosage form prepared from said composition.
In therapeutic dosing with a gaboxadol immediate release formulation, rapid
dissolution
results in a rapid increase in blood plasma levels of gaboxadol shortly after
administration
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2
followed by a decrease in blood plasma levels over several hours as gaboxadol
is metabolized
or eliminated, until sub-therapeutic plasma levels are approached.
Some pharmacological and physiological processes may require a prolonged
exposure at
therapeutic relevant plasma levels in order to reach optimal therapeutic
effects. Thus there is a
need for a pharmaceutical dosage form of gaboxadol capable of providing a
prolonged
exposure at therapeutic relevant plasma levels. Moreover there is a need for a
pharmaceutical
dosage form of gaboxadol that provides a plasma profile with a later Tmax
and/or a decreased
Cmax, possibly supplemented with an increase in AUC.
It has now surprisingly been found that it is possible to prepare a
formulation of gaboxadol
that have demonstrated to alter the absorption of gaboxadol and thereby
minimise the peak
concentration, extent the Tmax and in special situations further extent the
elimination phase
of the pharmacokinetic profile (i.e. to increase AUC).
SUMMARY OF THE INVENTION
In one aspect the present invention relates to a pharmaceutical composition
comprising
gaboxadol or a pharmaceutically acceptable salt thereof and one or more
inhibitors of PAT1
and/or one or more inhibitors of OAT.
In another aspect the present invention relates to a pharmaceutical
composition comprising
from about 0.5 mg to about 50 mg gaboxadol or a pharmaceutically acceptable
salt thereof,
wherein the composition provides an in vivo plasma profile comprising a mean
Tmax which
is longer than about 20 minutes.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1: Plasma gaboxadol concentrations vs. time profiles after IV dosing in
dog. Plasma
concentrations of gaboxadol vs. time profiles after an intravenous injection
of 2.5 mg/kg
gaboxadol (A, (A)). Blood samples were collected at 5, 15, 30, 60, 90, 120,
180, 240, 360,
480 and 600 minutes after the drug administration. Shown is mean S.E.M. of
six dogs, n=6.
Y-axis: plasma concentration of gaboxadol (ng/ml). X-axis: time (minutes).
Figure 2: Plasma gaboxadol concentrations vs. time profiles after PO dosing in
dog. Plasma
gaboxadol concentrations vs. time profiles of beagle dogs after PO
administration of 2.5
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3
mg/kg gaboxadol (B, (^)). The same dose was also given with 2.5 mg/kg Tip
(C,(A)), with
10.0 mg/kg Tip (D,(x)), with 50.0 mg/kg Trp (E,(o)) and with 150.0 mg/kg Trp
(F,(^)). The
Trp was given as a co-administration at the same time as gaboxadol. Samples
were collected
at 5, 15, 30, 60, 90, 120, 180, 240, 360, 480 and 600 minutes after the drug
administration.
Shown is mean S.E.M. of six dogs, n=6. Y-axis: plasma concentration of
gaboxadol
(ng/ml). X-axis: time (minutes).
Figure 3: Plasma gaboxadol concentrations vs. time profiles after PO dosing in
rat. Plasma
gaboxadol concentrations vs. time profiles of rats after PO administration of
gaboxadol. Dose
given was 0.5 mg/kg (G, (o)) or 5.0 mg/kg (H, (.)) of gaboxadol alone or with
a pre-
incubation of 200.0 mg/kg 5-HTP (I, (^)) or (J, ^)), respectively. 5-HTP 200.0
mg/kg was
given as a pre-incubation 30 min. before gaboxadol. Samples were collected at
5, 15, 30, 45,
60, 120, 240, 360 and 480 minutes after the drug administration. Shown is mean
S.E.M. of
five to six rats, n=5-6. Y-axis: plasma concentration of gaboxadol (ng/ml). X-
axis: time
(minutes).
Figure 4: Plasma gaboxadol concentrations vs. time profiles after IV dosing in
rat. Plasma
gaboxadol concentrations vs. time profiles of rats after IV administration of
gaboxadol. Rats
were given an intravenous injection of 2.5 mg/kg gaboxadol (K, (A)). The same
dose was also
given with 200.0 mg/kg 5-HTP (L, (A)). 5-HTP 200.0 mg/kg was given as a pre-
incubation
min. before the gaboxadol. Samples were collected at 5, 15, 30, 45, 60, 120,
240, 360 and
480 minutes after the drug administration. Shown is mean S.E.M. of five to
six rats, n=5-6.
Y-axis: plasma concentration of gaboxadol (ng/ml). X-axis: time (minutes).
25 DESCRIPTION OF THE INVENTION
The present inventors have found that therapeutic dosing with an immediate
release
formulation of gaboxadol in some patients with primary insomnia has resulted
in dose
dependent adverse events. The observed adverse events occurred about the same
time as mean
Cmax, and disappeared after a few hours after administration, thus the adverse
events are
30 correlated to Cmax. The observed adverse events with the immediate release
formulation of
gaboxadol include dizziness, nausea, vomiting, somnolence, tremor, malaise,
sedation, and
some psychiatric adverse events. By further analysis of the adverse events,
the present
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inventors found that by reducing the mean Cmax and/or by a longer mean Tmax,
the adverse
events are rare, milder, and the psychiatric adverse events are non-existing.
The present inventors have found that it is possible to prepare a
pharmaceutical composition
comprising gaboxadol and one or more inhibitors of PAT1 and/or one or more
inhibitors of
OAT to provide a modified absorption formulation of gaboxadol. According to
the present
invention it is possible to modulate the Cmax, the Tmax and in some instances
the AUC of
gaboxadol by varying the amount of gaboxadol, one or more inhibitors of PAT1
and/or of
OAT used in the pharmaceutical composition. The composition according to the
present
invention gives one or more of the following advantages: a rapid increase in
blood plasma
levels of gaboxadol can be avoided or diminished, a pharmacokinetic profile of
gaboxadol
with a later Tmax and/or a decreased Cmax can be achieved, which in some
circumstances
can be supplemented with an increase in AUC. One or more of the following
problems can
thus be solved by the present invention: effects associated with a rapid
increase in blood
plasma levels of gaboxadol can be avoided or diminished while reaching
relevant therapeutic
blood plasma levels and/or the time interval between dosing with gaboxadol can
be extended
compared to an immediate release formulation as the therapeutic relevant blood
plasma level
is maintained over a longer period of time. Thus according to the present
invention a
pharmaceutical composition comprising gaboxadol is provided, which is capable
of reaching
therapeutic relevant plasma levels without reaching plasma levels associated
with most
adverse events, and in some circumstances for an extended period of time.
