U.S. patent application number 17/073304 was filed with the patent office on 2021-02-04 for methods for the administration of certain vmat2 inhibitors.
The applicant listed for this patent is Neurocrine Biosciences, Inc.. Invention is credited to Haig P. Bozigian, Christopher F. O'Brien.
Application Number | 20210030742 17/073304 |
Document ID | / |
Family ID | 1000005150784 |
Filed Date | 2021-02-04 |
United States Patent
Application |
20210030742 |
Kind Code |
A1 |
O'Brien; Christopher F. ; et
al. |
February 4, 2021 |
Methods for the Administration of Certain VMAT2 Inhibitors
Abstract
Provided are methods of administering a vesicular monoamine
transport 2 (VMAT2) inhibitor chosen from valbenazine and
(+)-.alpha.-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2-
,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or
isotopic variant thereof to a patient in need thereof wherein the
patient is being treated with a strong cytochrome P450 3A4 (CYP3A4)
inducer.
Inventors: |
O'Brien; Christopher F.;
(San Diego, CA) ; Bozigian; Haig P.; (San Diego,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Neurocrine Biosciences, Inc. |
San Diego |
CA |
US |
|
|
Family ID: |
1000005150784 |
Appl. No.: |
17/073304 |
Filed: |
October 17, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16481033 |
Jul 25, 2019 |
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PCT/US2017/055877 |
Oct 10, 2017 |
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17073304 |
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62451605 |
Jan 27, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/4745
20130101 |
International
Class: |
A61K 31/4745 20060101
A61K031/4745 |
Claims
1.-78. (canceled)
79. A method of treating a patient with a hyperkinetic movement
disorder, wherein the patient is also being administered a strong
cytochrome P450 3A4 (CYP3A4) inducer, comprising: discontinuing
treatment of the strong CYP3A4 inducer, and then orally
administering once daily to the patient a vesicular monoamine
transporter 2 (VMAT2) inhibitor chosen from
(S)-2-amino-3-methyl-butyric acid
(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[-
2,1-a]isoquinolin-2-yl ester and a pharmaceutically acceptable salt
thereof, thereby avoiding the concomitant use of the VMAT2
inhibitor with the strong CYP3A4 inducer.
80. The method of claim 79, wherein the strong CYP3A4 inducer is
chosen from nevirapine, pentobarbital, phenytoin, lumacaftor,
rifabutin, rifampicin, carbamazepine, fosphenytoin, phenobarbital,
primidone, primidone, enzalutamide, mitotane, and St. John's
Wort.
81. The method of claim 79, wherein the strong CYP3A4 inducer is
chosen from rifampicin, carbamazepine, phenytoin, and St. John's
Wort.
82. The method of claim 79, wherein the strong CYP3A4 inducer is
rifampicin.
83. The method of claim 79, wherein the VMAT2 inhibitor is
administered in the form of a capsule.
84. The method of claim 79, wherein the hyperkinetic movement
disorder is tardive dyskinesia.
85. The method of claim 79, wherein the hyperkinetic movement
disorder is chorea.
86. The method of claim 79, wherein the hyperkinetic movement
disorder is chorea associated with Huntington's disease.
87. The method of claim 79, wherein the VMAT2 inhibitor is a
pharmaceutically acceptable salt of (S)-2-amino-3-methyl-butyric
acid
(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[-
2,1-a]isoquinolin-2-yl ester.
88. The method of claim 79, wherein the VMAT2 inhibitor is a
ditosylate salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,
11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]i-
soquinolin-2-yl ester.
89. The method of claim 79, wherein the ditosylate salt of
(S)-2-amino-3-methyl-butyric acid
(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[-
2,1-a]isoquinolin-2-yl ester is in polymorphic Form I.
90. The method of claim 79, wherein the therapeutically effective
amount is an amount equivalent to about 40 mg as measured by
(S)-2-amino-3-methyl-butyric acid
(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[-
2,1-a]isoquinolin-2-yl ester free base once daily for one week, and
an amount equivalent to about 80 mg as measured by
(S)-2-amino-3-methyl-butyric acid
(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[-
2,1-a]isoquinolin-2-yl ester free base once daily after one
week.
91. The method of claim 79, wherein the therapeutically effective
amount is an amount equivalent to about 40 mg as measured by
(S)-2-amino-3-methyl-butyric acid
(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[-
2,1-a]isoquinolin-2-yl ester free base once daily.
92. The method of claim 79, wherein the therapeutically effective
amount is an amount equivalent to about 60 mg as measured by
(S)-2-amino-3-methyl-butyric acid
(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[-
2,1-a]isoquinolin-2-yl ester free base once daily.
93. The method of claim 79, wherein the therapeutically effective
amount is an amount equivalent to about 80 mg as measured by
(S)-2-amino-3-methyl-butyric acid
(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[-
2,1-a]isoquinolin-2-yl ester free base once daily.
94. A method of treating a patient with a hyperkinetic movement
disorder, comprising: (a) orally administering to the patient a
therapeutically effective amount of a vesicular monoamine
transporter 2 (VMAT2) inhibitor chosen from
(S)-2-amino-3-methyl-butyric acid
(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[-
2,1-a]isoquinolin-2-yl ester and a pharmaceutically acceptable salt
thereof; (b) subsequently determining that the patient is being
administered a strong cytochrome P450 3A4 (CYP3A4) inducer; (c)
discontinuing the administration of the strong CYP3A4 inducer; and
(d) continuing the administration of the VMAT2 inhibitor.
95. The method of claim 94, wherein the strong CYP3A4 inducer is
chosen from nevirapine, pentobarbital, phenytoin, lumacaftor,
rifabutin, rifampicin, carbamazepine, fosphenytoin, phenobarbital,
primidone, primidone, enzalutamide, mitotane, and St. John's
Wort.
96. The method of claim 94, wherein the strong CYP3A4 inducer is
chosen from rifampicin, carbamazepine, phenytoin, and St. John's
Wort.
97. The method of claim 94, wherein the strong CYP3A4 inducer is
rifampicin.
98. The method of claim 94, wherein the VMAT2 inhibitor is
administered in the form of a capsule.
99. The method of claim 94, wherein the hyperkinetic movement
disorder is tardive dyskinesia.
100. The method of claim 94, wherein the hyperkinetic movement
disorder is chorea.
101. The method of claim 94, wherein the hyperkinetic movement
disorder is chorea associated with Huntington's disease.
102. The method of claim 94, wherein the VMAT2 inhibitor is a
pharmaceutically acceptable salt of (S)-2-amino-3-methyl-butyric
acid
(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[-
2,1-a]isoquinolin-2-yl ester.
103. The method of claim 94, wherein the VMAT2 inhibitor is a
ditosylate salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,
11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]i-
soquinolin-2-yl ester.
104. The method of claim 94, wherein the ditosylate salt of
(S)-2-amino-3-methyl-butyric acid
(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[-
2,1-a]isoquinolin-2-yl ester is in polymorphic Form I.
105. The method of claim 94, wherein the therapeutically effective
amount is an amount equivalent to about 40 mg as measured by
(S)-2-amino-3-methyl-butyric acid
(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[-
2,1-a]isoquinolin-2-yl ester free base once daily for one week, and
an amount equivalent to about 80 mg as measured by
(S)-2-amino-3-methyl-butyric acid
(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[-
2,1-a]isoquinolin-2-yl ester free base once daily after one
week.
106. The method of claim 94, wherein the therapeutically effective
amount is an amount equivalent to about 40 mg as measured by
(S)-2-amino-3-methyl-butyric acid
(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[-
2,1-a]isoquinolin-2-yl ester free base once daily.
107. The method of claim 94, wherein the therapeutically effective
amount is an amount equivalent to about 60 mg as measured by
(S)-2-amino-3-methyl-butyric acid
(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[-
2,1-a]isoquinolin-2-yl ester free base once daily.
108. The method of claim 94, wherein the therapeutically effective
amount is an amount equivalent to about 80 mg as measured by
(S)-2-amino-3-methyl-butyric acid
(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[-
2,1-a]isoquinolin-2-yl ester free base once daily.
Description
[0001] This application is a continuation of U.S. patent
application Ser. No. 16/481,033, filed on Jul. 25, 2019, which is a
371 of International Application Number PCT/US2017/055877, filed on
Oct. 10, 2017, which claims the benefit of U.S. Provisional
Application No. 62/451,605, filed Jan. 27, 2017, which is
incorporated herein by reference for all purposes.
[0002] Dysregulation of dopaminergic systems is integral to several
central nervous system (CNS) disorders, including neurological and
psychiatric diseases and disorders. These neurological and
psychiatric diseases and disorders include hyperkinetic movement
disorders, and conditions such as schizophrenia and mood disorders.
The transporter protein vesicular monoamine transporter-2 (VMAT2)
plays an important role in presynaptic dopamine release and
regulates monoamine uptake from the cytoplasm to the synaptic
vesicle for storage and release.
[0003] Despite the advances that have been made in this field,
there remains a need for new therapeutic products useful to
treatment of neurological and psychiatric diseases and disorders
and other related diseases or conditions described herein. One such
agent is valbenazine, which has the following chemical
structure:
##STR00001##
[0004] A formulation of valbenazine:4-toluenesulfonate (1:2)
(referred to herein as "valbenazine ditosylate") has been
previously reported in the FDA approved drug label
Ingrezza.RTM..
[0005] The cytochrome P450 enzyme system (CYP450) is responsible
for the biotransformation of drugs from active substances to
inactive metabolites that can be excreted from the body. In
addition, the metabolism of certain drugs by CYP450 can alter their
PK profile and result in sub-therapeutic plasma levels of those
drugs over time.
[0006] There are more than 1500 known P450 sequences which are
grouped into families and subfamily. The cytochrome P450 gene
superfamily is composed of at least 207 genes that have been named
based on the evolutionary relationships of the cytochromes P450.
For this nomenclature system, the sequences of all of the
cytochrome P450 genes are compared, and those cytochromes P450 that
share at least 40% identity are defined as a family (designated by
CYP followed by a Roman or Arabic numeral, e.g., CYP3), and further
divided into subfamilies (designated by a capital letter, e.g.,
CYP3A), which are comprised of those forms that are at least 55%
related by their deduced amino acid sequences. Finally, the gene
for each individual form of cytochrome P450 is assigned an Arabic
number (e.g., CYP3A4).
[0007] CYP3A isoenzyme is a member of the cytochrome P450
superfamily which constitutes up to 60% of the total human liver
microsomal cytochrome P450 and has been found in alimentary passage
of stomach and intestines and livers. CYP3A has also been found in
kidney epithelial cells, jejunal mucosa, and the lungs. CYP3A is
one of the most abundant subfamilies in cytochrome P450
superfamily.
[0008] At least five (5) forms of CYPs are found in human CYP3A
subfamily, and these forms are responsible for the metabolism of a
large number of structurally diverse drugs. In non-induced
individuals, CYP3A may constitute 15% of the P450 enzymes in the
liver; in enterocytes, members of the CYP3A subfamily constitute
greater than 70% of the CYP-containing enzymes.
[0009] CYP3A is responsible for metabolism of a large number of
drugs including nifedipine, macrofide antibiotics including
erythromycin and troleandomycin, cyclosporin, FK506, teffenadine,
tamoxifen, lidocaine, midazolam, triazolam, dapsone, diltiazem,
lovastatin, quinidine, ethylestradiol, testosterone, and
alfentanil. CYP3A is involved in erythromycin N-demethylation,
cyclosporine oxidation, nifedipine oxidation, midazolam
hydroxylation, testosterone 6-.beta.-hydroxylation, and cortisol
6-.beta.-hydroxylation. CYP3A has also been shown to be involved in
both bioactivation and detoxication pathways for several
carcinogens in vitro.
[0010] There is a significant, unmet need for methods for
administering a VMAT2 inhibitor, such as valbenazine or
(+)-.alpha.-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2-
,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or
isotopic variant thereof, to a patient in need thereof, wherein the
patient is also being treated with another substance which may
interact with the VMAT2 inhibitor, such as a CYP3A4 inducer. The
present disclosure fulfills these and other needs, as evident in
reference to the following disclosure.
BRIEF SUMMARY
[0011] Provided is a method of administering a vesicular monoamine
transport 2 (VMAT2) inhibitor chosen from valbenazine and
(+)-.alpha.-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2-
,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or
isotopic variant thereof to a patient in need thereof, comprising:
administering to the patient a therapeutically effective amount of
the VMAT2 inhibitor and informing the patient or a medical care
worker that co-administration of a strong cytochrome P450 3A4
(CYP3A4) inducer is not recommended.
[0012] Also provided is a method of administering a vesicular
monoamine transport 2 (VMAT2) inhibitor chosen from valbenazine and
(+)-.alpha.-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2-
,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or
isotopic variant thereof to a patient in need thereof wherein the
patient is being treated with a strong cytochrome P450 3A4 (CYP3A4)
inducer, comprising: discontinuing treatment of the strong CYP3A4
inducer and then administering the VMAT2 inhibitor to the patient,
thereby avoiding the use of the VMAT2 inhibitor in combination with
the strong CYP3A4 inducer.
[0013] These and other aspects of the invention will be apparent
upon reference to the following detailed description. To this end,
various references are set forth herein which describe in more
detail certain background information, procedures, compounds,
and/or compositions, and are each hereby incorporated by reference
in their entirety.
DETAILED DESCRIPTION
[0014] In the following description, certain specific details are
set forth in order to provide a thorough understanding of various
embodiments. However, one skilled in the art will understand that
the invention may be practiced without these details. In other
instances, well-known structures have not been shown or described
in detail to avoid unnecessarily obscuring descriptions of the
embodiments. Unless the context requires otherwise, throughout the
specification and claims which follow, the word "comprise" and
variations thereof, such as, "comprises" and "comprising" are to be
construed in an open, inclusive sense, that is, as "including, but
not limited to." Further, headings provided herein are for
convenience only and do not interpret the scope or meaning of the
claimed invention.
[0015] Reference throughout this specification to "one embodiment"
or "an embodiment" or "some embodiments" or "a certain embodiment"
means that a particular feature, structure or characteristic
described in connection with the embodiment is included in at least
one embodiment. Thus, the appearances of the phrases "in one
embodiment" or "in an embodiment" or "in some embodiments" or "in a
certain embodiment" in various places throughout this specification
are not necessarily all referring to the same embodiment.
Furthermore, the particular features, structures, or
characteristics may be combined in any suitable manner in one or
more embodiments.
[0016] Also, as used in this specification and the appended claims,
the singular forms "a," "an," and "the" include plural referents
unless the content clearly dictates otherwise.
[0017] As used herein, "valbenazine" may be referred to as
(S)-2-amino-3-methyl-butyric acid (2R,
3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1--
a]isoquinolin-2-yl ester; or as L-Valine,
(2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-
-benzo[a]quinolizin-2-yl ester or as NBI-98854.
[0018] As used herein, "(+)-.alpha.-HTBZ" means the compound which
is an active metabolite of valbenazine having the structure:
##STR00002##
(+)-.alpha.-HTBZ may be referred to as (2R, 3R, 11bR) or as
(+)-.alpha.-DHTBZ or as (+)-.alpha.-HTBZ or as R,R,R-DHTBZ or as
(+)-.alpha.-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2-
,1-a]isoquinolin-2-ol; or as (2R,
3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1--
a]isoquinolin-2-ol or as NBI-98782.
