Methods for the administration of certain VMAT2 inhibitors
Inventors
O'Brien, Christopher F. • Bozigian, Haig P.
Assignees
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Publication Number
US-11439629-B2
Publication Date
2022-09-13
Expiration Date
Abstract
Provided are methods of administering a vesicular monoamine transport 2 (VMAT2) inhibitor chosen from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1, 3,4, 6,7,11 b-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 a CYP2D6 poor metabolizer.
Core Innovation
The disclosure relates to a method of treating a patient with a hyperkinetic movement disorder, wherein the patient is a cytochrome P450 2D6 (CYP2D6) poor metabolizer. The method comprises orally administering once daily 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 pharmaceutically acceptable salts thereof, wherein the hyperkinetic movement disorder is chorea.
The disclosed approach includes subsequently determining that the patient is a CYP2D6 poor metabolizer and reducing dosage of the VMAT2 inhibitor to an amount equivalent to about 40 mg once daily 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. The disclosure further includes determining whether the patient is a poor metabolizer of CYP2D6 and, if the patient is not a poor metabolizer, subsequently administering an increased amount after one week.
The disclosure also addresses formulation and exposure-related aspects associated with VMAT2 inhibition. It specifies the VMAT2 inhibitor as a ditosylate salt of the (S)-2-amino-3-methyl-butyric acid compound, and it includes monitoring for one or more exposure-related adverse reactions, including QT prolongation.
Claims Coverage
The independent claims cover multiple method variants built around CYP2D6 status determination and VMAT2 inhibitor dosing for chorea, with dose adjustment to an amount equivalent to about 40 mg once daily for CYP2D6 poor metabolizers and an increased amount after one week for non-poor metabolizers. Across the independent claims, the inventive features focus on genotype-guided dosing, specified VMAT2 inhibitor selection/form, and optionally monitoring exposure-related adverse reactions, including QT prolongation.
CYP2D6 poor metabolizer chorea treatment with VMAT2 inhibitor about 40 mg once daily
A method of treating a patient with a hyperkinetic movement disorder, wherein the patient is a cytochrome P450 2D6 (CYP2D6) poor metabolizer, comprising orally administering once daily a therapeutically effective amount of a 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 pharmaceutically acceptable salts thereof, wherein the therapeutically effective amount is an amount equivalent to about 40 mg once daily wherein the hyperkinetic movement disorder is chorea.
Determine CYP2D6 poor metabolizer then reduce VMAT2 inhibitor dosage to about 40 mg once daily
A method of treating a patient with a hyperkinetic movement disorder comprising orally administering a therapeutically effective amount of a 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 pharmaceutically acceptable salts thereof; subsequently determining that the patient is a CYP2D6 poor metabolizer; and reducing dosage of the VMAT2 inhibitor administered to the patient to an amount equivalent to about 40 mg once daily 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 wherein the hyperkinetic movement disorder is chorea.
CYP2D6 status based dosing and increased VMAT2 inhibitor amount after one week
A method of treating a patient with a hyperkinetic movement disorder comprising determining if the patient is a poor metabolizer of cytochrome P450 2D6 (CYP2D6); if the patient is a poor metabolizer, then orally administering to the patient a first therapeutically effective amount of a 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 pharmaceutically acceptable salts thereof, wherein the first therapeutically effective amount is an amount equivalent to about 40 mg once daily; or if the patient is not a poor metabolizer, then orally administering to the patient a second therapeutically effective amount of the VMAT2 inhibitor chosen from the same compound and salts, wherein the second therapeutically effective amount is an amount equivalent to about 40 mg once daily for one week, and subsequently administering an increased amount of the VMAT2 inhibitor after one week wherein the hyperkinetic movement disorder is chorea.
Ditosylate salt VMAT2 inhibitor about 40 mg once daily with subsequent CYP2D6 poor metabolizer determination
A method of treating a patient with a hyperkinetic movement disorder comprising orally administering to the patient a therapeutically effective amount of a VMAT2 inhibitor which 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]isoquinolin-2-yl ester, wherein the therapeutically effective amount is an amount equivalent to about 40 mg once daily; subsequently determining that the patient is a poor metabolizer of cytochrome P450 2D6 (CYP2D6); and administering the same therapeutically effective amount of the VMAT2 inhibitor to the patient wherein the hyperkinetic movement disorder is chorea.
Overall, the independent claims establish VMAT2 inhibitor treatment for chorea with dosing that is governed by CYP2D6 poor metabolizer status. They require oral administration of a specified VMAT2 inhibitor compound, and in one independent claim a ditosylate salt, at an amount equivalent to about 40 mg once daily for CYP2D6 poor metabolizers, and they require a decision pathway for non-poor metabolizers that includes an increased amount after one week.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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