Thus the present invention relates to a pharmaceutical composition comprising
gaboxadol or a
pharmaceutically acceptable salt thereof wherein the composition provides a
decreased mean
Cmax as compared to an immediate release formulation of gaboxadol and still
provides
therapeutic relevant plasma levels of gaboxadol.
Without being bound by any particular theory it is hypothesized that the PAT1
inhibitor in the
composition according to the present invention decreases the absorption rate
of gaboxadol
from the gastrointestinal tract and thereby provides a modified absorption of
gaboxadol. It is
further hypothesized that some, maybe all PAT1 inhibitors, and OAT substrates
or inhibitors
interact with one or more organic anion transporters (OATs) in the kidneys
and/or reduce the
renal blood flow and thereby also decreases the elimination rate of gaboxadol
from the
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kidneys and thereby provides a blood plasma level of gaboxadol at the
therapeutic relevant
level over a longer period of time.
The human proton dependent amino acid transporter 1, hPATI, was cloned from
Caco-2 cells
5 in 2003 (Chen, Z. et al. 2003. J Physiol., Vol. 546. Pt 2. 349-361). The
transporter belongs to
the solute carrier family SLC36 and is the first (SLC36A1) of four. PAT3 and
PAT4 are
orphan transporters whereas PAT2 is expressed mainly in tissue of lung, heart,
kidney,
muscle, testis, spleen, adrenal gland, thymus and sciatic nerve. Analyses have
discovered
hPATI mRNA expression ubiquitously in human tissue and it has been detected
all along the
human gastrointestinal tract with maximal expression in the small intestine,
hence making the
transporter relevant for absorption of substrates at the hole length of the
intestinal tract (Chen,
Z. et al. 2003. J Physiol., Vol. 546. Pt 2. 349-361). The amino acid transport
via hPAT1 is
energized by a significant concentration gradient of protons (H) that is built
up across the
apical membrane due to an acidic microclimate in the intestinal (Lucas, M. L.
et al. 1975.
Proc R.Soc Lond.B Biol Sci., Vol. 192. 1106. 39-48).
The Caco-2 cell line can be used as a model of the human small intestinal
epithelium. The
proton dependent amino acid transporter has previously been characterized
thoroughly in this
vitro model and also to some extends, in transfected cell systems (Boll, M. et
al. 2002. J Biol
Chem., Vol. 277. 25. 22966-22973; Chen, Z. et al. 2003. J Physiol., Vol. 546.
Pt 2. 349-361).
By competition assays as well as translocation experiments, various compounds
have been
tested for interaction with PAT 1. According to these in vitro
characterizations of a PAT1
substrate refers to a compound that is transported across a (21-28 days old)
Caco-2 cell
monolayer with a flux increasing with the transmembrane pH gradient.
Furthermore, by
addition of a high concentration of another PAT1 substrate, which could be L-
Proline but not
limited to, this transport must be inhibited.
A PAT1 inhibitor refers to a compound that decreases the transport of PAT1
substrates across
a Caco-2 cell monolayer. The inhibitor can act in a competitive or non-
competitive manner,
depending if it binds the transporter in the substrate pocket or not.
Classic PAT1 substrates are small zwitterionic unbranched a-amino acids like
glycine,
alanine, serine and proline in addition to some (3-amino acids as (3-alanine
and AIB(a-
(Methylamino)-isobutyric acid) as well as a few y-amino acids like GABA (y-
amino butyric
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acid) (Metzner, L. et al. 2006. Amino.Acids., Vol. 31.2. 111-117). Some
xenobiotics have
been demonstrated to be among the hPAT1 substrates, e.g. the neuromodulatory
and
antibacterial agent D-cycloserine. Also several GABA receptor blockers and
reuptake
inhibitors as well as proline analogues used in treatment of cancer and
fibrotic diseases are
transported by PAT1 (Metzner, L. et al. 2006. Amino.Acids., Vol. 31. 2. 111-
117).
Possible competitive PAT1 inhibitors includes but are not limited to: Glycine,
L-Alanine, D-
Alanine, L-Serine, D-Serine, L-Proline, D-Proline, GABA (y-amino butyric
acid), Sarcosine,
Betaine, N-Methyl-L-alanine (AIB (a-(Methylamino)-isobutyric acid)), D-
cycloserine, J3-
Alanine, Vigabatrine, Guvacine, TACA (trans-4-aminocrotonic acid).
Possible PAT1 inhibitors could be but is not limited to: 5-hydroxy-tryptophan
(5-HTP),
Serotonin (5-HT), L-tryptophan (Trp), Tryptamine, Indole-3-propionic acid.
The organic anion transporters (OATs) were identified in 1997. The transporter
belongs to the
SLC22 gene family (Koepsell, H. et al. 2004. Pflugers.Arch., Vol. 447. 5. 666-
676) and are
characterised by a remarkable broad substrate specificity. The currently known
transporters
include OAT 1-4 and URAT 1, which are mainly located in kidneys (Rizwan, A. N.
et al. 2007.
Pharm.Res., Vol. 24. 3. 450-470), hence several publications have focused on
the transporters
contribution to renal secretion of xenobiotics and drugs (for review see
Burckhardt, B. C. et
al. 2003. Rev Physiol Biochem Pharmacol., Vol. 146. 95-158). Expression have
also been
reported in the brain, especially in the choroids plexus and the blood brain
barrier (Pritchard,
J. B. et al. 1999. J Biol Chem., Vol. 274. 47. 33382-33387), the eyes, the
skeletal muscle and
several organs in different stages of embryo development (Pavlova, A. et al.
2000. Am.J
Physiol Renal Physiol., Vol. 278. 4. F635-F643). OATs do not directly utilize
ATP hydrolysis
for energtisation of substrate translocation. Most, if not all members of the
OAT family
operate as anion exchangers, i.e. they couple the uptake of an organic anion
into the cell to the
release of another organic anion from the cell. Thereby, OAT utilize existing
intracellular>extracellular gradients of anions, e.g. a-ketoglutarate, lactate
and nicotinate, to
drive uphill uptake of organic anions against the negative membrane potential.
In the kidney
proximal tubule, OAT are functionally couples to Na+-driven mono- and
dicarboxylate
transporters that establish and maintain the intracellular>extracellular
gradients of lactate,
nicotinate and a-ketoglutarate (Rizwan, A. N. et al. 2007. Pharm.Res., Vol.
24. 3. 450-470).
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Typical substrates of OATs have a molecular weight of up to 400-500 (Sekine,
T. et al. 2006.
Am.J Physiol Renal Physiol., Vol. 290. 2. F251-F261; Wright, S. H. et al.