[0019] As used herein, "NBI-136110" means the compound which is
ametabolite of valbenazine having the structure:
##STR00003##
[0020] As used herein, "isotopic variant" means a compound that
contains an unnatural proportion of an isotope at one or more of
the atoms that constitute such a compound. In certain embodiments,
an "isotopic variant" of a compound contains unnatural proportions
of one or more isotopes, including, but not limited to, hydrogen
(.sup.1H), deuterium (.sup.2H), tritium (.sup.3H), carbon-11
(.sup.11C), carbon-12 (.sup.12C), carbon-13 (.sup.13C), carbon-14
(.sup.14C), nitrogen-13 (.sup.13N), nitrogen-14 (.sup.14N),
nitrogen-15 (.sup.15N), oxygen-14 (.sup.14O), oxygen-15 (.sup.15O),
oxygen-16 (.sup.16O), oxygen-17 (.sup.17O), oxygen-18 (.sup.18O),
fluorine-17 (.sup.17F), fluorine-18 (.sup.18F), phosphorus-31
(.sup.31P), phosphorus-32 (.sup.32P), phosphorus-33 (.sup.33P),
sulfur-32 (.sup.32S), sulfur-33 (.sup.33S), sulfur-34 (.sup.34S),
sulfur-35 (.sup.35S), sulfur-36 (.sup.36S), chlorine-35
(.sup.35Cl), chlorine-36 (.sup.36Cl), chlorine-37 (.sup.37Cl),
bromine-79 (.sup.79Br), bromine-81 (.sup.81Br), iodine-123
(.sup.123I), iodine-125 (.sup.125I), iodine-127 (.sup.127I),
iodine-129 (.sup.129I), and iodine-131 (.sup.131I). In certain
embodiments, an "isotopic variant" of a compound is in a stable
form, that is, non-radioactive. In certain embodiments, an
"isotopic variant" of a compound contains unnatural proportions of
one or more isotopes, including, but not limited to, hydrogen
(.sup.1H), deuterium (.sup.2H), carbon-12 (.sup.12C), carbon-13
(.sup.13C), nitrogen-14 (.sup.14N), nitrogen-15 (.sup.15N),
oxygen-16 (.sup.16O), oxygen-17 (.sup.17O), and oxygen-18
(.sup.18O). In certain embodiments, an "isotopic variant" of a
compound is in an unstable form, that is, radioactive. In certain
embodiments, an "isotopic variant" of a compound contains unnatural
proportions of one or more isotopes, including, but not limited to,
tritium (.sup.3H), carbon-11 (.sup.11C), carbon-14 (.sup.14C),
nitrogen-13 (.sup.13N), oxygen-14 (.sup.14O), and oxygen-15
(.sup.15O). It will be understood that, in a compound as provided
herein, any hydrogen can be .sup.2H, as example, or any carbon can
be .sup.13C, as example, or any nitrogen can be .sup.15N, as
example, and any oxygen can be .sup.18O, as example, where feasible
according to the judgment of one of skill in the art. In certain
embodiments, an "isotopic variant" of a compound contains an
unnatural proportion of deuterium.
[0021] With regard to the compounds provided herein, when a
particular atomic position is designated as having deuterium or "D"
or "d", it is understood that the abundance of deuterium at that
position is substantially greater than the natural abundance of
deuterium, which is about 0.015%. A position designated as having
deuterium typically has a minimum isotopic enrichment factor of, in
certain embodiments, at least 1000 (15% deuterium incorporation),
at least 2000 (30% deuterium incorporation), at least 3000 (45%
deuterium incorporation), at least 3500 (52.5% deuterium
incorporation), at least 4000 (60% deuterium incorporation), at
least 4500 (67.5% deuterium incorporation), at least 5000 (75%
deuterium incorporation), at least 5500 (82.5% deuterium
incorporation), at least 6000 (90% deuterium incorporation), at
least 6333.3 (95% deuterium incorporation), at least 6466.7 (97%
deuterium incorporation), at least 6600 (99% deuterium
incorporation), or at least 6633.3 (99.5% deuterium incorporation)
at each designated deuterium position. The isotopic enrichment of
the compounds provided herein can be determined using conventional
analytical methods known to one of ordinary skill in the art,
including mass spectrometry, nuclear magnetic resonance
spectroscopy, and crystallography.
[0022] As used herein, a substance is a "substrate" of enzyme
activity when it can be chemically transformed by action of the
enzyme on the substance. Substrates can be either activated or
deactivated by the enzyme.
[0023] "Enzyme activity" refers broadly to the specific activity of
the enzyme (i.e., the rate at which the enzyme transforms a
substrate per mg or mole of enzyme) as well as the metabolic effect
of such transformations.
[0024] A substance is an "inhibitor" of enzyme activity when the
specific activity or the metabolic effect of the specific activity
of the enzyme can be decreased by the presence of the substance,
without reference to the precise mechanism of such decrease. For
example, a substance can be an inhibitor of enzyme activity by
competitive, non-competitive, allosteric or other type of enzyme
inhibition, by decreasing expression of the enzyme, or other direct
or indirect mechanisms. Co-administration of a given drug with an
inhibitor may decrease the rate of metabolism of that drug through
the metabolic pathway listed.
[0025] A substance is an "inducer" of enzyme activity when the
specific activity or the metabolic effect of the specific activity
of the enzyme can be increased by the presence of the substance,
without reference to the precise mechanism of such increase. For
example, a substance can be an inducer of enzyme activity by
increasing reaction rate, by increasing expression of the enzyme,
by allosteric activation or other direct or indirect mechanisms.
Co-administration of a given drug with an enzyme inducer may
increase the rate of excretion of the drug metabolized through the
pathway indicated.
[0026] Any of these effects on enzyme activity can occur at a given
concentration of active agent in a single sample, donor, or patient
without regard to clinical significance. It is possible for a
substance to be a substrate, inhibitor, or inducer of an enzyme
activity. For example, the substance can be an inhibitor of enzyme
activity by one mechanism and an inducer of enzyme activity by
another mechanism. The function (substrate, inhibitor, or inducer)
of the substance with respect to activity of an enzyme can depend
on environmental conditions.
[0027] Lists of inhibitors, inducers and substrates for CYP3A4 can
be found, for instance, at
http://www.genemedrx.com/Cytochrome_P450_Metabolism_Table.php, and
other sites and
http://www.ildcare.eu/downloads/artseninfo/drugs_metabolized_by-
_cyp450s.pdf.
[0028] As used herein, a "strong CYP3A4 inducer" is a compound that
decreases the area under the concentration time curve (AUC) of a
sensitive index substrate of the CYP3A4 pathway by .gtoreq.80%.
Index substrates predictably exhibit exposure increase due to
inhibition or induction of a given metabolic pathway and are
commonly used in prospective clinical drug-drug interaction
studies. Sensitive index substrates are index substrates that
demonstrate an increase in AUC of .gtoreq.5-fold with strong index
inhibitors of a given metabolic pathway in clinical drug-drug
interaction studies. Examples of sensitive index substrates for the
CYP3A pathway are midazolam and triazolam. See, e.g., Drug
Development and Drug Interactions: Table of Substrates, Inhibitor
and Inducers at
https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources-
/druginteractionslabeling/ucm093664.htm.
[0029] As used herein, "hyperkinetic disorder" or "hyperkinetic
movement disorder" or "hyperkinesias" refers to disorders or
diseases characterized by excessive, abnormal, involuntary
movements. These neurological disorders include tremor, dystonia,
myoclonus, athetosis, Huntington's disease, tardive dyskinesia,
Tourette syndrome, dystonia, hemiballismus, chorea, senile chorea,
or tics.
[0030] As used herein, "tardive syndrome" encompasses but is not
limited to tardive dyskinesia, tardive dystonia, tardive akathisia,
tardive tics, myoclonus, tremor and withdrawal-emergent syndrome.
Tardive dyskinesia is characterized by rapid, repetitive,
stereotypic, involuntary movements of the face, limbs, or
trunk.
[0031] As used herein, "about" means.+-.20% of the stated value,
and includes more specifically values of .+-.10%, .+-.5%, .+-.2%
and .+-.1% of the stated value.
[0032] As used herein, "AUC" refers to the area under the curve, or
the integral, of the plasma concentration of an active
pharmaceutical ingredient or metabolite over time following a
dosing event.
[0033] As used herein "AUC.sub.0-t" is the integral under the
plasma concentration curve from time 0 (dosing) to time "t".
[0034] As used herein, "AUC.sub.0-.infin." is the AUC from time 0
(dosing) to time infinity. Unless otherwise stated, AUC refers to
AUC.sub.0-.infin.. Often a drug is packaged in a salt form, for
example valbenazine ditosylate, and the dosage form strength refers
to the mass of this salt form or the equivalent mass of the
corresponding free base, valbenazine.
[0035] As used herein, "C.sub.max" is a pharmacokinetic parameter
denoting the maximum observed blood plasma concentration following
delivery of an active pharmaceutical ingredient. C.sub.max occurs
at the time of maximum plasma concentration, t.sub.max.
[0036] As used herein, "co-administer" and "co-administration" and
variants thereof mean the administration of at least two drugs to a
patient either subsequently, simultaneously, or consequently
proximate in time to one another (e.g., within the same day, or
week or period of 30 days, or sufficiently proximate that each of
the at least two drugs can be simultaneously detected in the blood
plasma). When co-administered, two or more active agents can be
co-formulated as part of the same composition or administered as
separate formulations. This also may be referred to herein as
"concomitant" administration or variants thereof.
[0037] As used herein, "adjusting administration", "altering
administration", "adjusting dosing", or "altering dosing" are all
equivalent and mean tapering off, reducing or increasing the dose
of the substance, ceasing to administer the substance to the
patient, or substituting a different active agent for the
substance.
[0038] As used herein, "administering to a patient" refers to the
process of introducing a composition or dosage form into the
patient via an art-recognized means of introduction.
[0039] As used herein the term "disorder" is intended to be
generally synonymous, and is used interchangeably with, the terms
"disease," "syndrome," and "condition" (as in medical condition),
in that all reflect an abnormal condition of the human or animal
body or of one of its parts that impairs normal functioning, is
typically manifested by distinguishing signs and symptoms.
[0040] As used herein, a "dose" means the measured quantity of an
active agent to be taken at one time by a patient. In certain
embodiments, wherein the active agent is not valbenazine free base,
the quantity is the molar equivalent to the corresponding amount of
valbenazine free base. For example, often a drug is packaged in a
pharmaceutically acceptable salt form, for example valbenazine
ditosylate, and the dosage for strength refers to the mass of the
molar equivalent of the corresponding free base, valbenazine. As an
example, 73 mg of valbenazine tosylate is the molar equivalent of
40 mg of valbenazine free base.
[0041] As used herein, "dosing regimen" means the dose of an active
agent taken at a first time by a patient and the interval (time or
symptomatic) at which any subsequent doses of the active agent are
taken by the patient such as from about 20 to about 160 mg once
daily, e.g., about 20, about 40, about 60, about 80, about 100,
about 120, or about 160 mg once daily. The additional doses of the
active agent can be different from the dose taken at the first
time.
[0042] As used herein, "effective amount" and "therapeutically
effective amount" of an agent, compound, drug, composition or
combination is an amount which is nontoxic and effective for
producing some desired therapeutic effect upon administration to a
subject or patient (e.g., a human subject or patient). The precise
therapeutically effective amount for a subject may depend upon,
e.g., the subject's size and health, the nature and extent of the
condition, the therapeutics or combination of therapeutics selected
for administration, and other variables known to those of skill in
the art. The effective amount for a given situation is determined
by routine experimentation and is within the judgment of the
clinician.
[0043] As used herein, "informing" means referring to or providing
published material, for example, providing an active agent with
published material to a user; or presenting information orally, for
example, by presentation at a seminar, conference, or other
educational presentation, by conversation between a pharmaceutical
sales representative and a medical care worker, or by conversation
between a medical care worker and a patient; or demonstrating the
intended information to a user for the purpose of
comprehension.
[0044] As used herein, "labeling" means all labels or other means
of written, printed, graphic, electronic, verbal, or demonstrative
communication that is upon a pharmaceutical product or a dosage
form or accompanying such pharmaceutical product or dosage
form.
[0045] As used herein, "a "medical care worker" means a worker in
the health care field who may need or utilize information regarding
an active agent, including a dosage form thereof, including
information on safety, efficacy, dosing, administration, or
pharmacokinetics. Examples of medical care workers include
physicians, pharmacists, physician's assistants, nurses, aides,
caretakers (which can include family members or guardians),
emergency medical workers, and veterinarians.
[0046] As used herein, "Medication Guide" means an FDA-approved
patient labeling for a pharmaceutical product conforming to the
specifications set forth in 21 CFR 208 and other applicable
regulations which contains information for patients on how to
safely use a pharmaceutical product. A medication guide is
scientifically accurate and is based on, and does not conflict
with, the approved professional labeling for the pharmaceutical
product under 21 CFR 201.57, but the language need not be identical
to the sections of approved labeling to which it corresponds. A
medication guide is typically available for a pharmaceutical
product with special risk management information.
[0047] As used herein, "patient" or "individual" or "subject" means
a mammal, including a human, for whom or which therapy is desired,
and generally refers to the recipient of the therapy.
[0048] As used herein, "patient package insert" means information
for patients on how to safely use a pharmaceutical product that is
part of the FDA-approved labeling. It is an extension of the
professional labeling for a pharmaceutical product that may be
distributed to a patient when the product is dispensed which
provides consumer-oriented information about the product in lay
language, for example it may describe benefits, risks, how to
recognize risks, dosage, or administration.
[0049] As used herein, "pharmaceutically acceptable" refers to a
material that is not biologically or otherwise undesirable, i.e.,
the material may be incorporated into a pharmaceutical composition
administered to a patient without causing any undesirable
biological effects or interacting in a deleterious manner with any
of the other components of the composition in which it is
contained. When the term "pharmaceutically acceptable" is used to
refer to a pharmaceutical carrier or excipient, it is implied that
the carrier or excipient has met the required standards of
toxicological and manufacturing testing or that it is included on
the Inactive Ingredient Guide prepared by the U.S. Food and Drug
administration. "Pharmacologically active" (or simply "active") as
in a "pharmacologically active" (or "active") derivative or analog,
refers to a derivative or analog having the same type of
pharmacological activity as the parent compound and approximately
equivalent in degree. The term "pharmaceutically acceptable salts"
include acid addition salts which are formed with inorganic acids
such as, for example, hydrochloric or phosphoric acids, or such
organic acids as acetic, oxalic, tartaric, mandelic, and the like.
Salts formed with the free carboxyl groups can also be derived from
inorganic bases such as, for example, sodium, potassium, ammonium,
calcium, or ferric hydroxides, and such organic bases as
isopropylamine, trimethylamine, histidine, procaine and the
like.
[0050] As used herein, a "product" or "pharmaceutical product"
means a dosage form of an active agent plus published material, and
optionally packaging.
[0051] As used herein, "product insert" means the professional
labeling (prescribing information) for a pharmaceutical product, a
patient package insert for the pharmaceutical product, or a
medication guide for the pharmaceutical product.
[0052] As used herein, "professional labeling" or "prescribing
information" means the official description of a pharmaceutical
product approved by a regulatory agency (e.g., FDA or EMEA)
regulating marketing of the pharmaceutical product, which includes
a summary of the essential scientific information needed for the
safe and effective use of the drug, such as, for example indication
and usage; dosage and administration; who should take it; adverse
events (side effects); instructions for use in special populations
(pregnant women, children, geriatric, etc.); safety information for
the patient, and the like.
[0053] As used herein, "published material" means a medium
providing information, including printed, audio, visual, or
electronic medium, for example a flyer, an advertisement, a product
insert, printed labeling, an internet web site, an internet web
page, an internet pop-up window, a radio or television broadcast, a
compact disk, a DVD, an audio recording, or other recording or
electronic medium.
[0054] As used herein, "risk" means the probability or chance of
adverse reaction, injury, or other undesirable outcome arising from
a medical treatment. An "acceptable risk" means a measure of the
risk of harm, injury, or disease arising from a medical treatment
that will be tolerated by an individual or group. Whether a risk is
"acceptable" will depend upon the advantages that the individual or
group perceives to be obtainable in return for taking the risk,
whether they accept whatever scientific and other advice is offered
about the magnitude of the risk, and numerous other factors, both
political and social. An "acceptable risk" of an adverse reaction
means that an individual or a group in society is willing to take
or be subjected to the risk that the adverse reaction might occur
since the adverse reaction is one whose probability of occurrence
is small, or whose consequences are so slight, or the benefits
(perceived or real) of the active agent are so great. An
"unacceptable risk" of an adverse reaction means that an individual
or a group in society is unwilling to take or be subjected to the
risk that the adverse reaction might occur upon weighing the
probability of occurrence of the adverse reaction, the consequences
of the adverse reaction, and the benefits (perceived or real) of
the active agent. "At risk" means in a state or condition marked by
a high level of risk or susceptibility. Risk assessment consists of
identifying and characterizing the nature, frequency, and severity
of the risks associated with the use of a product.