2004. Am.J Physiol
Renal Physiol., Vol. 287. 3. F442-F451), and the specificity are very broad in
terms of
chemical structures being transported by the OATs, including but not limited
to: Kynurenate,
Xanthurenate, 5-hydroxyindol acetate, p-aminohippurate, 6-carboxyflurescein,
Benzylpenicillin, Cefadroxil, Cefamadole, Cefazolin, Cefoperazone, Cefotamime,
Cephalexine, Cephalotin, Cephradine, Acylovir, Adefovir, Cidofovir,
Ganciclovir, Tenofovir,
Valacylovir, Zidovudine, Acetazolamide, Bumetanide, Chlorothiazide,
Ethacrynate,
Furosemide, Hydrochlorothiazide, Methazolamide, Trichloromethiazide,
Acetaminophen,
Acetylsalicylate Dilofenac, Diflusinal, Etodolac, Flurbiprofen, Ibuprofen,
Indomethacin,
Ketoprofen, Loxoprofen, Mefanamate, Naproxen, Phenacetin, Piroxicam,
Salicylate, Sulidac.
An OAT substrate is here defined by a compound, which is transported into
oocytes
transfected with OAT mRNA, with a significant increased rate compared to a
control
situation.
Definitions
Cmax is defined as the highest plasma drug concentration estimated during an
experiment
(ng*ml'). Tmax is defined as the time when Cmax is estimated (min). AUC is the
total area
under the plasma drug concentration-time curve, from drug administration until
the drug is
eliminated (ng*min*m1-'). The area under the curve is governed by clearance.
Clearance is
defined as the volume of blood or plasma that is totally cleared of its
content of drug per unit
time (ml*hr-' *kg-z). Elimination rate constant relates to the amount of drug
in the body, which
is eliminated per unit time is defined as the velocity with which the drug is
eliminated (hr-1)
(Gabrielsson and Weiner. 2007. Pharmacokinetic and Pharmacodynamic Data
Analysis,
Concepts and Applications, 4th ed., CRC Press, Baco Raton, FL ISBN 978-9-1976-
5100-4).
The term "PK" refers to the pharmacokinetic profile.
As used herein, the term "subject" refers to any warm-blooded species such as
human and
animal. The subject, such as a human, to be treated with gaboxadol may in fact
be any subject
of the human population, male or female, which may be divided into children,
adults, or
elderly. Any one of these patient groups relates to an embodiment of the
invention.
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As used herein, the term "treating" or "treatment" refers to preventing or
delaying the
appearance of clinical symptoms of a disease or condition in a subject that
may be afflicted
with or predisposed to the disease or condition, but does not yet experience
or display clinical
or subclinical symptoms of the disease or condition. "Treating" or "treatment"
also refers to
inhibiting the disease or condition, i.e., arresting or reducing its
development or at least one
clinical or subclinical symptom thereof "Treating" or "treatment" further
refers to relieving
the disease or condition, i.e., causing regression of the disease or condition
or at least one of
its clinical or subclinical symptoms. The benefit to a subject to be treated
is either statistically
significant or at least perceptible to the subject and/or the physician.
Nonetherless,
prophylactic (preventive) and therapeutic (curative) treatment are two
separate embodiments
of the invention.
As used herein, the term "pharmaceutically acceptable" refers to molecular
entities and
compositions that are "generally regarded as safe" - e.g., that are
physiologically tolerable and
do not typically produce an allergic or similar untoward reaction, such as
gastric upset and the
like, when administered to a human. In another embodiment, this term refers to
molecular
entities and compositions approved by a regulatory agency of the federal or a
state
government, as the GRAS list under section 204(s) and 409 of the Federal Food,
Drug and
Cosmetic Act, that is subject to premarket review and approval by the FDA or
similar lists,
the U.S. Pharmacopeia or another generally recognized pharmacopeia for use in
animals, and
more particularly in humans.
According to a first aspect the present invention relates to a pharmaceutical
composition
comprising gaboxadol or a pharmaceutically acceptable salt thereof and one or
more
inhibitors of PAT1 and/or one or more inhibitors of OAT. In one embodiment of
the first
aspect of the invention the composition comprises one or more inhibitors of
PAT1 but not an
inhibitor of OAT. In another embodiment of the first aspect of the invention
the composition
comprises one or more inhibitors of OAT but not an inhibitor of PAT I. In
another
embodiment of the first aspect of the invention the composition comprises both
one or more
inhibitors of PAT1 and one or more inhibitors of OAT. In another embodiment of
the first
aspect of the invention gaboxadol is in the form of an acid addition salt, or
a zwitter ion
hydrate or zwitter ion anhydrate. In another embodiment of the first aspect of
the invention
gaboxadol is in the form of a pharmaceutically acceptable acid addition salt
selected from the
hydrochloride or hydrobromide salt, or in the form of the zwitter ion
monohydrate. In another
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embodiment of the first aspect of the invention the amount of gaboxadol ranges
from 0.5 mg
to 50 mg. In another embodiment of the first aspect of the invention the
composition is an oral
dose form. In another embodiment of the first aspect of the invention the
composition is a
solid oral dose form, such as tablets or capsules, or a liquid oral dose form.
In another
embodiment of the first aspect of the invention said gaboxadol is crystalline.
In another
embodiment of the first aspect of the invention PAT1 is human PAT 1. In
another embodiment
of the first aspect of the invention the inhibitor of PAT1 is selected from 5-
hydroxy-
tryptophan (5-HTP), L-Proline, D-Proline, Sarcosine, L-Alanine, D-Alanine, N-
Methyl-L-
alanine, N-Methyl-D-alanine, a-(Methylamino)-isobutyric acid, Betaine, D-
cycloserine, L-
cycloserine, (3-Alanine, Serotonin, L-tryptophan, D-tryptophan, Tryptamine,
Indole-3-
propionic acid. In another embodiment of the first aspect of the invention the
amount of PAT1
inhibitor ranges from about 0.5 to about 3000 mg, such as about 1, 5, 10, 25,
50, 100, 150,
200, 250, 300, 350, 400, 450, 500, 750, 1000, 1250, 1500, 1750, 2000, 2250,
2500, 2750 or
3000 mg. In another embodiment of the first aspect of the invention OAT is
human OAT. In
another embodiment of the first aspect of the invention the inhibitor of OAT
is selected from
Kynurenate, Xanthurenate, 5-hydroxyindol acetate, p-aminohippurate, 6-
carboxyflurescein,
Benzylpenicillin, Cefadroxil, Cefamadole, Cefazolin, Cefoperazone, Cefotamime,
Cephalexine, Cephalotin, Cephradine, Acylovir, Adefovir, Cidofovir,
Ganciclovir, Tenofovir,
Valacylovir, Zidovudine, Acetazolamide, Bumetanide, Chlorothiazide,
Ethacrynate,
Furosemide, Hydrochlorothiazide, Methazolamide, Trichloromethiazide,
Acetaminophen,
Acetylsalicylate Dilofenac, Diflusinal, Etodolac, Flurbiprofen, Ibuprofen,
Indomethacin,
Ketoprofen, Loxoprofen, Mefanamate, Naproxen, Phenacetin, Piroxicam,
Salicylate, Sulidac.