[0055] As used herein, "safety" means the incidence or severity of
adverse events associated with administration of an active agent,
including adverse effects associated with patient-related factors
(e.g., age, gender, ethnicity, race, target illness, abnormalities
of renal or hepatic function, co-morbid illnesses, genetic
characteristics such as metabolic status, or environment) and
active agent-related factors (e.g., dose, plasma level, duration of
exposure, or concomitant medication).
[0056] As used herein, "t.sub.max" is a pharmacokinetic parameter
denoting the time to maximum blood plasma concentration following
delivery of an active pharmaceutical ingredient
[0057] As used herein, "t.sub.1/2" or "plasma half-life" or
"elimination half-life" or the like is a pharmacokinetic parameter
denoting the apparent plasma terminal phase half-life, i.e., the
time, after absorption and distribution of a drug is complete, for
the plasma concentration to fall by half.
[0058] As used herein, "treating" or "treatment" refers to
therapeutic applications to slow or stop progression of a disorder,
prophylactic application to prevent development of a disorder,
and/or reversal of a disorder. Reversal of a disorder differs from
a therapeutic application which slows or stops a disorder in that
with a method of reversing, not only is progression of a disorder
completely stopped, cellular behavior is moved to some degree,
toward a normal state that would be observed in the absence of the
disorder.
[0059] As used herein, "VMAT2" refers to human vesicular monoamine
transporter isoform 2, an integral membrane protein that acts to
transport monoamines, particularly neurotransmitters such as
dopamine, norepinephrine, serotonin, and histamine, from cellular
cytosol into synaptic vesicles.
[0060] As used herein, the term "VMAT2 inhibitor", "inhibit VMAT2",
or "inhibition of VMAT2" refers to the ability of a compound
disclosed herein to alter the function of VMAT2. A VMAT2 inhibitor
may block or reduce the activity of VMAT2 by forming a reversible
or irreversible covalent bond between the inhibitor and VMAT2 or
through formation of a noncovalently bound complex. Such inhibition
may be manifest only in particular cell types or may be contingent
on a particular biological event. The term "VMAT2 inhibitor",
"inhibit VMAT2", or "inhibition of VMAT2" also refers to altering
the function of VMAT2 by decreasing the probability that a complex
forms between a VMAT2 and a natural substrate.
[0061] Provided is a method of administering a vesicular monoamine
transport 2 (VMAT2) inhibitor chosen from valbenazine and
(+)-.alpha.-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2-
,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or
isotopic variant thereof to a patient in need thereof, comprising:
administering to the patient a therapeutically effective amount of
the VMAT2 inhibitor and informing the patient or a medical care
worker that co-administration of a strong cytochrome P450 3A4
(CYP3A4) inducer is not recommended.
[0062] In certain embodiments, the method further comprises
determining whether the patient is being administered a strong
CYP3A4 inducer.
[0063] In certain embodiments, the patient or medical care worker
is informed that co-administration of the strong CYP3A4 inducer
should be avoided or discontinued.
[0064] Also provided is a method of administering a vesicular
monoamine transport 2 (VMAT2) inhibitor chosen from valbenazine and
(+)-.alpha.-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2-
,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or
isotopic variant thereof to a patient in need thereof wherein the
patient is being treated with a strong cytochrome P450 3A4 (CYP3A4)
inducer, comprising: discontinuing treatment of the strong CYP3A4
inducer and then administering the VMAT2 inhibitor to the patient,
thereby avoiding the use of the VMAT2 inhibitor in combination with
the strong CYP3A4 inducer.
[0065] In certain embodiments, the strong CYP3A4 inducer is chosen
from nevirapine, pentobarbital, phenytoin, lumacaftor, rifabutin,
rifampicin, carbamazepine, fosphenytoin, phenobarbital, primidone,
primidone, enzalutamide, mitotane, and St. John's Wort. In certain
embodiments, the strong CYP3A4 inducer is chosen from rifampicin,
carbamazepine, phenytoin, and St. John's Wort. In certain
embodiments, the strong CYP3A4 inducer is rifampicin.
[0066] In certain embodiments, the VMAT2 inhibitor is administered
to the patient to treat a neurological or psychiatric disease or
disorder.
[0067] In certain embodiments, the neurological or psychiatric
disease or disorder is a hyperkinetic movement disorder, mood
disorder, bipolar disorder, schizophrenia, schizoaffective
disorder, mania in mood disorder, depression in mood disorder,
treatment-refractory obsessive compulsive disorder, neurological
dysfunction associated with Lesch-Nyhan syndrome, agitation
associated with Alzheimer's disease, Fragile X syndrome or Fragile
X-associated tremor-ataxia syndrome, autism spectrum disorder, Rett
syndrome, or chorea-acanthocytosis.
[0068] In certain embodiments, the neurological or psychiatric
disease or disorder is a hyperkinetic movement disorder. In certain
embodiments, the hyperkinetic movement disorder is tardive
dyskinesia. In certain embodiments, the hyperkinetic movement
disorder is Tourette's syndrome. In certain embodiments, the
hyperkinetic movement disorder is Huntington's disease. In certain
embodiments, the hyperkinetic movement disorder is tics. In certain
embodiments, hyperkinetic movement disorder is chorea associated
with Huntington's disease. In certain embodiments, the hyperkinetic
movement disorder is ataxia, chorea, dystonia, Huntington's
disease, myoclonus, restless leg syndrome, or tremors.
[0069] In certain embodiments, the VMAT2 inhibitor is administered
orally.
[0070] In certain embodiments, the VMAT2 inhibitor is administered
in the form of a tablet or capsule.
[0071] In certain embodiments, the VMAT2 inhibitor is administered
with or without food.
[0072] In certain embodiments, the VMAT2 inhibitor is valbenazine
or a pharmaceutically acceptable salt and/or isotopic variant
thereof. In certain embodiments, the VMAT2 inhibitor is valbenazine
or a pharmaceutically acceptable salt thereof. In certain
embodiments, the VMAT2 inhibitor is a valbenazine tosylate salt. In
certain embodiments, the VMAT2 inhibitor is a ditosylate salt of
valbenazine. In certain embodiments, the VMAT2 inhibitor is an
isotopic variant that is L-Valine, (2R,
3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d.sub.3)-3-(2-methy-
lpropyl)-2H-benzo[a]quinolizin-2-yl ester or a pharmaceutically
acceptable salt thereof.
[0073] In certain embodiments the VMAT2 inhibitor is
(+)-.alpha.-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2-
,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or
isotopic variant thereof. In certain embodiments the VMAT2
inhibitor is
(+)-.alpha.-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2-
,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt
thereof. In certain embodiments the VMAT2 inhibitor is an isotopic
variant that is
(+)-.alpha.-3-isobutyl-9,10-di(methoxy-d.sub.3)-1,3,4,6,7,11b-hexahydro-2-
H-pyrido[2,1-a]isoquinolin-2-ol or a pharmaceutically acceptable
salt thereof.
[0074] In certain embodiments, the VMAT2 inhibitor is administered
in an amount equivalent to between about 20 mg and about 160 mg of
valbenazine free base. In certain embodiments, the VMAT2 inhibitor
is administered in an amount equivalent to about 20 mg of
valbenazine free base. In certain embodiments, the VMAT2 inhibitor
is administered in an amount equivalent to about 40 mg of
valbenazine free base. In certain embodiments, the VMAT2 inhibitor
is administered in an amount equivalent to about 60 mg of
valbenazine free base. In certain embodiments, the VMAT2 inhibitor
is administered in an amount equivalent to about 80 mg of
valbenazine free base. In certain embodiments, the VMAT2 inhibitor
is administered in an amount equivalent to about 120 mg of
valbenazine free base. In certain embodiments, the VMAT2 inhibitor
is administered in an amount equivalent to about 160 mg of
valbenazine free base.
[0075] In certain embodiments, the VMAT2 inhibitor is administered
for a first period of time in a first amount and then the amount is
increased to a second amount. In certain embodiments, the first
period of time is a week. In certain embodiments, the first amount
is equivalent to about 40 mg of valbenazine free base. In certain
embodiments, the second amount is equivalent to about 80 mg of
valbenazine free base.
[0076] In certain embodiments, the VMAT2 inhibitor is administered
in an amount sufficient to achieve a maximal blood plasma
concentration (C.sub.max) of (+)-.alpha.-DHTBZ of between about 15
ng to about 60 ng per mL plasma and a minimal blood plasma
concentration (C.sub.min) of (+)-.alpha.-DHTBZ of at least 15 ng
per mL plasma over an 8 hour period.
[0077] In certain embodiments, the VMAT2 inhibitor is administered
in an amount sufficient to achieve a maximal blood plasma
concentration (C.sub.max) of (+)-.alpha.-DHTBZ of between about 15
ng to about 60 ng per mL plasma and a minimal blood plasma
concentration (C min) of approximately between about at least
33%-50% of the C.sub.max over a 12 hour period.
[0078] In certain embodiments, the VMAT2 inhibitor is administered
in an amount sufficient to achieve: (i) a therapeutic concentration
range of about 15 ng to about 60 ng of (+)-.alpha.-DHTBZ per mL
plasma; and (ii) a threshold concentration of at least 15 ng
(+)-.alpha.-DHTBZ per mL plasma over a period of about 8 hours to
about 24 hours.
[0079] In certain embodiments, a method for treating neurological
or psychiatric disease or disorders is provided herein that
comprises administering to a subject a pharmaceutical composition
comprising the VMAT2 inhibitor, in an amount sufficient to achieve
a maximal blood plasma concentration (C.sub.max) of R,R,R-DHTBZ of
between about 15 ng to about 60 ng per mL plasma and a minimal
blood plasma concentration (C.sub.min) of R,R,R-DHTBZ of at least
15 ng per mL plasma over an 8 hour period.
[0080] In certain embodiments, the C.sub.max of R,R,R-DHTBZ is
about 15 ng/mL, about 20 ng/mL, about 25 ng/mL, about 30 ng/mL,
about 35 ng/mL, about 40 ng/mL, about 45 ng/mL, about 50 ng/mL,
about 55 ng/mL or about 60 ng/mL plasma. In certain embodiments,
the C.sub.min of R,R,R-DHTBZ is at least 15 ng/mL, at least 20
ng/mL, at least 25 ng/mL, at least 30 ng/mL, or at least 35 ng/mL
plasma, over a period of 8 hrs, 12 hrs, 16 hrs, 20 hrs, 24 hrs, 28
hrs, or 32 hrs. In certain embodiments, the C.sub.min of
R,R,R-DHTBZ is between about 15 ng/mL to about 35 ng/mL.
[0081] In certain embodiments, the pharmaceutical composition is
administered in an amount sufficient to provide a C.sub.max of
R,R,R-DHTBZ of about 15 ng/mL to about 60 ng/mL plasma and a
C.sub.min of approximately at least 33% of the C.sub.max over a 24
hour period. In certain embodiments, the pharmaceutical composition
is administered in an amount sufficient to provide a C.sub.max of
R,R,R-DHTBZ of about 15 ng/mL to about 60 ng/mL plasma and a
C.sub.min of approximately at least 50% of the C.sub.max over a 24
hour period. In certain embodiments, the pharmaceutical composition
is administered in an amount sufficient to provide a C.sub.max of
R,R,R-DHTBZ of about 15 ng/mL to about 60 ng/mL plasma and a
C.sub.min of approximately between about at least 33%-50% of the
C.sub.max over a 24 hour period.
[0082] In certain embodiments, the pharmaceutical composition is
administered in an amount sufficient to provide a C.sub.max of
R,R,R-DHTBZ of about 15 ng/mL to about 60 ng/mL plasma and a
C.sub.min of approximately at least 33% of the C.sub.max over a 12
hour period. In certain embodiments, the pharmaceutical composition
is administered in an amount sufficient to provide a C.sub.max of
R,R,R-DHTBZ of about 15 ng/mL to about 60 ng/mL plasma and a
C.sub.min of approximately at least 50% of the C.sub.max over a 12
hour period. In certain embodiments, the pharmaceutical composition
is administered in an amount sufficient to provide a C.sub.max of
R,R,R-DHTBZ of about 15 ng/mL to about 60 ng/mL plasma and a
C.sub.min of approximately between about at least 33%-50% of the
C.sub.max over a 12 hour period.
[0083] In certain embodiments, the pharmaceutical composition is
administered to a subject in an amount that provides a C.sub.max of
R,R,R-DHTBZ of about 15 ng/mL to about 60 ng/mL plasma and a
C.sub.min of between about 5 ng/mL to about 30 ng/mL plasma over a
24 hour period. In certain embodiments, the pharmaceutical
composition is administered to a subject in an amount that provides
a C.sub.max of R,R,R-DHTBZ of about 15 ng/mL to about 60 ng/mL
plasma and a C.sub.min of between about 7.5 ng/mL to about 30 ng/mL
plasma over a 24 hour period.
[0084] In certain embodiments, a method for treating neurological
or psychiatric disease or disorders is provided herein that
comprises administering to a subject a pharmaceutical composition
comprising the VMAT2 inhibitor, as an active pharmaceutical
ingredient, in an amount sufficient to provide: (i) a therapeutic
concentration range of about 15 ng to about 60 ng of R,R,R-DHTBZ
per mL plasma; and (ii) a threshold concentration of at least 15 ng
R,R,R-DHTBZ per mL plasma over a period of about 8 hours to about
24 hours.
[0085] In certain embodiments, the therapeutic concentration range
is about 15 ng to about 35 ng, to about 40 ng, to about 45 ng, to
about 50 ng, or to about 55 ng R,R,R-DHTBZ per mL plasma.
[0086] In certain embodiments, the threshold concentration of
R,R,R-DHTBZ is about 15 ng/mL, about 20 ng/mL, about 25 ng/mL,
about 30 ng/mL, about 35 ng/mL, about 40 ng/mL, about 45 ng/mL,
about 50 ng/mL, about 55 ng/mL or about 60 ng/mL plasma, over a
period of about 8 hrs, about 12 hrs, about 16 hrs, about 20 hrs,
about 24 hrs, about 28 hrs, or about 32 hrs. In certain
embodiments, the threshold concentration of R,R,R-DHTBZ is between
about 15 ng/mL to about 35 ng/mL over a period of about 8 hours to
about 24 hours.
[0087] Plasma concentrations may be measured by methods known in
the art and generally by tandem mass spectroscopy.
[0088] Also provided is a vesicular monoamine transport 2 (VMAT2)
inhibitor chosen from valbenazine and
(+)-.alpha.-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2-
,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or
isotopic variant thereof, for use in a method of treating a
neurological or psychiatric disease or disorder in a patient in
need thereof wherein the patient has previously been determined to
have discontinued treatment of a strong CYP3A4 inducer, comprising:
administering to the patient a therapeutically effective amount of
the VMAT2 inhibitor.
[0089] Also provided is a vesicular monoamine transport 2 (VMAT2)
inhibitor chosen from valbenazine and
(+)-.alpha.-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2-
,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or
isotopic variant thereof, for use in a method of treating a
neurological or psychiatric disease or disorder in a patient in
need thereof, comprising: determining if the patient is being
administered a strong CYP3A4 inducer, selecting the patient for
treatment where the patient is not being administered a strong
CYP3A4 inducer, and administering to the selected patient a
therapeutically effective amount of the VMAT2 inhibitor.
[0090] Also provided is a vesicular monoamine transport 2 (VMAT2)
inhibitor chosen from valbenazine and
(+)-.alpha.-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2-
,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or
isotopic variant thereof, for use in a method of treating a
neurological or psychiatric disease or disorder in a patient in
need thereof, comprising: administering to the patient a
therapeutically effective amount of the VMAT2 inhibitor,
subsequently determining whether the patient is being administered
a strong CYP3A4 inducer, selecting the patient for treatment where
the patient is not being administered a strong CYP3A4 inducer, and
administering to the patient a therapeutically effective amount of
the VMAT2 inhibitor.
[0091] Valbenazine can be prepared according to U.S. Pat. Nos.
8,039,627 and 8,357,697, the disclosure of each of which is
incorporated herein by reference in its entirety. Tetrabenazine may
be administered by a variety of methods including the formulations
disclosed in PCT Publications WO 2010/018408, WO 2011/019956, and
WO 2014/047167, the disclosure of each of which is incorporated
herein by reference in its entirety. In certain embodiments, the
valbenazine for use in the compositions and methods provided herein
is in polymorphic Form I as disclosed in U.S. Ser. No. 15/338,214,
the disclosure of which is incorporated herein by reference in its
entirety.