In another embodiment of the first aspect of the invention the amount of OAT
inhibitor ranges
from about 0.5 to about 500 mg, such as about 1, 5, 10, 25, 50, 100, 150, 200,
250, 300, 350,
400, 450 or 500 mg. In another embodiment of the first aspect of the invention
the
composition comprises one or more excipients. In another embodiment of the
first aspect of
the invention the composition comprises a compound, which is a serotonin
reuptake inhibitor,
or any other compound which causes an elevation in the level of extracellular
serotonin. In
another embodiment of the first aspect of the invention the serotonin uptake
inhibitor is
selected from citalopram, escitalopram, fluoxetine, sertraline, paroxetine,
fluvoxamine,
venlafaxine, duloxetine, dapoxetine, nefazodone, imipramin, femoxetine and
clomipramine or
a pharmaceutically acceptable salt of any of these compounds. In another
embodiment of the
first aspect of the invention the serotonin uptake inhibitor is escitalopram,
as the base or a
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pharmaceutically acceptable salt thereof, such as the oxalate, hydrobromide or
hydrochloride
salt.
According to a second aspect the present invention relates to a pharmaceutical
composition
5 comprising from about 0.5 mg to about 50 mg gaboxadol or a pharmaceutically
acceptable
salt thereof, wherein the composition provides an in vivo plasma profile
comprising a mean
Tmax which is longer than about 20 minutes. In one embodiment of the second
aspect of the
invention said mean Tmax is longer than about 25, 30, 35, 40, 45, 50, 55, 60,
65, 70 or 75
minutes. In another embodiment of the second aspect of the invention the
composition
10 provides an in vivo plasma profile comprising a mean Cmax of less than
about 2250 ng/ml. In
another embodiment of the second aspect of the invention said mean Cmax is
less than about
2000, 1750, 1500, 1250, 1000, 750, 500, 250, 200 or 100 ng/ml. In another
embodiment of
the second aspect of the invention the composition provides an in vivo plasma
profile
comprising a mean AUCo_- of more than about 8.000 ng=min=ml-1. In another
embodiment of
the second aspect of the invention said mean AUC0_- is more than about 16.000,
20.000,
40.000, 80.000, 120.000 or 200.000 ng=min=ml-1. In another embodiment of the
second aspect
of the invention the clearance is lower than 40 ml/min. In another embodiment
of the second
aspect of the invention said clearance is lower than 30 ml/min, 20 ml/min, 10
ml/min or 5
ml/min. In another embodiment of the second aspect of the invention the
composition
comprises about 2 mg gaboxadol or a pharmaceutically acceptable salt thereof
and provides
an in vivo plasma profile comprising: a mean Tmax of more than about 20
minutes; a mean
Cmax of less than about 100 ng/ml; and a mean AUC0_- of more than about 8.000
ng=min=ml-
In another embodiment of the second aspect of the invention the composition
comprises
about 4 mg gaboxadol or a pharmaceutically acceptable salt thereof and
provides an in vivo
plasma profile comprising: a mean Tmax of more than about 20 minutes; a mean
Cmax of
less than about 200 ng/ml; and a mean AUC0_- of more than about 16.000
ng=min=ml-1. In
another embodiment of the second aspect of the invention the composition
comprises about 5
mg gaboxadol or a pharmaceutically acceptable salt thereof and provides an in
vivo plasma
profile comprising: a mean Tmax of more than about 20 minutes hours; a mean
Cmax of less
than about 250 ng/ml; and a mean AUC0_- of more than about 20.000 ng=min=ml-1.
In another embodiment of the second aspect of the invention the composition
comprises about
10 mg gaboxadol or a pharmaceutically acceptable salt thereof and provides an
in vivo plasma
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profile comprising: a mean Tmax of more than about 20 minutes; a mean Cmax of
less than
about 500 ng/ml; and a mean AUC0_- of more than about 40.000 ng=min=ml-1.
In another embodiment of the second aspect of the invention the composition
comprises about
20 mg gaboxadol or a pharmaceutically acceptable salt thereof and provides an
in vivo plasma
profile comprising: a mean Tmax of more than about 20 minutes; a mean Cmax of
less than
about 1000 ng/ml; and a mean AUC0_- of more than about 80.000 ng=min=ml-1.
In another embodiment of the second aspect of the invention the composition
comprises about
30 mg gaboxadol or a pharmaceutically acceptable salt thereof and provides an
in vivo plasma
profile comprising: a mean Tmax of more than about 20 minutes; a mean Cmax of
less than
about 1500 ng/ml; and a mean AUC0_- of more than about 120.000 ng=min=ml-1.
In another embodiment of the second aspect of the invention the composition
comprises about
50 mg gaboxadol or a pharmaceutically acceptable salt thereof and provides an
in vivo plasma
profile comprising: a mean Tmax of more than about 20 minutes; a mean Cmax of
less than
about 2500 ng/ml; and a mean AUC0_- of more than about 200.000 ng=min=ml-1.
In another embodiment of the second aspect of the invention the clearance is
lower than 40
ml/min and the AUC higher than 200.000 ng=min=ml-1.
In another embodiment of the second aspect of the invention said mean Tmax,
Cmax and/or
AUC0_- is obtained when the composition is administered to a dog and said
clearance is
obtained when the composition is administered to a dog or rat.