Pharmaceutical Compositions
[0092] Also provided is a composition for treating a patient in
need of a vesicular monoamine transport 2 (VMAT2) inhibitor chosen
from valbenazine and
(+)-.alpha.-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyri-
do[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt
and/or isotopic variant thereof, comprising a therapeutically
effective amount of the VMAT2 inhibitor, wherein the patient or a
medical care worker is informed that co-administration of a strong
cytochrome P450 3A4 (CYP3A4) inducer is not recommended.
[0093] In certain embodiments, the patient or medical care worker
is informed that co-administration of the strong CYP3A4 inducer
should be avoided or discontinued.
[0094] Also provided is a composition for treating a patient in
need of a vesicular monoamine transport 2 (VMAT2) inhibitor chosen
from valbenazine and
(+)-.alpha.-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyri-
do[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt
and/or isotopic variant thereof, and being treated with a strong
cytochrome P450 3A4 (CYP3A4) inducer, comprising the VMAT2
inhibitor, wherein treatment of the strong CYP3A4 inducer is
discontinued prior to administration of the composition to the
patient, thereby avoiding the use of the composition in combination
with the strong CYP3A4 inducer.
[0095] In certain embodiments, the composition is for treating a
neurological or psychiatric disease or disorder.
[0096] In certain embodiments, the composition is administered in
an amount equivalent to between about 20 mg and about 120 mg of
valbenazine free base of the VMAT2 inhibitor. In certain
embodiments, the composition is administered in an amount
equivalent to about 20 mg of valbenazine free base of the VMAT2
inhibitor. In certain embodiments, the composition is administered
in an amount equivalent to about 40 mg of valbenazine free base of
the VMAT2 inhibitor. In certain embodiments, the composition is
administered in an amount equivalent to about 80 mg of valbenazine
free base of the VMAT2 inhibitor. In certain embodiments, the
composition is administered in an amount equivalent to about 60 mg
of valbenazine free base of the VMAT2 inhibitor. In certain
embodiments, the composition is administered in an amount
equivalent to about 120 mg of valbenazine free base of the VMAT2
inhibitor.
[0097] In certain embodiments, the composition is administered for
a first period of time in a first amount of the VMAT2 inhibitor and
then the amount is increased to a second amount. In certain
embodiments, the first period of time is a week. In certain
embodiments, the first amount is equivalent to about 40 mg of
valbenazine free base. In certain embodiments, the second amount is
equivalent to about 80 mg of valbenazine free base.
[0098] Also provided herein is a pharmaceutical composition for use
in treating neurological or psychiatric disease or disorders,
comprising the VMAT2 inhibitor as an active pharmaceutical
ingredient, in combination with one or more pharmaceutically
acceptable carriers or excipients.
[0099] The choice of excipient, to a large extent, depends on
factors, such as the particular mode of administration, the effect
of the excipient on the solubility and stability of the active
ingredient, and the nature of the dosage form.
[0100] The pharmaceutical compositions provided herein may be
provided in unit dosage forms or multiple-dosage forms. Unit-dosage
forms, as used herein, refer to physically discrete units suitable
for administration to human and animal subjects and packaged
individually as is known in the art. Each unit-dose contains a
predetermined quantity of the active ingredient(s) sufficient to
produce the desired therapeutic effect, in association with the
required pharmaceutical carriers or excipients. Examples of
unit-dosage forms include ampoules, syringes, and individually
packaged tablets and capsules. Unit dosage forms may be
administered in fractions or multiples thereof. A multiple-dosage
form is a plurality of identical unit-dosage forms packaged in a
single container to be administered in segregated unit-dosage form.
Examples of multiple-dosage forms include vials, bottles of tablets
or capsules, or bottles of pints or gallons.
[0101] The pharmaceutical compositions provided herein may be
administered alone, or in combination with one or more other
compounds provided herein, one or more other active ingredients.
The pharmaceutical compositions provided herein may be formulated
in various dosage forms for oral, parenteral, and topical
administration. The pharmaceutical compositions may also be
formulated as a modified release dosage form, including delayed-,
extended-, prolonged-, sustained-, pulsatile-, controlled-,
accelerated- and fast-, targeted-, programmed-release, and gastric
retention dosage forms. These dosage forms can be prepared
according to conventional methods and techniques known to those
skilled in the art). The pharmaceutical compositions provided
herein may be administered at once, or multiple times at intervals
of time. It is understood that the precise dosage and duration of
treatment may vary with the age, weight, and condition of the
patient being treated, and may be determined empirically using
known testing protocols or by extrapolation from in vivo or in
vitro test or diagnostic data. It is further understood that for
any particular individual, specific dosage regimens should be
adjusted over time according to the individual need and the
professional judgment of the person administering or supervising
the administration of the formulations.
Oral Administration
[0102] The pharmaceutical compositions provided herein may be
provided in solid, semisolid, or liquid dosage forms for oral
administration. As used herein, oral administration also includes
buccal, lingual, and sublingual administration. Suitable oral
dosage forms include, but are not limited to, tablets, capsules,
pills, troches, lozenges, pastilles, cachets, pellets, medicated
chewing gum, granules, bulk powders, effervescent or
non-effervescent powders or granules, solutions, emulsions,
suspensions, solutions, wafers, sprinkles, elixirs, and syrups. In
addition to the active ingredient(s), the pharmaceutical
compositions may contain one or more pharmaceutically acceptable
carriers or excipients, including, but not limited to, binders,
fillers, diluents, disintegrants, wetting agents, lubricants,
glidants, coloring agents, dye-migration inhibitors, sweetening
agents, and flavoring agents.
[0103] Binders or granulators impart cohesiveness to a tablet to
ensure the tablet remaining intact after compression. Suitable
binders or granulators include, but are not limited to, starches,
such as corn starch, potato starch, and pre-gelatinized starch
(e.g., STARCH 1500); gelatin; sugars, such as sucrose, glucose,
dextrose, molasses, and lactose; natural and synthetic gums, such
as acacia, alginic acid, alginates, extract of Irish moss, Panwar
gum, ghatti gum, mucilage of isabgol husks, carboxymethylcellulose,
methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch
arabogalactan, powdered tragacanth, and guar gum; celluloses, such
as ethyl cellulose, cellulose acetate, carboxymethyl cellulose
calcium, sodium carboxymethyl cellulose, methyl cellulose,
hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC),
hydroxypropyl methyl cellulose (HPMC); microcrystalline celluloses,
such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105
(FMC Corp., Marcus Hook, Pa.); and mixtures thereof. Suitable
fillers include, but are not limited to, talc, calcium carbonate,
microcrystalline cellulose, powdered cellulose, dextrates, kaolin,
mannitol, silicic acid, sorbitol, starch, pregelatinized starch,
and mixtures thereof. The binder or filler may be present from
about 50 to about 99% by weight in the pharmaceutical compositions
provided herein.
[0104] Suitable diluents include, but are not limited to, dicalcium
phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol,
cellulose, kaolin, mannitol, sodium chloride, dry starch, and
powdered sugar. Certain diluents, such as mannitol, lactose,
sorbitol, sucrose, and inositol, when present in sufficient
quantity, can impart properties to some compressed tablets that
permit disintegration in the mouth by chewing. Such compressed
tablets can be used as chewable tablets.
[0105] Suitable disintegrants include, but are not limited to,
agar; bentonite; celluloses, such as methylcellulose and
carboxymethylcellulose; wood products; natural sponge;
cation-exchange resins; alginic acid; gums, such as guar gum and
Vee gum HV; citrus pulp; cross-linked celluloses, such as
croscarmellose; cross-linked polymers, such as crospovidone;
cross-linked starches; calcium carbonate; microcrystalline
cellulose, such as sodium starch glycolate; polacrilin potassium;
starches, such as corn starch, potato starch, tapioca starch, and
pre-gelatinized starch; clays; aligns; and mixtures thereof. The
amount of disintegrant in the pharmaceutical compositions provided
herein varies upon the type of formulation, and is readily
discernible to those of ordinary skill in the art. The
pharmaceutical compositions provided herein may contain from about
0.5 to about 15% or from about 1 to about 5% by weight of a
disintegrant.
[0106] Suitable lubricants include, but are not limited to, calcium
stearate; magnesium stearate; mineral oil; light mineral oil;
glycerin; sorbitol; mannitol; glycols, such as glycerol behenate
and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate;
talc; hydrogenated vegetable oil, including peanut oil, cottonseed
oil, sunflower oil, sesame oil, olive oil, com oil, and soybean
oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch;
lycopodium; silica or silica gels, such as AEROSIL.RTM.200 (W.R.
Grace Co., Baltimore, Md.) and CAB-0-SIL.RTM. (Cabot Co. of Boston,
Mass.); and mixtures thereof. The pharmaceutical compositions
provided herein may contain about 0.1 to about 5% by weight of a
lubricant. Suitable glidants include colloidal silicon dioxide,
CAB-0-SIL.RTM. (Cabot Co. of Boston, Mass.), and asbestos-free
talc. Coloring agents include any of the approved, certified, water
soluble FD&C dyes, and water insoluble FD&C dyes suspended
on alumina hydrate, and color lakes and mixtures thereof. A color
lake is the combination by adsorption of a water-soluble dye to a
hydrous oxide of a heavy metal, resulting in an insoluble form of
the dye. Flavoring agents include natural flavors extracted from
plants, such as fruits, and synthetic blends of compounds which
produce a pleasant taste sensation, such as peppermint and methyl
salicylate. Sweetening agents include sucrose, lactose, mannitol,
syrups, glycerin, and artificial sweeteners, such as saccharin and
aspartame. Suitable emulsifying agents include gelatin, acacia,
tragacanth, bentonite, and surfactants, such as polyoxyethylene
sorbitan monooleate (TWEEN.RTM. 20), polyoxyethylene sorbitan
monooleate 80 (TWEEN.RTM. 80), and triethanolamine oleate.
Suspending and dispersing agents include sodium
carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium
carbomethylcellulose, hydroxypropyl methylcellulose, and
polyvinylpyrolidone. Preservatives include glycerin, methyl and
propylparaben, benzoic add, sodium benzoate and alcohol. Wetting
agents include propylene glycol monostearate, sorbitan monooleate,
diethylene glycol monolaurate, and polyoxyethylene lauryl ether.
Solvents include glycerin, sorbitol, ethyl alcohol, and syrup.
Examples of non-aqueous liquids utilized in emulsions include
mineral oil and cottonseed oil. Organic acids include citric and
tartaric acid. Sources of carbon dioxide include sodium bicarbonate
and sodium carbonate.
[0107] It should be understood that many carriers and excipients
may serve several functions, even within the same formulation. The
pharmaceutical compositions provided herein may be provided as
compressed tablets, tablet triturates, chewable lozenges, rapidly
dissolving tablets, multiple compressed tablets, or enteric-coating
tablets, sugar-coated, or film-coated tablets. Enteric coated
tablets are compressed tablets coated with substances that resist
the action of stomach acid but dissolve or disintegrate in the
intestine, thus protecting the active ingredients from the acidic
environment of the stomach. Enteric-coatings include, but are not
limited to, fatty acids, fats, phenylsalicylate, waxes, shellac,
ammoniated shellac, and cellulose acetate phthalates. Sugar-coated
tablets are compressed tablets surrounded by a sugar coating, which
may be beneficial in covering up objectionable tastes or odors and
in protecting the tablets from oxidation. Film-coated tablets are
compressed tablets that are covered with a thin layer or film of a
water-soluble material. Film coatings include, but are not limited
to, hydroxyethylcellulose, sodium carboxymethylcellulose,
polyethylene glycol 4000, and cellulose acetate phthalate. Film
coating imparts the same general characteristics as sugar coating.
Multiple compressed tablets are compressed tablets made by more
than one compression cycle, including layered tablets, and
press-coated or dry-coated tablets.
[0108] The tablet dosage forms may be prepared from the active
ingredient in powdered, crystalline, or granular forms, alone or in
combination with one or more carriers or excipients described
herein, including binders, disintegrants, controlled-release
polymers, lubricants, diluents, and/or colorants. Flavoring and
sweetening agents are especially useful in the formation of
chewable tablets and lozenges.
[0109] The pharmaceutical compositions provided herein may be
provided as soft or hard capsules, which can be made from gelatin,
methylcellulose, starch, or calcium alginate. The hard gelatin
capsule, also known as the dry-filled capsule (DFC), consists of
two sections, one slipping over the other, thus completely
enclosing the active ingredient. The soft elastic capsule (SEC) is
a soft, globular shell, such as a gelatin shell, which is
plasticized by the addition of glycerin, sorbitol, or a similar
polyol. The soft gelatin shells may contain a preservative to
prevent the growth of microorganisms. Suitable preservatives are
those as described herein, including methyl- and propyl-parabens,
and sorbic acid. The liquid, semisolid, and solid dosage forms
provided herein may be encapsulated in a capsule. Suitable liquid
and semisolid dosage forms include solutions and suspensions in
propylene carbonate, vegetable oils, or triglycerides. The capsules
may also be coated as known by those of skill in the art in order
to modify or sustain dissolution of the active ingredient.
[0110] The pharmaceutical compositions provided herein may be
provided in liquid and semisolid dosage forms, including emulsions,
solutions, suspensions, elixirs, and syrups. An emulsion is a
two-phase system, in which one liquid is dispersed in the form of
small globules throughout another liquid, which can be oil-in-water
or water-in-oil. Emulsions may include a pharmaceutically
acceptable non-aqueous liquids or solvent, emulsifying agent, and
preservative. Suspensions may include a pharmaceutically acceptable
suspending agent and preservative. Aqueous alcoholic solutions may
include a pharmaceutically acceptable acetal, such as a di(lower
alkyl) acetal of a lower alkyl aldehyde (the term "lower" means an
alkyl having between 1 and 6 carbon atoms), e.g., acetaldehyde
diethyl acetal; and a water-miscible solvent having one or more
hydroxyl groups, such as propylene glycol and ethanol. Elixirs are
clear, sweetened, and hydroalcoholic solutions. Syrups are
concentrated aqueous solutions of a sugar, for example, sucrose,
and may also contain a preservative. For a liquid dosage form, for
example, a solution in a polyethylene glycol may be diluted with a
sufficient quantity of a pharmaceutically acceptable liquid
carrier, e.g., water, to be measured conveniently for
administration.
[0111] Other useful liquid and semisolid dosage forms include, but
are not limited to, those containing the active ingredient(s)
provided herein, and a dialkylated mono- or polyalkylene glycol,
including, 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme,
polyethylene glycol-350-dimethyl ether, polyethylene
glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether,
wherein 350, 550, and 750 refer to the approximate average
molecular weight of the polyethylene glycol. These formulations may
further comprise one or more antioxidants, such as butylated
hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl
gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,
lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric
acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its
esters, and dithiocarbamates.
[0112] The pharmaceutical compositions provided herein for oral
administration may be also provided in the forms of liposomes,
micelles, microspheres, or nanosystems.
[0113] The pharmaceutical compositions provided herein may be
provided as noneffervescent or effervescent, granules and powders,
to be reconstituted into a liquid dosage form. Pharmaceutically
acceptable carriers and excipients used in the non-effervescent
granules or powders may include diluents, sweeteners, and wetting
agents. Pharmaceutically acceptable carriers and excipients used in
the effervescent granules or powders may include organic acids and
a source of carbon dioxide. Coloring and flavoring agents can be
used in all of the above dosage forms. The pharmaceutical
compositions provided herein may be formulated as immediate or
modified release dosage forms, including delayed-, sustained,
pulsed-, controlled, targeted-, and programmed-release forms.
[0114] The pharmaceutical compositions provided herein may be
co-formulated with other active ingredients which do not impair the
desired therapeutic action, or with substances that supplement the
desired action, such as antacids, proton pump inhibitors, and
H.sub.2-receptor antagonists.
[0115] The pharmaceutical compositions provided herein may be
administered parenterally by injection, infusion, or implantation,
for local or systemic administration. Parenteral administration, as
used herein, include intravenous, intraarterial, intraperitoneal,
intrathecal, intraventricular, intraurethral, intrasternal,
intracranial, intramuscular, intrasynovial, and subcutaneous
administration.