In another embodiment of the second aspect of the invention said mean Tmax is
longer than
about 30 minutes. In another embodiment of the second aspect of the invention
the
composition provides an in vivo plasma profile comprising a mean Cmax of less
than about
300 ng/ml. In another embodiment of the second aspect of the invention the
amount of
gaboxadol is selected from about 2.5 mg, about 5 mg or about 10 mg. In another
embodiment
of the second aspect of the invention the amount of gaboxadol is 2.5 mg, mean
Cmax is less
than about 40 ng/ml, such as 35 about ng/ml, 30 ng/ml, 25 ng/ml or 20 ng/ml,
and mean Tmax
is longer than about 1 hour, such as 1.5 hours, 2 hours or 2.5 hours. In
another embodiment of
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12
the second aspect of the invention the amount of gaboxadol is 5 mg, mean Cmax
is less than
about 85 ng/ml, such as 80 about ng/ml, 75 ng/ml, 70 ng/ml or 65 ng/ml, and
mean Tmax is
longer than about 1 hour, such as 1.5 hours, 2 hours or 2.5 hours. In another
embodiment of
the second aspect of the invention the amount of gaboxadol is 10 mg, mean Cmax
is less than
about 150 ng/ml, such as 145 about ng/ml, 140 ng/ml, 135 ng/ml or 130 ng/ml,
and mean
Tmax is longer than about 1 hour, such as 1.5 hours, 2 hours or 2.5 hours. In
another
embodiment of the second aspect of the invention said mean Tmax and Cmax is
obtained
when the composition is administered to a human. In another embodiment of the
second
aspect of the invention gaboxadol is in the form of an acid addition salt, or
a zwitter ion
hydrate or zwitter ion anhydrate. In another embodiment of the second aspect
of the invention
gaboxadol is in the form of a pharmaceutically acceptable acid addition salt
selected from the
hydrochloride or hydrobromide salt, or in the form of the zwitter ion
monohydrate. In another
embodiment of the second aspect of the invention the composition is an oral
dose form. In
another embodiment of the second aspect of the invention the composition is a
solid oral dose
form, such as tablets or capsules, or a liquid oral dose form. In another
embodiment of the
second aspect of the invention said gaboxadol is crystalline. In another
embodiment of the
second aspect of the invention the composition comprises one or more
excipients.
In one embodiment of the invention, the pharmaceutical composition provides a
mean Cmax
corresponding to 80% such as 75%, 70%, or 65% of the Cmax observed with an
immediate
release formulation of gaboxadol. Furthermore the present invention relates to
a
pharmaceutical composition comprising gaboxadol or a pharmaceutically
acceptable salt
thereof wherein the composition provides a mean Tmax which is longer than is
observed with
an immediate release formulation of gaboxadol and still provides therapeutic
relevant plasma
levels of gaboxadol.
In a further embodiment a compound provides inhibition of both PAT1 and OAT.
In a further embodiment, wherein the mean Tmax, Cmax and/or AUC0_- is obtained
when the
composition of the invention is administered to a dog, said dog is a beagle
and said beagle is
fasted 20-24 hours (h) before administration of said composition.
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13
In a further embodiment, wherein the clearance is obtained when the
composition of the
invention is administered to a dog, said dog is a beagle and said beagle is
fasted 20-24 hours
(h) before administration of said composition.
In a further embodiment, wherein the clearance is obtained when the
composition of the
invention is administered to a rat, said rat is a male Sprague-Dawley rat
(Charles River
Laboratories, Wilmington, MA, USA) and said rat is maintained on standard food
and water
until 16-20 hours prior to administration of said composition.
In a further embodiment, the pharmaceutical composition of the present
invention is for the
treatment of a sleep disorder, such as primary insomnia, or depression, such
as major
depression.
Throughout this description, "gaboxadol" is intended to include any form of
the compound,
such as the free base (zwitter ion), pharmaceutically acceptable salts, e.g.,
pharmaceutically
acceptable acid addition salts, hydrates or solvates of the base or salt, as
well as anhydrates,
and also amorphous, or crystalline forms.
In a further embodiment, gaboxadol is selected from the zwitter ion, typically
a hydrate
thereof, although the anhydrate is also suitable. A suitable embodiment is the
zwitter ion
monohydrate.
In a further embodiment, gaboxadol is selected from an acid addition salt,
typically a
pharmaceutically acceptable acid addition salt. A suitable embodiment is an
organic acid
addition salt, such as any one of the maleic, fumaric, benzoic, ascorbic,
succinic, oxalic, bis-
methylenesalicylic, methanesulfonic, ethane-disulfonic, acetic, propionic,
tartaric, salicylic,
citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic,
stearic, palmitic,
itaconic, glycolic, p-amino-benzoic, glutamic, benzene sulfonic or
theophylline acetic acid
addition salts, as well as the 8-halotheophyllines, for example 8-bromo-
theophylline. Another
suitable embodiment is an inorganic acid addition salt, such as any one of the
hydrochloric,
hydrobromic, sulfuric, sulfamic, phosphoric or nitric acid addition salts.
In another embodiment, gaboxadol is in the form of the hydrochloric acid salt,
the
hydrobromic acid salt, or the zwitter ion monohydrate.
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In a further embodiment, gaboxadol is crystalline, such as the crystalline
hydrochloric acid
salt, the crystalline hydrobromic acid salt, or the crystalline zwitter ion
monohydrate.
In a further embodiment, the pharmaceutical composition of the present
invention does
contain hydrophilic cellulose ether polymer, such as
hydroxypropylmethylcellulose, such as
Metolose 90SH-15.000 and Metolose 90SH-100.000.
The acid addition salts according to the invention may be obtained by
treatment of gaboxadol
with the acid in an inert solvent followed by precipitation, isolation and
optionally re-
crystallization by known methods and if desired micronization of the
crystalline product by
wet or dry milling or another convenient process, or preparation of particles
from a solvent-
emulsification process. Suitable methods are described in EP Patent No.
0000338, for
example.
Precipitation of the salt of gaboxadol is typically carried out in an inert
solvent, e.g., an inert
polar solvent such as an alcohol (e.g., ethanol, 2-propanol and n-propanol),
but water or
mixtures of water and inert solvent may also be used.
Gaboxadol may be administered as an oral dose form, such as a solid oral dose
form, typically
tablets or capsules, or as a liquid oral dose form. Gaboxadol may be
administered in an
immediate release dosage form or a controlled or sustained release dosage
form. According to
one embodiment, the dosage form provides controlled or sustained release of
the gaboxadol in
an amount less than a sleep-inducing amount. Gaboxadol may be conveniently
administered
orally in unit dosage forms, such as tablets or capsules, containing the
active ingredient in an
amount from about 0.1 to about 150 mg/day, from about 0.2 to about 100 mg/day,
from about
0.5 to about 50 mg/day, from about 0.1 to about 50 mg/day, from about 1 to
about 15 mg/day,
or from about 2 to about 5 mg/day. Typically, the pharmaceutical composition
comprises
from about 0.5 mg to about 20 mg, such as about 0.5 mg, about 1 mg, about 1.5
mg, about 2
mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5
mg, about 5.5
mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5
mg, about 9
mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg,
about 12 mg,
about 12.5 mg, about 13 mg, about 13.5 mg, about 14 mg, about 14.5 mg, about
15 mg, about
15.5 mg, about 16 mg, about 16.5 mg, about 17 mg, about 17.5 mg, about 18 mg,
about 18.5
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mg, about 19 mg, about 19.5 mg or about 20 mg of gaboxadol. The amount of
gaboxadol is
calculated based on the free base (zwitter ion) form.
In one embodiment, gaboxadol is administered once daily (for example, in the
morning or
5 afternoon) using doses of about 2.5 mg to about 20 mg. In another embodiment
gaboxadol is
administered twice daily.
According to the present invention, gaboxadol or a pharmaceutically acceptable
salt thereof
may be administered in any suitable way, e.g., orally or parenterally, and it
may be presented
10 in any suitable form for such administration, e.g., in the form of tablets,
capsules, powders,
syrups or solutions or dispersions for injection. In another embodiment, and
in accordance
with the purpose of the present invention, gaboxadol is administered in the
form of a solid
pharmaceutical entity, suitably as a tablet or a capsule or in the form of a
suspension, solution
or dispersion for injection. Additionally, gaboxadol may be administered with
a
15 pharmaceutically acceptable carrier, such as an adjuvant and/or diluent.
The invention also relates to a pharmaceutical composition or kit comprising
gaboxadol and a
compound, which is a serotonin reuptake inhibitor (SRI), or any other compound
which
causes an elevation in extracellular 5-HT, and optionally pharmaceutically
acceptable carriers
or diluents.
In an embodiment, the SRIs is selected from citalopram, escitalopram,
fluoxetine, sertraline,
paroxetine, fluvoxamine, duloxetine, venlafaxine, duloxetine, dapoxetine,
nefazodone,
imipramin, femoxetine and clomipramine. Just to clarify, each of these SRIs
constitute
individual embodiments, and may be the subject of individual claims.
The term selective serotonin reuptake inhibitor (SSRI) means an inhibitor of
the monoamine
transporters which has stronger inhibitory effect at the serotonin transporter
than the
dopamine and the noradrenaline transporters.
Selective serotonin reuptake inhibitors (SSRIs) are among the most preferred
serotonin
reuptake inhibitors used according to the present invention. Thus, in a
further embodiment the
SRI is selected from SSRIs, such as citalopram, escitalopram, fluoxetine,
fluvoxamine,
sertraline or paroxetine.
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Citalopram is preferably used in the form of the hydrobromide or as the base,
escitalopram in
the form of the oxalate, fluoxetine, sertraline and paroxetine in the form of
the hydrochloride
and fluvoxamine in the form of the maleate.
Serotonin reuptake inhibitors, including the SSRIs specifically mentioned
hereinabove, differ
both in molecular weight and in activity. As a consequence, the amount of
serotonin reuptake
inhibitor used in combination therapy depends on the nature of said serotonin
reuptake
inhibitor. In one embodiment of the invention, the serotonin reuptake
inhibitor or the
compound causing an increase in the level of extracellular 5-HT, is
administered at lower
doses than required when the compound is used alone. In another embodiment,
the serotonin
reuptake inhibitor or the compound causing an increase in the level of
extracellular 5-HT, is
administered in normal doses.
In a further embodiment the pharmaceutical composition comprising gaboxadol
and a
compound, which is a serotonin reuptake inhibitor (SRI), or any other compound
which
causes an elevation in extracellular 5-HT, and optionally pharmaceutically
acceptable carriers
or diluents may be administered as an oral dose form, such as a solid oral
dose form, typically
tablets or capsules, or as a liquid oral dose form. The composition may be
administered in an
immediate release dosage form or in a controlled or sustained release dosage
form.
Methods for the preparation of solid or liquid pharmaceutical preparations are
well known in
the art. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.,
Lippincott
Williams & Wilkins (2005). Tablets may thus be prepared by mixing the active
ingredients
with excipients known in the art, such as an ordinary carrier, such as an
adjuvant and/or
diluent, and subsequently compressing the mixture in a tabletting machine. Non-
limiting
examples of adjuvants and/or diluents include: corn starch, lactose, mannitol
calcium
phosphate, microcrystalline cellulose, talcum, magnesium stearate, gelatine,
gums, and the
like. Any other adjuvant or additive such as colourings, aroma, and
preservatives may also be
used provided that they are compatible with the active ingredients.
All non-patent references, patents, and patent applications cited and
discussed in this
specification are incorporated herein by reference in their entirety and to
the same extent as if
each was individually incorporated by reference.
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Reference List
1. Boll, M. et al. (2004) Pflugers.Arch. Vol. 447. 5. 776-779
2. Boll, M. et al. (2002) J Biol Chem. Vol. 277. 25. 22966-22973
3. Burckhardt, B. C. et al. (2003) Rev Physiol Biochem Pharmacol. Vol. 146. 95-
158
4. Chen, Z. et al. (2003) J Physiol. Vol. 546. Pt 2. 349-361
5. Gabrielsson, J. and Weiner, D. (2007) Pharmacokinetic and Pharmacodynamic
Data
Analysis, Concepts and Applications, 4th ed., CRC Press, Baco Raton, FL ISBN
978-9-
1976-5100-4
6. Koepsell, H. et al. (2004) Pflugers.Arch. Vol. 447. 5. 666-676
7. Lucas, M. L. et al. (1975) Proc R.Soc Lond.B Biol Sci. Vol. 192. 1106. 39-
48
8. Metzner, L. et al. (2006) Amino.Acids. Vol. 31.2. 111-117
9. Pavlova, A. et al. (2000) Am.J Physiol Renal Physiol. Vol. 278. 4. F635-
F643
10. Pritchard, J. B. et al. (1999) J Biol Chem. Vol. 274. 47. 33382-33387
11. Rizwan, A. N. et al. (2007) Pharm.Res. Vol. 24. 3.450-470
12. Sekine, T. et al. (2006) Am.J Physiol Renal Physiol. Vol. 290. 2. F251-
F261
13. Wright, S. H. et al. (2004) Am.J Physiol Renal Physiol. Vol. 287. 3. F442-
F451
EXAMPLES
Example 1
This example describes data from a study conducted in beagle dogs.
Materials
4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol hydrochloride / C6HgN202, HC1,
(gaboxadol
hydrochloride) and the deuto substituted form C6H4D4N202 , HCL, (deuto-
gaboxadol
hydrochloride) were supplied by H. Lundbeck. 5-Hydroxy-L-tryptophan (5-HTP), L-
tryptophan (Trp), L-proline (Pro), acetonitrile (ACN) and methanol were
obtained from
Sigma-Aldrich (St.Louis, MO, USA). Acetic acid was from MERCK. Heparin, 5000
IE/a.e./ml was purchased from LEO (Ballerup, Dk).