Parenteral Administration
[0116] The pharmaceutical compositions provided herein may be
formulated in any dosage forms that are suitable for parenteral
administration, including solutions, suspensions, emulsions,
micelles, liposomes, microspheres, nanosystems, and solid forms
suitable for solutions or suspensions in liquid prior to injection.
Such dosage forms can be prepared according to conventional methods
known to those skilled in the art of pharmaceutical science.
[0117] The pharmaceutical compositions intended for parenteral
administration may include one or more pharmaceutically acceptable
carriers and excipients, including, but not limited to, aqueous
vehicles, water-miscible vehicles, non-aqueous vehicles,
antimicrobial agents or preservatives against the growth of
microorganisms, stabilizers, solubility enhancers, isotonic agents,
buffering agents, antioxidants, local anesthetics, suspending and
dispersing agents, wetting or emulsifying agents, complexing
agents, sequestering or chelating agents, cryoprotectants,
lyoprotectants, thickening agents, pH adjusting agents, and inert
gases.
[0118] Suitable aqueous vehicles include, but are not limited to,
water, saline, physiological saline or phosphate buffered saline
(PBS), sodium chloride injection, Ringers injection, isotonic
dextrose injection, sterile water injection, dextrose and lactated
Ringers injection. Non-aqueous vehicles include, but are not
limited to, fixed oils of vegetable origin, castor oil, com oil,
cottonseed oil, olive oil, peanut oil, peppermint oil, safflower
oil, sesame oil, soybean oil, hydrogenated vegetable oils,
hydrogenated soybean oil, and medium-chain triglycerides of coconut
oil, and palm seed oil. Water-miscible vehicles include, but are
not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol
(e.g., polyethylene glycol 300 and polyethylene glycol 400),
propylene glycol, glycerin, N-methyl-2-pyrrolidone,
dimethylacetamide, and dimethylsulfoxide.
[0119] Suitable antimicrobial agents or preservatives include, but
are not limited to, phenols, cresols, mercurials, benzyl alcohol,
chlorobutanol, methyl and propyl phydroxybenzates, thimerosal,
benzalkonium chloride, benzethonium chloride, methyl- and
propylparabens, and sorbic acid. Suitable isotonic agents include,
but are not limited to, sodium chloride, glycerin, and dextrose.
Suitable buffering agents include, but are not limited to,
phosphate and citrate. Suitable antioxidants are those as described
herein, including bisulfite and sodium metabisulfite. Suitable
local anesthetics include, but are not limited to, procaine
hydrochloride. Suitable suspending and dispersing agents are those
as described herein, including sodium carboxymethylcelluose,
hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable
emulsifying agents include those described herein, including
polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan
monooleate 80, and triethanolamine oleate. Suitable sequestering or
chelating agents include, but are not limited to EDTA. Suitable pH
adjusting agents include, but are not limited to, sodium hydroxide,
hydrochloric acid, citric acid, and lactic acid. Suitable
complexing agents include, but are not limited to, cyclodextrins,
including alpha-cyclodextrin, beta-cyclodextrin,
hydroxypropyl-beta-cyclodextrin, sulfobutylether-beta-cyclodextrin,
and sulfobutylether 7-beta-cyclodextrin (CAPTISOL.RTM., CyDex,
Lenexa, Kans.).
[0120] The pharmaceutical compositions provided herein may be
formulated for single or multiple dosage administration. The single
dosage formulations are packaged in an ampule, a vial, or a
syringe. The multiple dosage parenteral formulations must contain
an antimicrobial agent at bacteriostatic or fungistatic
concentrations. All parenteral formulations must be sterile, as
known and practiced in the art.
[0121] In certain embodiments, the pharmaceutical compositions are
provided as ready-to-use sterile solutions. In certain embodiments,
the pharmaceutical compositions are provided as sterile dry soluble
products, including lyophilized powders and hypodermic tablets, to
be reconstituted with a vehicle prior to use. In certain
embodiments, the pharmaceutical compositions are provided as
ready-to-use sterile suspensions. In certain embodiments, the
pharmaceutical compositions are provided as sterile dry insoluble
products to be reconstituted with a vehicle prior to use. In
certain embodiments, the pharmaceutical compositions are provided
as ready-to-use sterile emulsions.
[0122] The pharmaceutical compositions provided herein may be
formulated as immediate or modified release dosage forms, including
delayed-, sustained, pulsed-, controlled, targeted-, and
programmed-release forms.
[0123] The pharmaceutical compositions may be formulated as a
suspension, solid, semi-solid, or thixotropic liquid, for
administration as an implanted depot. In certain embodiments, the
pharmaceutical compositions provided herein are dispersed in a
solid inner matrix, which is surrounded by an outer polymeric
membrane that is insoluble in body fluids but allows the active
ingredient in the pharmaceutical compositions diffuse through.
[0124] Suitable inner matrixes include polymethylmethacrylate,
polybutylmethacrylate, plasticized or unplasticized
polyvinylchloride, plasticized nylon, plasticized
polyethyleneterephthalate, natural rubber, polyisoprene,
polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate
copolymers, silicone rubbers, polydimethylsiloxanes, silicone
carbonate copolymers, hydrophilic polymers, such as hydrogels of
esters of acrylic and methacrylic acid, collagen, cross-linked
polyvinylalcohol, and cross-linked partially hydrolyzed polyvinyl
acetate.
[0125] Suitable outer polymeric membranes include polyethylene,
polypropylene, ethylene/propylene copolymers, ethylene/ethyl
acrylate copolymers, ethylene/vinylacetate copolymers, silicone
rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated
polyethylene, polyvinylchloride, vinylchloride copolymers with
vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer
polyethylene terephthalate, butyl rubber epichlorohydrin rubbers,
ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl
alcohol terpolymer, and ethylene/vinyloxyethanol copolymer.
Topical Administration
[0126] The pharmaceutical compositions provided herein may be
administered topically to the skin, orifices, or mucosa. The
topical administration, as used herein, include (intra)dermal,
conjuctival, intracorneal, intraocular, ophthalmic, auricular,
transdermal, nasal, vaginal, uretheral, respiratory, and rectal
administration.
[0127] The pharmaceutical compositions provided herein may be
formulated in any dosage forms that are suitable for topical
administration for local or systemic effect, including emulsions,
solutions, suspensions, creams, gels, hydrogels, ointments, dusting
powders, dressings, elixirs, lotions, suspensions, tinctures,
pastes, foams, films, aerosols, irrigations, sprays, suppositories,
bandages, dermal patches. The topical formulation of the
pharmaceutical compositions provided herein may also comprise
liposomes, micelles, microspheres, nanosystems, and mixtures
thereof.
[0128] Pharmaceutically acceptable carriers and excipients suitable
for use in the topical formulations provided herein include, but
are not limited to, aqueous vehicles, water miscible vehicles,
non-aqueous vehicles, antimicrobial agents or preservatives against
the growth of microorganisms, stabilizers, solubility enhancers,
isotonic agents, buffering agents, antioxidants, local anesthetics,
suspending and dispersing agents, wetting or emulsifying agents,
complexing agents, sequestering or chelating agents, penetration
enhancers, cryopretectants, lyoprotectants, thickening agents, and
inert gases.
[0129] The pharmaceutical compositions may also be administered
topically by electroporation, iontophoresis, phonophoresis,
sonophoresis and microneedle or needle-free injection, such as
POWDERJECT.TM. (Chiron Corp., Emeryville, Calif.), and BIOJECT.TM.
(Bioject Medical Technologies Inc., Tualatin, Oreg.).
[0130] The pharmaceutical compositions provided herein may be
provided in the forms of ointments, creams, and gels. Suitable
ointment vehicles include oleaginous or hydrocarbon bases,
including such as lard, benzoinated lard, olive oil, cottonseed
oil, and other oils, white petrolatum; emulsifiable or absorption
bases, such as hydrophilic petrolatum, hydroxystearin sulfate, and
anhydrous lanolin; water-removable bases, such as hydrophilic
ointment; water-soluble ointment bases, including polyethylene
glycols of varying molecular weight; emulsion bases, either
water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions,
including cetyl alcohol, glyceryl monostearate, lanolin, and
stearic acid. These vehicles are emollient but generally require
addition of antioxidants and preservatives.
[0131] Suitable cream base can be oil-in-water or water-in-oil.
Cream vehicles may be water-washable, and contain an oil phase, an
emulsifier, and an aqueous phase. The oil phase is also called the
"internal" phase, which is generally comprised of petrolatum and a
fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase
usually, although not necessarily, exceeds the oil phase in volume,
and generally contains a humectant. The emulsifier in a cream
formulation may be a nonionic, anionic, cationic, or amphoteric
surfactant.
[0132] Gels are semisolid, suspension-type systems. Single-phase
gels contain organic macromolecules distributed substantially
uniformly throughout the liquid carrier. Suitable gelling agents
include crosslinked acrylic acid polymers, such as carbomers,
carboxypolyalkylenes, Carbopol.RTM.; hydrophilic polymers, such as
polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers,
and polyvinylalcohol; cellulosic polymers, such as hydroxypropyl
cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose,
hydroxypropyl methylcellulose phthalate, and methylcellulose; gums,
such as tragacanth and xanthan gum; sodium alginate; and gelatin.
In order to prepare a uniform gel, dispersing agents such as
alcohol or glycerin can be added, or the gelling agent can be
dispersed by trituration, mechanical mixing, and/or stirring.
[0133] The pharmaceutical compositions provided herein may be
administered rectally, urethrally, vaginally, or perivaginally in
the forms of suppositories, pessaries, bougies, poultices or
cataplasm, pastes, powders, dressings, creams, plasters,
contraceptives, ointments, solutions, emulsions, suspensions,
tampons, gels, foams, sprays, or enemas. These dosage forms can be
manufactured using conventional processes.
[0134] Rectal, urethral, and vaginal suppositories are solid bodies
for insertion into body orifices, which are solid at ordinary
temperatures but melt or soften at body temperature to release the
active ingredient(s) inside the orifices. Pharmaceutically
acceptable carriers utilized in rectal and vaginal suppositories
include vehicles, such as stiffening agents, which produce a
melting point in the proximity of body temperature, when formulated
with the pharmaceutical compositions provided herein; and
antioxidants as described herein, including bisulfite and sodium
metabisulfite. Suitable vehicles include, but are not limited to,
cocoa butter (theobroma oil), glycerin-gelatin, carbowax
(polyoxyethylene glycol), spermaceti, paraffin, white and yellow
wax, and appropriate mixtures of mono-, di- and triglycerides of
fatty acids, hydrogels, such as polyvinyl alcohol, hydroxyethyl
methacrylate, polyacrylic acid; glycerinated gelatin. Combinations
of the various vehicles may be used. Rectal and vaginal
suppositories may be prepared by the compressed method or molding.
The typical weight of a rectal and vaginal suppository is about 2
to 3 g.
[0135] The pharmaceutical compositions provided herein may be
administered ophthalmically in the forms of solutions, suspensions,
ointments, emulsions, gel-forming solutions, powders for solutions,
gels, ocular inserts, and implants.
[0136] The pharmaceutical compositions provided herein may be
administered intranasally or by inhalation to the respiratory
tract. The pharmaceutical compositions may be provided in the form
of an aerosol or solution for delivery using a pressurized
container, pump, spray, atomizer, such as an atomizer using
electrohydrodynamics to produce a fine mist, or nebulizer, alone or
in combination with a suitable propellant, such as
1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. The
pharmaceutical compositions may also be provided as a dry powder
for insufflation, alone or in combination with an inert carrier
such as lactose or phospholipids; and nasal drops. For intranasal
use, the powder may comprise a bioadhesive agent, including
chitosan or cyclodextrin.
[0137] Solutions or suspensions for use in a pressurized container,
pump, spray, atomizer, or nebulizer may be formulated to contain
ethanol, aqueous ethanol, or a suitable alternative agent for
dispersing, solubilizing, or extending release of the active
ingredient provided herein, a propellant as solvent; and/or a
surfactant, such as sorbitan trioleate, oleic acid, or an
oligolactic acid.
[0138] The pharmaceutical compositions provided herein may be
micronized to a size suitable for delivery by inhalation, such as
50 micrometers or less, or 10 micrometers or less. Particles of
such sizes may be prepared using a comminuting method known to
those skilled in the art, such as spiral jet milling, fluid bed jet
milling, supercritical fluid processing to form nanoparticles, high
pressure homogenization, or spray drying.
[0139] Capsules, blisters and cartridges for use in an inhaler or
insufflator may be formulated to contain a powder mix of the
pharmaceutical compositions provided herein; a suitable powder
base, such as lactose or starch; and a performance modifier, such
as /-leucine, mannitol, or magnesium stearate. The lactose may be
anhydrous or in the form of the monohydrate. Other suitable
excipients include dextran, glucose, maltose, sorbitol, xylitol,
fructose, sucrose, and trehalose. The pharmaceutical compositions
provided herein for inhaled/intranasal administration may further
comprise a suitable flavor, such as menthol and levomenthol, or
sweeteners, such as saccharin or saccharin sodium.
[0140] The pharmaceutical compositions provided herein for topical
administration may be formulated to be immediate release or
modified release, including delayed-, sustained-, pulsed-,
controlled-, targeted, and programmed release.
Modified Release
[0141] The pharmaceutical compositions provided herein may be
formulated as a modified release dosage form. As used herein, the
term "modified release" refers to a dosage form in which the rate
or place of release of the active ingredient(s) is different from
that of an immediate dosage form when administered by the same
route. Modified release dosage forms include delayed-, extended-,
prolonged-, sustained-, pulsatile- or pulsed-, controlled-,
accelerated- and fast-, targeted-, programmed-release, and gastric
retention dosage forms.
[0142] The pharmaceutical compositions in modified release dosage
forms can be prepared using a variety of modified release devices
and methods known to those skilled in the art, including, but not
limited to, matrix controlled release devices, osmotic controlled
release devices, multiparticulate controlled release devices,
ion-exchange resins, enteric coatings, multilayered coatings,
microspheres, liposomes, and combinations thereof. The release rate
of the active ingredient(s) can also be modified by varying the
particle sizes and polymorphorism of the active ingredient(s).
[0143] The pharmaceutical compositions provided herein in a
modified release dosage form may be fabricated using a matrix
controlled release device known to those skilled in the art.
[0144] In certain embodiments, the pharmaceutical compositions
provided herein in a modified release dosage form is formulated
using an erodible matrix device, which is water swellable,
erodible, or soluble polymers, including synthetic polymers, and
naturally occurring polymers and derivatives, such as
polysaccharides and proteins.
[0145] Materials useful in forming an erodible matrix include, but
are not limited to, chitin, chitosan, dextran, and pullulan; gum
agar, gum arabic, gum karaya, locust bean gum, gum tragacanth,
carrageenans, gum ghatti, guar gum, xanthan gum, and scleroglucan;
starches, such as dextrin and maltodextrin; hydrophilic colloids,
such as pectin; phosphatides, such as lecithin; alginates;
propylene glycol alginate; gelatin; collagen; and cellulosics, such
as ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl
cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl
cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP),
cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP,
CAT, hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS,
hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), and
ethylhydroxy ethylcellulose (EHEC); polyvinyl pyrrolidone;
polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters;
polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or
methacrylic acid (EUDRAGIT.RTM., Rohm America, Inc., Piscataway,
N.J.); poly(2-hydroxyethyl-methacrylate); polylactides; copolymers
of L-glutamic acid and ethyl-L-glutamate; degradable lactic
acidglycolic acid copolymers; poly-D-(-)-3-hydroxybutyric acid; and
other acrylic acid derivatives, such as homopolymers and copolymers
of butylmethacrylate, methylmethacrylate, ethylmethacrylate,
ethylacrylate, (2-dimethylaminoethyl)methacrylate, and
(trimethylaminoethyl)methacrylate chloride.