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Methods
In vivo study
Prior to commencement of the studies the protocols were approved by the Animal
Welfare
Committee, appointed by the Danish Ministry of Justice and all animal
procedures were
carried out in compliance with EC Directive 86/609/EEC, the Danish law
regulating
experiments on animals and NIH Guidelines for the Care and Use of Laboratory
Animals. 6
full-grown male beagle dogs (body weight 15.9-21.7 kg) were selected and
allocated into a
roman quadrant design and assigned to receive all 6 formulations of gaboxadol
hydrochloride
randomly during 6 weeks. The dogs were fasted 20-24 hours before the
initiation of the
experiment and fed again 10 hours after the administration. The gaboxadol dose
was given
either as an intravenous injection (1.0 ml/kg) or as an oral solution given by
gavage (5.0
ml/kg) directly into the stomach using a soft tube. All dogs received 2.5
mg/kg gaboxadol. In
addition to gaboxadol, the oral formulations contained 0, 2.5, 10.0, 50.0 or
150.0 mg/kg of
tryptophan to ensure simultaneous co-administration of the two compounds. All
solutions
were adjusted to a pH of 5.2 and osmolarity was checked with a Vapro vapour
pressure
osmometer (model 5520, Wescor Inc. Logan, UT, USA), the intravenous solutions
were
adjusted to isoosmolarity with glucose. Blood samples of 2.0 ml were taken
from the vena
cephalica by individual vein puncture and collected into Eppendorf tubes
containing 200 IE
heparin as anticoagulant. Samples were collected before administration of
gaboxadol and after
5, 15, 30, 60, 90 minutes and 2, 3, 4, 6, 8 and 10 hours after gaboxadol
administration. The
plasma was harvested immediately by centrifugation for 15 minutes at 2200 g
and 4-8 C and
stored at -80 C until further analysis. After each day of gaboxadol dosing the
animals had 6
days of washout.
The pharmacokinetics (PK) was evaluated in WinNonlin. Plasma concentrations
curves of the
animals dosed intravenously were fitted to a 2-compartment model whereas the
data from
animals dosed orally were analysed in a non-compartment model. Statistical
analysis was
done in Sigma Stat.
Quantitative analysis by HPLC and MS/MS detection.
Gaboxadol was extracted from plasma and HBSS+ samples by liquid extraction.
100 l
HBSS+ (80 l purified water were added to the 20 l samples) or 100 l plasma
samples were
mixed with 25 l intern standard (d4-gaboxadol) and 25 l purified water.
Protein
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19
precipitation was carried out by addition of 400 l cold acetonitrile. After
centrifugation at
10,000 g in 15 minutes, 425 l supernatant was transferred to glass tubes and
evaporated to
dryness under nitrogen at 45 C. The samples were re-solved in 80 l
methanol/acetonitrile
(30:70), whirl mixed for 10 minutes and centrifuged in 3 minutes at 3000 rpm,
before
transferral to medium well plates and placed at 10 C in the autosampler.
Gaboxadol
concentration in the extracted samples was subsequently quantified by
hydrophilic interaction
chromatography (HILIC-chromatography) followed by MS/MS detection. The LC
system
comprised of an Agilent 1100 series pump and degasser, a CTC Analytics
interface
transferred data to the computer and a Peltier Thermostat and HTC Pal
autosampler handled
the samples. An Asahipak amino column, (NH2P-50, 150 x 2 mm) from Phenomenex
was
used for the chromatographic separation with a mobile phase of 20.0 mM
ammoniumacetat
pH=4: acetonitrile (30:70) and a flow rate of 0.2 ml/min. 20 L samples were
injected onto
the column, which was kept at room temperature. The total runtime was 10
minutes with the
first 5 minutes of elution let to waste. The elution time of gaboxadol on the
column was
approximately 8 minutes. The MS/MS system used consisted of a Sciex API 4000
MS/MS
detector with a Turbo Ion Spray and Turbo V source (Applied Biosystems). The
detection was
performed in negative ionization mode where gaboxadol (precursor 139.1 Da,
product 110.1
Da) and d4-gaboxadol (precursor 143.0, product 112.2 Da) were measured by
multiple-
reaction-monitoring (MRM). The signals were linear between 0.5 and 2500.0
ng/ml and the
limit of quantification by this procedure was 0.5 ng/ml. The software was from
AnalystTM
(Applied Biosystem, version 4.0).
Results and discussion
The plasma concentrations versus time profiles are presented in figure 1 and
2.
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Table 1. Pharmacokinetic parameters obtained from the animals in example 1. IV
(A) and PO
(B-F) administration of 2.5 mg gaboxadol/kg. Data represents mean SEM, n =
6.
Group A (IV) B C D E F
Tryptophan 0 0 2.5 10 50 150
(mg/kg)
ke(hr) 1.02 0.14 0.46 0.02 0.50 0.03 0.44 0.03 0.50 0.03 0.48 0.07
AUC 5618 +377 4715 248 4760 +350 4032 339 4294 +211 4405 +801
(hr=ng=ml-')
Tmax (hr) - 0.46 0.12 0.35 0.13 0.54 0.15 0.46 0.12 1.50 0.39
Cmax (ng/ml) 5489 +404 2502 43 2473 178 1868+114 1662 37 1419 161
** *** ***
CL (ml/hr/kg) 456 +32 538 29 537 34 645 59 589 26 700 152
Fa - 85.3 5.7 86.1 6.7 75.0 10.4 78.2 6.3 79.7 14.5
** Significant statistical difference from formulation B, P<0.01 in a Pairwise
Multiple Tukey
5 comparison test.
* * * Significant statistical difference from formulation B, P<0.005 in a
Pairwise Multiple
Tukey comparison test.
The bioavailability, Fa, of gaboxadol after oral administration in dog was
found to be 85.3
10 5.7 % (Table 1). Oral coadministration of 2.5-150 mg/kg tryptophan did not
change the AUC
of gaboxadol significantly, and the mean relative bioavailability of the
formulations varied
between 75.0 % (10 mg/kg tryptophan) and 86.1 % (2.5 mg/kg tryptophan).
Likewise, the
elimination rate constants (ke) and the clearance (CL) of gaboxadol did not
change by
coadministration of tryptophan. However, tryptophan coadministration decreased
the maximal
15 gaboxadol plasma concentration, Cmax, by 57% from 2502 ng/ml to 1419 ng/ml
in the absence
and presence of 150 mg/kg tryptophan (p<0.001). Furthermore, the time required
to reach the
maximal plasma concentration, Tmax, was increased from 0.46 hour to 1.5 hours
(p<0.01). The
changes in the Cmax values of the five dose groups clearly indicated a direct
interaction
between gaboxadol and tryptophan
Based upon these data it is evident that Trp has an effect on the absorption
profile of
gaboxadol. This effect is considered to be mediated by the two compounds
interacting with
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21
the PAT1 transporter, i.e. in situations of high Trp doses, gaboxadol can not
be transported by
the PAT 1, as many of the binding sites are taken up by Trp. Co-administration
of a compound
that inhibits or is a substrate to the PAT1 may consequently modify the
absorption profile of
gaboxadol.
Example 2
This example describes data from a study conducted in rats.
Materials
As in example 1
Experimental methods
As in example 1, with the following exception:
Oral formulations
0.05 or 0.5 mg gaboxadol as well as 0.0 or 20.0 mg 5-HTP was dissolved in
purified water pr
ml. at room temperature and placed on ice in ultrasound for 10 min. The
formulations were
adjusted to pH 4-5 and with NaOH/HCl and made isotonic by addition of
mannitol. pH of all
solutions was adjusted to pH above 4.0 and below 5.0, the osmolality was
adjusted with
mannitol to 280 mmol/kg.
In vivo experiments
Male Sprague-Dawley rats (Charles River Laboratories, Wilmington, MA, USA) of
220-240
gram were housed and acclimated for 7 days before entering the experiments.
The rats were
maintained on standard food and water until 16-20 hours prior to dosing when
food was
retrieved to insure complete gastric emptying before experiments were
conducted. Water was
available to the animals until beginning of experiment and again 2 hours
after. Each animal
was randomly assigned to receive either one of the intravenous or oral
formulations.
6 parallel groups of rats (n=6) were given isotonic solutions of 0.5 or 5.0
mg/kg of gaboxadol
together with saline or 200.0 mg/kg 5-HTP, by oral gavage (10.0 ml/kg). The
suspensions of
5-HTP were given as a pre-incubation 30 min. prior to the gaboxadol solutions.
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Blood samples of 0.2 ml were taken from the tail vein by individual vein
puncture and
collected into plasma collection tubes containing 20 IE heparin. Samples were
collected at 5,
15, 30, 45, 60 minutes and after 2, 3, 4, 6, 8 hours after gaboxadol
administration. The plasma
was harvested immediately by centrifugation for 10 min. at 3.600 g and stored
at -80 C until
further analysis. At the conclusion of the experiment the animals were
euthanized.
Results and discussion
The plasma concentrations versus time profiles are presented in figure 3.
Table 2. Pharmacokinetic parameters obtained from the animals in example 2, PO
administration of 0.5 and 5.0 mg gaboxadol/kg. Data represents mean SEM, n =
6.
Treatment G H I J
Gaboxadol (mg/kg) 0.5 0.5 5.0 5.0
5-http (mg/kg) - 200.0 - 200.0
K, S.E.M. (min') 0.0164 0.0021 0.0038 0.0004 0.0199 0.0017 0.0058
0.0008
Tv, (min) 46 190 36 141
AUC S.E.M. 13980 1273 75403 12665 114055 10058 379724 126717
(ng=mm=ml-)
Tmax S.E.M. (min) 16 3.3 63 12.5 20 3.2 43 2.5
Cmax S.E.M. (ng/ml) 273 26.7 294 39.4 2061 153.1 1854 509.4
As seen in Figure 3 and Table 2 absorption of gaboxadol after oral
administration happened
mostly within 15-20 minutes after dosing as the plasma concentration of
gaboxadol increased
in this period. After 15-20 minutes elimination of gaboxadol was increasing
and the plasma
concentration of gaboxadol decreased. The time of peak plasma gaboxadol
concentration
(Tmax) was postponed from 16 to 63 minutes when 200 mg 5-HTP/kg was given as a
pre-
incubation before 0.5 mg gaboxadol/kg. When rats were given 5.0 mg
gaboxadol/kg the Tmax
was postponed from 20 to 43 minutes after pre-incubation with 5-HTP. The
maximum plasma
concentration Cmax did not seem to change by pre-incubation of 5-HTP.
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When the animals were dosed with gaboxadol and PAT1 inhibitor 5-HTP, the AUC
increased
compared to control animals (not dosed with 5-HTP). The dose of 5-HTP (200
mg/kg) was 40
or 400 times higher than the dose of gaboxadol (5.0 or 0.5 mg/kg) and the AUC
increased by
330 and 540% compared to the control groups. The AUC may be increased because
of a
decreased elimination rate. The gaboxadol elimination rate constant was
reduced to about
25% when 5-HTP was present.
Taken together, the absorption of gaboxadol seems to be altered by co-
administration of the
PAT inhibitor 5HTP. Further the elimination of gaboxadol seems affected by
interaction with
the PAT, OAT or other transporters which 5-HTP interacts with.
Example 3
Materials
As in example 1
Experimental methods
As in example 2, with the following exception:
Intravenous formulations
0.25 mg gaboxadol as well as 0.0 or 10.0 mg 5-HTP was dissolved in purified
water pr ml. at
room temperature and placed on ice in ultrasound for 10 min. The solutions of
gaboxadol
used for intravenous injection was filtered through a 0.45 m filter.
Animals were administered with 100.0 mg/kg 5-HTP or saline by oral gavage 30
min. prior to
intravenous injection of 2.5 mg/kg gaboxadol into the tail vein (5.0 ml/kg).
Results and discussion
The plasma concentrations versus time profiles are presented in figure 4.
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24
Table 3. Pharmacokinetic parameters obtained from the animals in example 3, IV
administration of 2.5 mg gaboxadol/kg. Data represents mean SEM, n = 6.
Treatment K L
Gaboxadol (mg/kg) 2.5 2.5
5-http (mg/kg) - 100
Ke S.E.M. (mm-') 0.0266 0.0008 0.0181 0.0030
Tv, (min) 26 44
AUC S.E.M. (ng=mm=ml-) 72546 6145 213756 44021
Tmax S.E.M. (min) 5 0.0 5 0.0
Cm S.E.M. (ng/ml) 2854 312.2 4109 302.6
The plasma profile of the IV group pre-incubated with 5-HTP (group L) was
different from
that of rats in the group that received only gaboxadol (group K). The AUC of
group K was
almost 3 times as big as group L, which probably was caused by a smaller
elimination rate
constant Ke (Table 3). These results suggest that 5-HTP interfere with the
clearance of
gaboxadol by interaction with the OAT or other transporters.
AUC-dose-linearity was observed for gaboxadol as the AUC of group G (0.5 mg
gaboxadol/kg) was five times the size of group K (2.5 mg gaboxadol/kg) and AUC
of group J
(5 mg/kg) is almost 10 times the size of group G.