[0146] In certain embodiments, the pharmaceutical compositions are
formulated with a non-erodible matrix device. The active
ingredient(s) is dissolved or dispersed in an inert matrix and is
released primarily by diffusion through the inert matrix once
administered. Materials suitable for use as a non-erodible matrix
device included, but are not limited to, insoluble plastics, such
as polyethylene, polypropylene, polyisoprene, polyisobutylene,
polybutadiene, polymethylmethacrylate, polybutylmethacrylate,
chlorinated polyethylene, polyvinylchloride, methyl acrylate-methyl
methacrylate copolymers, ethylene-vinylacetate copolymers,
ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,
vinylchloride copolymers with vinyl acetate, vinylidene chloride,
ethylene and propylene, ionomer polyethylene terephthalate, butyl
rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,
ethylene/vinyl acetate/vinyl alcohol terpolymer, and
ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticized
nylon, plasticized polyethyleneterephthalate, natural rubber,
silicone rubbers, polydimethylsiloxanes, silicone carbonate
copolymers, and; hydrophilic polymers, such as ethyl cellulose,
cellulose acetate, crospovidone, and cross-linked partially
hydrolyzed polyvinyl acetate; and fatty compounds, such as camauba
wax, microcrystalline wax, and triglycerides.
[0147] In a matrix controlled release system, the desired release
kinetics can be controlled, for example, via the polymer type
employed, the polymer viscosity, the particle sizes of the polymer
and/or the active ingredient(s), the ratio of the active
ingredient(s) versus the polymer, and other excipients in the
compositions.
[0148] The pharmaceutical compositions provided herein in a
modified release dosage form may be prepared by methods known to
those skilled in the art, including direct compression, dry or wet
granulation followed by compression, melt-granulation followed by
compression.
[0149] The pharmaceutical compositions provided herein in a
modified release dosage form may be fabricated using an osmotic
controlled release device, including one-chamber system,
two-chamber system, asymmetric membrane technology (AMT), and
extruding core system (ECS). In general, such devices have at least
two components: (a) the core which contains the active
ingredient(s); and (b) a semipermeable membrane with at least one
delivery port, which encapsulates the core. The semipermeable
membrane controls the influx of water to the core from an aqueous
environment of use so as to cause drug release by extrusion through
the delivery port(s).
[0150] In addition to the active ingredient(s), the core of the
osmotic device optionally includes an osmotic agent, which creates
a driving force for transport of water from the environment of use
into the core of the device. One class of osmotic agents
waterswellable hydrophilic polymers, which are also referred to as
"osmopolymers" and "hydrogels," including, but not limited to,
hydrophilic vinyl and acrylic polymers, polysaccharides such as
calcium alginate, polyethylene oxide (PEO), polyethylene glycol
(PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl
methacrylate), poly(acrylic) acid, poly(methacrylic) acid,
polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol
(PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic
monomers such as methyl methacrylate and vinyl acetate, hydrophilic
polyurethanes containing large PEO blocks, sodium croscarmellose,
carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose
(HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl
cellulose (CMC) and carboxyethyl, cellulose (CEC), sodium alginate,
polycarbophil, gelatin, xanthan gum, and sodium starch
glycolate.
[0151] The other class of osmotic agents is osmogens, which are
capable of imbibing water to affect an osmotic pressure gradient
across the barrier of the surrounding coating. Suitable osmogens
include, but are not limited to, inorganic salts, such as magnesium
sulfate, magnesium chloride, calcium chloride, sodium chloride,
lithium chloride, potassium sulfate, potassium phosphates, sodium
carbonate, sodium sulfite, lithium sulfate, potassium chloride, and
sodium sulfate; sugars, such as dextrose, fructose, glucose,
inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose,
trehalose, and xylitol; organic acids, such as ascorbic acid,
benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid,
sorbic acid, adipic acid, edetic acid, glutamic acid,
p-tolunesulfonic acid, succinic acid, and tartaric acid; urea; and
mixtures thereof.
[0152] Osmotic agents of different dissolution rates may be
employed to influence how rapidly the active ingredient(s) is
initially delivered from the dosage form. For example, amorphous
sugars, such as Mannogeme EZ (SPI Pharma, Lewes, Del.) can be used
to provide faster delivery during the first couple of hours to
promptly produce the desired therapeutic effect, and gradually and
continually release of the remaining amount to maintain the desired
level of therapeutic or prophylactic effect over an extended period
of time. In this case, the active ingredient(s) is released at such
a rate to replace the amount of the active ingredient metabolized
and excreted.
[0153] The core may also include a wide variety of other excipients
and carriers as described herein to enhance the performance of the
dosage form or to promote stability or processing.
[0154] Materials useful in forming the semipermeable membrane
include various grades of acrylics, vinyls, ethers, polyamides,
polyesters, and cellulosic derivatives that are water-permeable and
water-insoluble at physiologically relevant pHs, or are susceptible
to being rendered water-insoluble by chemical alteration, such as
crosslinking. Examples of suitable polymers useful in forming the
coating, include plasticized, unplasticized, and reinforced
cellulose acetate (CA), cellulose diacetate, cellulose triacetate,
CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB),
CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate,
cellulose acetate trimellitate (CAT), CA dimethylaminoacetate,
CAethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl
sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar
acetate, amylose triacetate, beta glucan acetate, beta glucan
triacetate, acetaldehyde dimethyl acetate, triacetate of locust
bean gum, hydroxlated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPG
copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT,
poly(acrylic) acids and esters and poly(methacrylic) acids and
esters and copolymers thereof, starch, dextran, dextrin, chitosan,
collagen, gelatin, polyalkenes, polyethers, polysulfones,
polyethersulfones, polystyrenes, polyvinyl halides, polyvinyl
esters and ethers, natural waxes, and synthetic waxes.
[0155] Semipermeable membrane may also be a hydrophobic microporous
membrane, wherein the pores are substantially filled with a gas and
are not wetted by the aqueous medium but are permeable to water, as
disclosed in U.S. Pat. No. 5,798,119. Such hydrophobic but
water-permeable membrane are typically composed of hydrophobic
polymers such as polyalkenes, polyethylene, polypropylene,
polytetrafluoroethylene, polyacrylic acid derivatives, polyethers,
polysulfones, polyethersulfones, polystyrenes, polyvinyl halides,
polyvinylidene fluoride, polyvinyl esters and ethers, natural
waxes, and synthetic waxes. The delivery port(s) on the
semipermeable membrane may be formed postcoating by mechanical or
laser drilling. Delivery port(s) may also be formed in situ by
erosion of a plug of water-soluble material or by rupture of a
thinner portion of the membrane over an indentation in the core. In
addition, delivery ports may be formed during coating process.
[0156] The total amount of the active ingredient(s) released and
the release rate can substantially by modulated via the thickness
and porosity of the semipermeable membrane, the composition of the
core, and the number, size, and position of the delivery ports.
[0157] The pharmaceutical compositions in an osmotic
controlled-release dosage form may further comprise additional
conventional excipients as described herein to promote performance
or processing of the formulation.
[0158] The osmotic controlled-release dosage forms can be prepared
according to conventional methods and techniques known to those
skilled in the art.
[0159] In certain embodiments, the pharmaceutical compositions
provided herein are formulated as AMT controlled-release dosage
form, which comprises an asymmetric osmotic membrane that coats a
core comprising the active ingredient(s) and other pharmaceutically
acceptable excipients. The AMT controlled-release dosage forms can
be prepared according to conventional methods and techniques known
to those skilled in the art, including direct compression, dry
granulation, wet granulation, and a dip-coating method.
[0160] In certain embodiments, the pharmaceutical compositions
provided herein are formulated as ESC controlled-release dosage
form, which comprises an osmotic membrane that coats a core
comprising the active ingredient(s), hydroxylethyl cellulose, and
other pharmaceutically acceptable excipients.
[0161] The pharmaceutical compositions provided herein in a
modified release dosage form may be fabricated a multiparticulate
controlled release device, which comprises a multiplicity of
particles, granules, or pellets, ranging from about 10 pm to about
3 mm, about 50 pm to about 2.5 mm, or from about 100 pm to 1 mm in
diameter. Such multiparticulates may be made by the processes know
to those skilled in the art, including wet- and dry-granulation,
extrusion/spheronization, roller-compaction, melt-congealing, and
by spray-coating seed cores.
[0162] Other excipients as described herein may be blended with the
pharmaceutical compositions to aid in processing and forming the
multiparticulates. The resulting particles may themselves
constitute the multiparticulate device or may be coated by various
filmforming materials, such as enteric polymers, water-swellable,
and water-soluble polymers. The multiparticulates can be further
processed as a capsule or a tablet.
Targeted Delivery
[0163] The pharmaceutical compositions provided herein may also be
formulated to be targeted to a particular tissue, receptor, or
other area of the body of the subject to be treated, including
liposome-, resealed erythrocyte-, and antibody-based delivery
systems.
Dosages
[0164] In the treatment, prevention, or amelioration of one or more
symptoms of tic disorders or other conditions, disorders or
diseases associated with VMAT2 inhibition, an appropriate dosage
level generally is about 0.001 to 100 mg per kg patient body weight
per day (mg/kg per day), about 0.01 to about 80 mg/kg per day,
about 0.1 to about 50 mg/kg per day, about 0.5 to about 25 mg/kg
per day, or about 1 to about 20 mg/kg per day, which may be
administered in single or multiple doses. Within this range the
dosage may be 0.005 to 0.05, 0.05 to 0.5, or 0.5 to 5.0, 1 to 15, 1
to 20, or 1 to 50 mg/kg per day. In certain embodiments, the dosage
level is about 0.001 to 100 mg/kg per day.
[0165] In certain embodiments, the dosage level is about from 25 to
100 mg/kg per day. In certain embodiments, the dosage level is
about 0.01 to about 40 mg/kg per day. In certain embodiments, the
dosage level is about 0.1 to about 80 mg/kg per day. In certain
embodiments, the dosage level is about 0.1 to about 50 mg/kg per
day. In certain embodiments, the dosage level is about 0.1 to about
40 mg/kg per day. In certain embodiments, the dosage level is about
0.5 to about 80 mg/kg per day. In certain embodiments, the dosage
level is about 0.5 to about 40 mg/kg per day. In certain
embodiments, the dosage level is about 0.5 to about 25 mg/kg per
day. In certain embodiments, the dosage level is about 1 to about
80 mg/kg per day. In certain embodiments, the dosage level is about
1 to about 75 mg/kg per day. In certain embodiments, the dosage
level is about 1 to about 50 mg/kg per day. In certain embodiments,
the dosage level is about 1 to about 40 mg/kg per day. In certain
embodiments, the dosage level is about 1 to about 25 mg/kg per
day.
[0166] In certain embodiments, the dosage level is about from 5.0
to 150 mg per day, and in certain embodiments from 10 to 100 mg per
day. In certain embodiments, the dosage level is about 80 mg per
day. In certain embodiments, the dosage level is about 40 mg per
day.
[0167] For oral administration, the pharmaceutical compositions can
be provided in the form of tablets containing 1.0 to 1,000 mg of
the active ingredient, particularly about 1, about 5, about 10,
about 15, about 20, about 25, about 30, about 40, about 45, about
50, about 75, about 80, about 100, about 150, about 200, about 250,
about 300, about 400, about 500, about 600, about 750, about 800,
about 900, and about 1,000 mg of the active ingredient for the
symptomatic adjustment of the dosage to the patient to be treated.
In certain embodiments, the pharmaceutical compositions can be
provided in the form of tablets containing about 100 mg of the
active ingredient. In certain embodiments, the pharmaceutical
compositions can be provided in the form of tablets containing
about 80 mg of the active ingredient. In certain embodiments, the
pharmaceutical compositions can be provided in the form of tablets
containing about 75 mg of the active ingredient. In certain
embodiments, the pharmaceutical compositions can be provided in the
form of tablets containing about 50 mg of the active ingredient. In
certain embodiments, the pharmaceutical compositions can be
provided in the form of tablets containing about 40 mg of the
active ingredient. In certain embodiments, the pharmaceutical
compositions can be provided in the form of tablets containing
about 25 mg of the active ingredient. The compositions may be
administered on a regimen of 1 to 4 times per day, including once,
twice, three times, and four times per day.
[0168] It will be understood, however, that the specific dose level
and frequency of dosage for any particular patient may be varied
and will depend upon a variety of factors including the activity of
the specific compound employed, the metabolic stability and length
of action of that compound, the age, body weight, general health,
sex, diet, mode and time of administration, rate of excretion, drug
combination, the severity of the particular condition, and the host
undergoing therapy.
[0169] The compounds provided herein may also be combined or used
in combination with other agents useful in the treatment,
prevention, or amelioration of one or more symptoms of the diseases
or conditions for which the compounds provided herein are useful,
including tic disorders and other conditions commonly treated with
antipsychotic medication.
[0170] In certain embodiments, the compounds provided herein may
also be combined or used in combination with a typical
antipsychotic drug. In certain embodiments, the typical
antipsychotic drug is fluphenazine, haloperidol, loxapine,
molindone, perphenazine, pimozide, sulpiride, thioridazine, or
trifluoperazine. In certain embodiments, the antipsychotic drug is
an atypical antipsychotic drug. In certain embodiments, the
atypical antipsychotic drug is aripiprazole, asenapine, clozapine,
iloperidone, olanzapine, paliperidone, quetiapine, risperidone, or
ziprasidone. In certain embodiments, the atypical antipsychotic
drug is clozapine.
[0171] Such other agents, or drugs, may be administered, by a route
and in an amount commonly used thereof, simultaneously or
sequentially with the compounds provided herein. When compounds
provided herein are used contemporaneously with one or more other
drugs, a pharmaceutical composition containing such other drugs in
addition to the compounds provided herein may be utilized, but is
not required. Accordingly, the pharmaceutical compositions provided
herein include those that also contain one or more other active
ingredients or therapeutic agents, in addition to the compounds
provided herein.
[0172] The weight ratio of the compounds provided herein to the
second active ingredient may be varied, and will depend upon the
effective dose of each ingredient. Generally, an effective dose of
each will be used. Thus, for example, when the compounds provided
herein are used in combination with the second drug, or a
pharmaceutical composition containing such other drug, the weight
ratio of the particulates to the second drug may range from about
1,000:1 to about 1:1,000, or about 200:1 to about 1:200.
[0173] Combinations of the particulates provided herein and other
active ingredients will generally also be within the aforementioned
range, but in each case, an effective dose of each active
ingredient should be used.
[0174] Examples of embodiments of the present disclosure are
provided in the following examples. The following examples are
presented only by way of illustration and to assist one of ordinary
skill in using the disclosure. The examples are not intended in any
way to otherwise limit the scope of the disclosure.
EXAMPLES
Example 1
A Phase 1, Open-Label, One-Sequence Crossover Study to Assess the
Effect of Rifampin on the Pharmacokinetics of Valbenazine Tosylate
in Healthy Subjects
[0175] This was a Phase 1, open-label, one-sequence crossover,
drug-interaction study of valbenazine tosylate in a total of 12
healthy subjects (6 males and 6 females). After providing informed
consent, subjects were screened for eligibility to participate in
the study within 21 days before Day 1 (the first day of study drug
administration). Subjects who met the eligibility criteria were
admitted to the study center on the morning of Day -1 (the day
before dosing). Subjects received a single dose of 80 mg
valbenazine tosylate on Days 1 and 11 between 0800 and 1000 hours.
In addition, subjects received 600 mg rifampin (300 mg.times.2
capsules) once daily on Days 5 (after collection of the 96-hour PK
sample) through 14 between 0830 and 1030 hours. Subjects were
required to fast overnight before receiving the study drugs
(valbenazine tosylate and rifampin). Subjects were discharged from
the study center on Day 15 (final study day or upon early
termination) after all safety evaluations and study assessments had
been completed.
[0176] Blood samples were collected for PK analyses of NBI-98854
and its metabolites, NBI-98782 and NBI-136110, and for rifampin
plasma concentrations at scheduled times during the study. Safety
was assessed throughout the study.
[0177] NBI-98854 40 mg capsules were administered orally. The dose
of NBI-98854 was based on ditosylate salt (dose expressed as free
base). Subjects received a single dose of NBI-98854 80 mg (as two
40 mg capsules) twice during the study, on Days 1 and 11.
[0178] Rifampin 300 mg capsules were administered orally. Subjects
received a single dose of rifampin 600 mg (as two 300 mg capsules)
on Days 5 (after collection of the 96 hour NBI-98854 PK sample)
through 14 between 0830 and 1030 hours.
Pharmacokinetics
[0179] Blood samples to determine plasma concentrations of
NBI-98854, and the metabolites NBI-98782 and NBI-136110, were
collected on Days 1 and 11 at 30 minutes before NBI-98854 dosing,
and at 15, 30, and 45 minutes, and at 1, 1.5, 2, 3, 4, 8, 12, 18,
24, 48, 72, and 96 hours after NBI-98854 dosing or upon early
termination.
[0180] The following plasma PK parameters were assessed for
NBI-98854, NBI-98782, and NBI-136110: [0181] Area under the plasma
concentration versus time curve (AUC) from 0 to 24 hours
(AUC.sub.0-24) [0182] AUC from 0 hours to last measureable
concentration (AUC.sub.tlast) [0183] AUC from 0 hours extrapolated
to infinity (AUC.sub.0-.infin.) [0184] Maximum plasma concentration
(C.sub.max) [0185] Time prior to the first measurable concentration
(T.sub.lag) [0186] Apparent terminal half-life (t.sub.1/2) [0187]
Time to maximum plasma concentration (t.sub.max) [0188] Apparent
mean residence time (MRT) [0189] Molar ratio of the metabolites
NBI-98782 and NBI-136110 to the parent drug NBI-98854
[0190] The following plasma PK parameters were calculated only for
NBI-98854: [0191] Apparent systemic clearance after oral
administration (CL/F) [0192] Apparent volume of distribution during
the terminal phase after oral administration (V.sub.z/F)
[0193] The PK data for t.sub.max, T.sub.lag, t.sub.1/2, MRT, and
Vz/F were rounded to 2 significant figures and all other parameters
(AUC.sub.0-24, AUC.sub.tlast, AUC.sub.0-.infin., C.sub.max, and
CL/F) were rounded to 3 significant figures. The last significant
figure was rounded up if the digit to the right of it was >5,
and was rounded down if the digit to the right of it was <4.
[0194] Blood samples to determine rifampin plasma concentration
were collected at 30 minutes predose and 1, 2.5, 3.5, 7.5, 11.5,
and 23.5 hours after rifampin dosing on Days 5 and 11; at 2.5 hours
after rifampin dosing on Days 6 through 10 and Days 12 through 13;
at 2.5 and 8 hours after rifampin dosing on Day 14; and at
approximately 0800 hours on Day 15 (final study day or upon early
termination). The following plasma PK parameters were calculated
for rifampin: AUC.sub.0-24, AUC.sub.0-tlast, C.sub.max' and
t.sub.max.
[0195] The PK data for t.sub.max, T.sub.lag, t.sub.1/2, MRT, and
Vz/F were rounded to 2 significant figures and all other parameters
(AUC.sub.0-24, AUC.sub.0-last, AUC.sub.0-.infin., C.sub.max, and
CL/F) were rounded to 3 significant figures. The last significant
figure was rounded up if the digit to the right of it was
.gtoreq.5, and was rounded down if the digit to the right of it was
.ltoreq.4.
Pharmacokinetic Results
[0196] Concomitant administration of NBI-98854 and rifampin led to
an approximate 30% decrease in C.sub.max and an approximate 70%
decrease in AUC.sub.0-.infin. of NBI-98854 compared with
administration of NBI-98854 alone. The 90% confidence interval (CI)
for the geometric mean ratios (57.9% to 80.3% for C.sub.max and
25.5% to 30.1% for AUC.sub.0- ) were outside the `no effect` range
of 80% to 125% indicating an effect of treatment with rifampin on
NBI-98854 AUC.sub.0-.infin. and C.sub.max. Mean t.sub.1/2 of
NBI-98854 decreased from 16 to 10 hours when NBI-98854 was
administered with rifampin. This decrease in NBI-98854 C.sub.max,
AUC.sub.0-.infin., and t.sub.1/2 is consistent with in vitro data
that suggests a significant role of rifampin-inducible cytochrome
P450 (CYP) enzymes (eg, CYP3A4) in the metabolism of NBI-98854.
[0197] Coadministration of NBI-98854 and rifampin also led to an
approximately 50% decrease in C.sub.max and an approximately 80%
decrease in AUC.sub.0-.infin. of an active metabolite NBI-98782
compared with administration of NBI-98854 alone. The 90% CI for the
geometric mean ratios were outside the `no effect` range of 80% to
125%. Mean t.sub.1/2 of NBI-98782 decreased from 19 to 12 hours
when NBI-98854 was administered with rifampin. This decrease in
NBI-98782 C.sub.max and AUC.sub.0-.infin. could be due to its
decreased formation because of reduced bioavailability of NBI-98854
and/or increased metabolism of NBI-98782 by rifampin-inducible CYP
enzymes (eg, CYP3A4).
[0198] For the metabolite NBI-136110, mean C.sub.max increased
1.4-fold; however, mean AUC.sub.0-.infin. decreased approximately
70% after treatment with NBI-98854 plus rifampin compared with
administration of NBI-98854 alone. The 90% CI for the geometric
mean ratio was outside the `no effect` range of 80% to 125%. Mean
t.sub.1/2 of NBI-136110 decreased from 27 to 12 hours when
NBI-98854 was administered with rifampin. The increase in C.sub.max
of NBI-136110 is consistent with the in vitro data, which suggests
that CYP3A4 is involved in the conversion of NBI-98854 to
NBI-136110. Additionally, the decrease in AUC and t.sub.1/2 of
NBI-136110 provides evidence that NBI-136110 is further metabolized
by rifampin-inducible CYP enzymes (eg, CYP3A4).
TABLE-US-00001 Summary of Pharmacokinetic Parameters NBI-98854 (80
mg) + Parameter NBI-98854 (80 mg) Rifampin (600 mg) Statistic (N =
11) (N = 11) AUC.sub.0-24 (ng hr/mL) Mean (SD) 4480 (897) 1510
(471) Geometric CV % 19.8 27.2 AUC.sub.0-tlast (ng hr/mL) Mean (SD)
5930 (1180) 1670 (555) Geometric CV % 20.0 27.8 AUC.sub.0-.infin.
(ng hr/mL) Mean (SD) 6020 (1210) 1700 (553) Geometric CV % 20.2
27.3 C.sub.max (ng/mL) Mean (SD) 795 (386) 542 (299) Geometric CV %
45.5 42.9 t.sub.max (hours) Median (min, max) 0.75 (0.50, 2.1) 0.75
(0.50, 1.0) T.sub.lag (hours) Mean (SD) 0.12 (0.13) 0.091 (0.13)
t.sub.1/2 (hours) Mean (SD) 16 (2.3) 10 (2.1) Geometric CV %
15.sup. 28.sup. MRT (hours) Mean (SD) 17 (2.8) 8.7 (1.3) Geometric
CV % 16.sup. 17.sup. CL/F (L/hr) Mean (SD) 13.8 (2.77) 50.3 (11.4)
Geometric CV % 20.2 27.3 Vz/F (L) Mean (SD) 330 (79) 730 (230)
Geometric CV % 25.sup. 37.sup.
[0199] The geometric mean ratios and associated 90% CIs for
AUC.sub.0-.infin. and C.sub.max for NBI-98854 after treatment with
NBI-98854 in combination with rifampin or NBI-98854 alone or are
provided below.
TABLE-US-00002 NBI-98854 Geometric Mean Ratios for Pharmacokinetic
Exposure Parameters (PK Analysis Set) Ratio.sup.a (%) (NBI-98854
with rifampin vs. 90% Confidence Parameter NBI-98854 alone)
Interval.sup.b AUC.sub.0-.infin. (ng .times. hr/mL) 27.7 25.5, 30.1
C.sub.max (ng/mL) 68.2 57.9, 80.3 .sup.aRatio of geometric
least-squares means was based on a mixed model using
log-transformed (base 10) data .sup.bThe 90% confidence interval
for geometric mean ratio was based on least-squares means using
log-transformed (base 10) data
[0200] Geometric mean ratios for AUC.sub.0-.infin. and C.sub.max
for NBI-98854 after administration of NBI-98854 in combination with
rifampin compared with NBI-98854 alone were 27.7% and 68.2%,
respectively. The corresponding upper and lower 90% CI bounds for
AUC.sub.0-.infin. (25.5% to 30.1%) and C.sub.max (57.9% to 80.3%)
were outside the `no effect` range of 80% to 125%, indicating an
effect of treatment with rifampin on NBI-98854 AUC.sub.0-.infin.
and C.sub.max
[0201] PK parameters for NBI-98782 after treatment with NBI-98854
alone or in combination with rifampin are summarized below.
TABLE-US-00003 NBI-98854 (80 mg) + Parameter NBI-98854 (80 mg)
Rifampin (600 mg) Statistic (N = 11) (N = 11) AUC.sub.0-24 (ng
.times. hr/mL) Mean (SD) 364 (90.9) 115 (32.3) Geometric CV % 24.0
25.0 AUC.sub.0-tlast (ng .times. hr/mL) Mean (SD) 665 (193) 153
(43.9) Geometric CV % 26.0 23.7 AUC.sub.0-.infin. (ng .times.
hr/mL) Mean (SD) 689 (203) 156 (43.9) Geometric CV % 26.5 23.2
C.sub.max (ng/mL) Mean (SD) 21.5 (4.60) 11.2 (5.83) Geometric CV %
22.6 44.8 t.sub.max (hr) Median (min, max) 4.0 (0.52, 18) 3.0
(0.50, 4.0) T.sub.lag (hr) Mean (SD) 0.25 (0.16) 0.23 (0.075)
t.sub.1/2 (hr) Mean (SD) 19 (2.3) 12 (1.7) Geometric CV % 13.sup.
15.sup. MRT (hr) Mean (SD) 28 (3.8) 17 (2.5) Geometric CV % 14.sup.
15.sup.
[0202] Mean C.sub.max for NBI-98782 after treatment with NBI-98854
plus rifampin was approximately 50% lower than that after treatment
with NBI-98854 alone. Mean AUC.sub.0-.infin. for NBI-98782 after
treatment with NBI-98854 in combination with rifampin was
approximately 80% lower than that after treatment with NBI-98854
alone. Median t.sub.max values were similar after treatment with
NBI-98854 plus rifampin (3.0 hours) and NBI-98854 alone (4.0 hours)
and mean t.sub.1/2 was lower after treatment with NBI-98854 plus
rifampin than after treatment with NBI-98854 alone (12 and 19
hours, respectively).
[0203] The variability in PK (ie, geometric CV %) for NBI-98782
after treatment with NBI-98854 alone and in combination with
rifampin was generally similar for AUC.sub.0-24, AUC.sub.tlast,
f/.sub.2, and MRT; but was higher for C.sub.max after NBI-98854 in
combination with rifampin.
[0204] Geometric mean ratios for AUC.sub.0-.infin. and C.sub.max
for NBI-98782 after administration of NBI-98854 in combination with
rifampin compared with NBI-98854 alone were 22.8% and 48.5%,
respectively. The corresponding upper and lower 90% CI bounds for
AUC.sub.0-.infin. (20.5% to 25.4%) and C.sub.max (41.3% to 56.9%)
were outside the `no effect` range of 80% to 125%, indicating an
effect of treatment with rifampin on NBI-98782 AUC.sub.0-.infin.
and C.sub.max.
[0205] The mean NBI-136110 plasma concentration versus time
profiles for NBI-98854 alone or in combination with rifampin are
presented below.
TABLE-US-00004 NBI-98854 (80 mg) + Parameter NBI-98854 (80 mg)
Rifampin (600 mg) Statistic (N = 11) (N = 11) AUC.sub.0-24
(ngxhr/mL) Mean (SD) 963 (271) 554 (133) Geometric CV % 39.8 22.3
AUC0-.sub.tlast (ng .times. hr/mL) Mean (SD) 1890 (451) 658 (166)
Geometric CV % 28.3 22.4 AUC.sub.0-.infin. (ng .times. hr/mL) Mean
(SD) 2080 (463) 663 (166) Geometric CV % 24.0 22.3 C.sub.max
(ng/mL) Mean (SD) 59.8 (16.9) 81.5 (24.6) Geometric CV % 45.7 29.6
t.sub.max (hr) Median (min, max) 3.0 (2.0, 8.0) 1.5 (0.75, 2.1)
T.sub.lag (hr) Mean (SD) 0.23 (0.14) 0.16 (0.13) t.sub.1/2 (hr)
Mean (SD) 27 (6.7) 12 (3.0) Geometric CV % 21.sup. 23.sup. MRT (hr)
Mean (SD) 39 (11) 12 (1.5) Geometric CV % 23.sup. 13.sup.
[0206] Mean C.sub.max was approximately 1.4-fold higher after
treatment with NBI-98854 in combination with rifampin than that
after treatment with NBI-98854 alone. Mean AUC.sub.0-.infin. for
NBI-136110 after treatment with NBI-98854 in combination with
rifampin was approximately 70% lower than that after treatment with
NBI-98854 alone. Median t.sub.max was 1.5 hours shorter (1.5 hours
versus 3.0 hours) after treatment with NBI-98854 in combination
with rifampin than that after treatment with NBI-98854 alone. Mean
t.sub.1/2 for NBI-136110 after treatment with NBI-98854 in
combination with rifampin was approximately 40% shorter than that
after treatment with NBI-98854 alone. The variability in PK (ie,
geometric CV %) for NBI-136110 after treatment with NBI-98854 alone
and in combination with rifampin was generally similar for
AUC.sub.tlast and f/.sub.2; but was lower for AUC.sub.0-24, MRT,
and C.sub.max after NBI-98854 in combination with rifampin.
[0207] Geometric mean ratios for AUC.sub.0-.infin. and C.sub.max
for NBI-136110 after administration of NBI-98854 in combination
with rifampin compared with NBI-98854 alone were 31.9% and 139.5%,
respectively. The 90% CI for AUC.sub.0-.infin. (28.9% to 35.2%) and
C.sub.max (112.3% to 173.3%) were outside the "no effect" range of
80% to 125%, indicating an effect of treatment with rifampin on
NBI-136110 AUC.sub.0-.infin. and C.sub.max.
[0208] Concomitant administration of NBI-98854 and rifampin led to
an approximate 30% decrease in C.sub.max and an approximate 70%
decrease in AUC.sub.0-.infin. of NBI-98854 compared with
administration of NBI-98854 alone. The 90% CI for the geometric
mean ratios (57.9% to 80.3% for C.sub.max and 25.5% to 30.1% for
AUC.sub.0-.infin.) were outside the `no effect` range of 80% to
125% indicating an effect of treatment with rifampin on NBI-98854
AUC.sub.0-.infin. and C.sub.max. Mean t.sub.1/2 of NBI-98854
decreased from 16 to 10 hours when NBI-98854 was administered with
rifampin. This decrease in NBI-98854 C.sub.max and AUC is
consistent with in vitro data that suggests a significant role of
rifampin-inducible CYP enzymes (eg, CYP3A4) in the metabolism of
NBI-98854.
[0209] Concomitant administration of NBI-98854 and rifampin also
led to an approximate 50% decrease in C.sub.max and an approximate
80% decrease in AUC.sub.0-.infin. of an active metabolite NBI-98782
compared with administration of NBI-98854 alone. The 90% CI for the
geometric mean ratios were outside the `no effect` range of 80% to
125%. Mean t.sub.1/2 of NBI-98782 decreased from 19 to 12 hours
when NBI-98854 was administered with rifampin. This decrease in
NBI-98782 C.sub.max and AUC could be due to its decreased formation
because of reduced bioavailability of NBI-98854 and/or increased
metabolism of NBI-98782 by rifampin-inducible CYP enzymes (eg,
CYP3A4).
[0210] For the metabolite NBI-136110, mean C.sub.max increased
1.4-fold; however, mean AUC.sub.0-.infin. decreased approximately
70% after treatment with NBI-98854 plus rifampin compared with
administration of NBI-98854 alone. The 90% CI for the geometric
mean ratio was outside the `no effect` range of 80% to 125%. Mean
t.sub.1/2 of NBI-136110 decreased from 27 to 12 hours when
NBI-98854 was administered with rifampin. The increase in C.sub.max
of NBI-136110 is consistent with the in vitro data, which suggests
that CYP3A4 is involved in the conversion of NBI-98854 to
NBI-136110. Additionally, the decrease AUC.sub.0-.infin. of
NBI-136110 provides evidence that NBI-136110 is further metabolized
by rifampin-inducible CYP enzymes (eg, CYP3A4).
Safety
[0211] Safety was assessed based on adverse events (AEs), clinical
laboratory tests, vital signs, physical examinations, and
electrocardiograms (ECGs).
[0212] Statistical Methods: Plasma concentrations of NBI-98854, its
metabolites, NBI-98782 and NBI-136110, and rifampin were summarized
with descriptive statistics and in figures. An analysis of variance
(ANOVA) model was used to compare AUC.sub.0-.infin. and C.sub.max
for NBI-98854 administered with rifampin ("test") versus
AUC.sub.0-.infin. and C.sub.max for NBI-98854 alone ("reference").
The PK parameters for metabolites of NBI-98854 and rifampin were
also evaluated. Safety data were summarized using descriptive
statistics.
Safety Results
[0213] No deaths, serious or severe treatment-emergent adverse
events (TEAEs), or discontinuations due to an AE were reported in
this study. All 12 subjects (100%) experienced chromaturia after
beginning rifampin. Chromaturia is a known side effect of rifampin.
The other most frequently reported AE was headache (3 subjects,
25.0%).
[0214] There were no important differences in the number and types
of AEs reported across treatments, with the exception of
chromaturia. There were no clinically significant changes in
clinical laboratory test results, vital sign measurements, or ECG
parameters during the study and no clinically important differences
were noted across groups. Most subjects had normal physical
examinations during the study and none of the abnormal findings
were considered clinically significant. There were no important
changes in body weight from baseline to the final visit. No subject
had a corrected QT interval using Fridericia's formula (QTcF)
interval >450 msec or a maximum increase from baseline >30
msec.
[0215] The number and percentage of subjects who experienced TEAEs
are summarized by treatment below.
TABLE-US-00005 Number and Percentage of Subjects Who Experienced a
Treatment- Emergent Adverse Event (Safety Analysis Set) NBI-98854
Rifampin NBI-98854 (80 mg) + (80 mg).sup.a (600 mg).sup.b Rifampin
(600 mg).sup.c N = 12 N = 12 N = 11 Preferred Term n (%) n (%) n
(%) Overall 6 (50.0) 12 (100) 1 (9.1) Abdominal pain 1 (8.3) 0 0
Abdominal pain upper 0 1 (8.3) 1 (9.1) Non-cardiac chest pain 0 1
(8.3) 0 Vessel puncture site 1 (8.3) 0 0 haemorrhage Arthropod bite
1 (8.3) 0 0 Headache 3 (25.0) 0 1 (9.1) Hypoaesthesia 0 0 1 (9.1)
Paraesthesia 0 1 (8.3) 0 Chromaturia 0 12 (100) 0 .sup.aOnset on or
after the first dose (Day 1) of NBI-98854 but prior to the first
dose of rifampin .sup.bOnset on or after the first dose of rifampin
but prior to the Day 11 dose of NBI-98854 plus rifampin .sup.cOnset
on or after the Day 11 dose of NBI-98854 plus rifampin Note:
Subjects may have more than one TEAE per system organ class or
preferred term.
CONCLUSIONS
[0216] The major metabolic clearance pathways for NBI-98854 are
ester hydrolysis to form an active metabolite NBI-98782 and
mono-oxidation to form NBI-136110. In vitro studies have indicated
the hydrolysis of NBI-98854 to form NBI-98782 can occur both
enzymatically (via esterases) and non-enzymatically (via chemical
hydrolysis), whereas CYP3A4/5 is the major enzyme involved in the
oxidative metabolism of NBI-98854. The oxidative metabolism of the
metabolite NBI-98782 is mediated primarily by CYP2D6 with
contribution from CYP3A4/5 (and possibly other enzymes). Given the
role of CYP enzymes in the metabolism and elimination of NBI-98854,
pleiotropic CYP inducer like rifampin would be expected to decrease
the systemic exposure to NBI-98854 and its metabolites.
[0217] The data from the present study provided clinical data
demonstrating that concomitant administration of NBI-98854 and
rifampin results in decrease in systemic exposure to NBI-98854,
which is consistent with a significant role of inducible CYP
enzymes (eg, CYP3A4) in the metabolism of NBI-98854. Systemic
exposure to NBI-98782 was decreased, which could be due to (1)
reduced bioavailability of NBI-98854 and/or (2) increased
metabolism of NBI-98782 by rifampin-inducible CYP enzymes (eg,
CYP3A4). The effect of rifampin on NBI-136110 exposure measures was
characterized by an increase in C.sub.max, but a decrease in AUC.
The increase in C.sub.max of NBI-136110 is consistent with the in
vitro data which suggests that CYP3A4 is involved in the conversion
of NBI-98854 to NBI-136110. Induction of this pathway would be
expected to increase the rate of formation of NBI-136110, as
evidenced by an increase in C.sub.max. Conversely, the decrease in
AUC.sub.0-.infin. and t.sub.1/2 of NBI-136110 provides evidence
that NBI-136110 is metabolized and eliminated by hepatic CYP
enzymes.
[0218] Overall, NBI-98854 was well tolerated in this study. No
deaths or serious or severe TEAEs were reported and no subject
discontinued the study due to a TEAE. There were no clinically
significant changes in clinical laboratory test results, vital sign
measurements, or ECG parameters during the study.
[0219] Concomitant administration of NBI-98854 and rifampin results
in a decrease in systemic exposure to NBI-98854 and NBI-98782.
[0220] NBI-98854 80 mg was well tolerated in healthy subjects when
administered alone or concomitantly with rifampin.
Example 2: Pharmacologic Characterization of Valbenazine,
Tetrabenazine, and Metabolite Thereof
[0221] Upon oral administration, TBZ is reduced to form four
discrete isomeric secondary alcohol metabolites, collectively
referred to as dihydrotetrabenazine (DHTBZ), which contains three
asymmetric carbon centers (C-2, C-3, and C-11.beta.), which could
hypothetically result in eight stereoisomers. However, because the
C-3 and C-11.beta. carbons have fixed relative configurations, only
four stereoisomers are possible: (R,R,R-DHTBZ or (+)-.alpha.-DHTBZ
(alternate nomenclature) or NBI-98782 (laboratory nomenclature);
S,S,S-DHTBZ or (-)-.alpha.-DHTBZ or NBI-98771; S,R,R-DHTBZ or
(+)-.beta.-DHTBZ or NBI-98795; and R,S,S-DHTBZ or (-)-.beta.-DHTBZ
or NBI-98772.
[0222] The affinity of each compound was measured by inhibition of
[.sup.3H]-DHTBZ binding to rat forebrain membranes. The affinities
relative to R,R,R-DHTBZ were also calculated and are presented.
Data are reported as both the negative logarithm of the Ki (pKi)
for statistical calculation with the normally distributed binding
parameter used to determine the mean and SEM. The Ki value was
determined from the mean pKi as 10(-pKi). The R,R,R-DHTBZ
stereoisomer binds with the highest affinity to both rat and human
VMAT2 (Ki=1.0 to 4.2 nM). In comparison, the remaining three DHTBZ
stereoisomers (S,R,R-DHTBZ, S,S,S-DHTBZ, R,S,S-DHTBZ) bind to VMAT2
with a Ki values of 9.7, 250, and 690 nM, respectively.
TABLE-US-00006 In Vitro VMAT2 Binding Affinity in Rat Forebrain
VMAT2 Affinity K.sub.i,, pK.sub.i mean Relative to Compound nm
(SEM) N R,R,R-DHTBZ.sup.a R,R,R-DHTBZ 4.2 8.38 (0.42) 27 1.0
S,R,R-DHTBZ 9.7 8.01 (0.32) 6 2.3 S,S,S-DHTBZ 250 6.60 (0.22) 4 60
R,S,S-DHTBZ 690 6.16 (0.05) 5 160 .sup.aAffinity relative to
R,R,R-DHTBZ was calculated using the K.sub.i value determined in
the same study
[0223] The primary metabolic clearance pathways of valbenazine
(VBZ, NBI-98854) are hydrolysis (to form R,R,R-DHTBZ) and
mono-oxidation (to form the metabolite NBI-136110). R,R,R-DHTBZ and
NBI-136110, the two most abundant circulating metabolites of VBZ,
are formed gradually and their plasma concentrations decline with
half-lives similar to VBZ.
[0224] VBZ and its metabolites, R,R,R-DHTBZ and NBI-136110, were
tested for their ability to inhibit the binding of [3H]-DHTBZ to
VMAT2 in cell lines or native tissues. The affinity of each
compound was measured by inhibition of [.sup.3H]-DHTBZ binding to
either human platelets or rat striatal membranes. The affinities
relative to R,R,R-DHTBZ were also calculated and are presented.
Data are reported as both the negative logarithm of the K.sub.i
(pKi) for statistical calculation with the normally distributed
binding parameter used to determine the mean and SEM (n=4 for each
compound in each tissue). The K.sub.i value was determined from the
mean pKi as 10.sup.(-pKi). The primary metabolite R,R,R-DHTBZ, was
the most potent inhibitor of VMAT2 in rat striatum and human
platelet homogenates.
TABLE-US-00007 In Vitro VMAT2 Binding Affinity of Valbenazine and
its Metabolites Rat Striatum Human Platelets Affinity Affinity
K.sub.i, pK.sub.i mean Relative to K.sub.i, pK.sub.i mean Relative
to Compound nm (SEM) R,R,R-DHTBZ nm (SEM) R,R,R-DHTBZ Valbenazine
110 6.95 (0.02) 39 150 6.82 (0.02) 45 R,R,R-DHTBZ 1.98 8.70 (0.09)
1.0 3.1 8.52 (0.03) 1.0 NBI-136610 160 6.80 (0.02) 57 220 6.65
(0.04) 67
[0225] VBZ and NBI-136110 had similar effects on VMAT2 inhibition,
but with Ki values that were approximately 40-65 times the Ki
values (lower affinity) of R,R,R-DHTBZ. These results were
corroborated by the radioligand binding assay of DHTBZ
stereoisomers (i.e., TBZ metabolites) in the rat forebrain, which
also showed R,R,R-DHTBZ to be the most potent inhibitor of VMAT2,
followed by S,R,R-DHTBZ. Comparatively, S,S,S-DHTBZ and
R,S,S-DHTBZ, the other two primary metabolites of TBZ, were found
to be poor VMAT2 inhibitors with affinities approximately 60 and
160 times weaker than R,R,R-DHTBZ.
[0226] The affinity of VBZ and its metabolites R,R,R-DHTBZ and
NBI-136110 for other targets beyond VMAT2 was assessed in an
extensive Cerep screen of multiple classes of protein targets
including GPCRs, cell-surface monoamine transporters, and ion
channels including the cardiac potassium channel, human
ether-a-go-go-related gene (HERG).
[0227] The multi-target activity screen of more than 80 targets for
these compounds (Cerep screen) demonstrated that VBZ and its
metabolites, R,R,R-DHTBZ and NBI-136110, did not inhibit the
binding of cognate ligands to any of the targets by more than 50%
at concentrations of 1-10 .mu.M. In contrast, the other three DHTBZ
stereoisomers (S,R,R-DHTBZ, S,S,S-DHTBZ, R,S,S-DHTBZ), which are
metabolites of TBZ but not VBZ, demonstrated >50% inhibition of
ligand binding to a number of receptor subtypes including
serotonin, dopamine and adrenergic receptors. Results expressed as
percent of control specific binding: (tested compound specific
binding/control specific binding).times.100. All compounds were
tested at 1 or 10 .mu.M final concentration and results are an
excerpt of a larger 80 target panel performed as an initial screen
at Cerep (n=2 for each compound at each target). Bolded results
(>50%) indicate activity at target receptor.
TABLE-US-00008 In Vitro Activity Of Valbenazine And DHTBZ
Stereoisomers At Dopamine, Serotonin, And Adrenergic Receptors
R,R,R- S,R,R- S,S,S-DHTBZ/ Receptor Target Valbenazine DHTBZ DHTBZ
R,S,S-DHTBZ.sup.a Serotonin5-HT.sub.1A 26 17 69 96
Serotonin5-HT.sub.2A 1 -4 3 84 Serotonin5-HT.sub.7 4 3 80 98
Dopamine D.sub.1 8 -6 -5 82 Dopamine D.sub.2(s) 2 6 25 89 .sup.aFor
purposes of the broad panel screen, the S,S,S- and
R,S,S-metabolites were tested as a 50/50 mixture.
[0228] To describe the monoamine systems in greater detail,
detailed radioligand binding assays were performed for dopamine,
serotonin and adrenergic receptor subtypes as well as the
transporters for dopamine (DAT), serotonin (SERT), and
norepinephrine (NET) for the common metabolite of TBZ and VBZ
(R,R,R-DHTBZ) and the other relevant metabolites unique to TBZ and
VBZ. This detailed analysis revealed the high specificity of
R,R,R-DHTBZ for the VMAT2 transporter and the non-specific
activities of the other TBZ metabolites, including relatively high
affinity for dopamine and serotonin receptor subtypes.
Interestingly, the R,R,R-DHTBZ metabolite showed the greatest
non-selectivity with respect to the monoamine receptors. None of
the TBZ or VBZ metabolites had any affinity for the monoamine
transporters DAT, SERT or NET. To complete the selectivity profile
for VMAT2, the functional activity for the human VMAT1 transporter
of these compounds was tested in cells expressing VMAT1. While the
non-selective irreversible high-affinity uptake inhibitor of VMAT1,
reserpine, substantially inhibited uptake through VMAT1, there was
no significant inhibitory activity of TBZ, VBZ, or its metabolites
R,R,R-DHTBZ or NBI-136110 at concentrations up to 10 .mu.M. For
both VMAT1 and VMAT2, uptake was measured in the untransfected host
cells and was found to be similar to transfected cells in the
presence of excess reserpine.
[0229] Radioligand binding assays and the broad panel screen
indicate that in addition to varying potency at the VMAT2
transporter, two of the other DHTBZ metabolites of TBZ (S,S,S-DHTBZ
and R,S,S-DHTBZ) interact with D1 and D2 receptors. Since VBZ is
not metabolized to either of these DHTBZ stereoisomers, its effects
on postsynaptic dopamine receptors either directly or indirectly
through the metabolites are non-existent.
[0230] Moreover, results from the broad panel screen indicate that
VBZ and its major metabolites (R,R,R-DHTBZ and NBI-136110) have
little to no affinity for more than 80 binding sites, including
receptors, monoamine transporters, and ion channels. This profile
suggests a low potential for off-target pharmacological effects. In
addition, uptake studies using TBZ, VBZ and its metabolites,
R,R,R-DHTBZ and NBI-136110, confirmed the selectivity of these
compounds for VMAT2 as they had no significant effect on the uptake
of monoamines through VMAT1 compared to reserpine, a known
VMAT1/VMAT2 inhibitor.
[0231] The selectivity and specificity of VBZ was distinctively
demonstrated using two in vivo surrogate measures of
pharmacological effects. Ptosis, known to occur via adrenergic
activation and prolactin release from the pituitary, modulated
through the D2 dopamine receptor, demonstrated the difference
between treatment with TBZ and VBZ. TBZ, VBZ and R,R,R-DHTBZ
induced ptosis in an equivalent manner. This confirms that the
metabolites formed by dosing TBZ or VBZ, or dosing of the active
metabolite itself (R,R,R-DHTBZ) all have activity at VMAT2
affecting presynaptic monoamine release, in this case, related to
norepinephrine release specifically to induce ptosis. Following
similar treatment, but this time using prolactin release as a
surrogate for dopaminergic modulation, R,R,R-DHTBZ and VBZ (to a
lesser extent) induced a similar increase in serum prolactin levels
as TBZ.
[0232] The various embodiments described above can be combined to
provide further embodiments. All of the U.S. patents, U.S. patent
application publications, U.S. patent applications, foreign
patents, foreign patent applications and non-patent publications
referred to in this specification and/or listed in the Application
Data Sheet are incorporated herein by reference, in their entirety.
Aspects of the embodiments can be modified, if necessary to employ
concepts of the various patents, applications and publications to
provide yet further embodiments.
[0233] These and other changes can be made to the embodiments in
light of the above-detailed description. In general, in the
following claims, the terms used should not be construed to limit
the claims to the specific embodiments disclosed in the
specification and the claims, but should be construed to include
all possible embodiments along with the full scope of equivalents
to which such claims are entitled. Accordingly, the claims are not
limited by the disclosure.
* * * * *
References