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Methods for the Administration of Certain VMAT2 Inhibitors

a technology of vmat2 inhibitors and methods, applied in the direction of nervous disorders, drug compositions, organic chemistry, etc., can solve the problems of sub-therapeutic plasma levels of those drugs over tim

Inactive Publication Date: 2020-03-26
NEUROCRINE BIOSCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text describes methods for administering a vesicular monoamine transport 2 (VMAT2) inhibitor to patients who are also taking a strong cytochrome P450 3A4 (CYP3A4) inhibitor. The methods involve adjusting the amount of the VMAT2 inhibitor given to the patient based on the level of CYP3A4 inhibition. This allows for a safer and more effective treatment for patients who need both the VMAT2 inhibitor and the CYP3A4 inhibitor. The technical effect of the patent text is to provide a more effective and safe treatment for patients who require a combination of a VMAT2 inhibitor and a CYP3A4 inhibitor.

Problems solved by technology

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.

Method used

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  • Methods for the Administration of Certain VMAT2 Inhibitors
  • Methods for the Administration of Certain VMAT2 Inhibitors
  • Methods for the Administration of Certain VMAT2 Inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example 1

A Phase 1, Open-Label Study to Assess the Effect of Ketoconazole on the Pharmacokinetics of NBI-98854 in Healthy Subjects

[0234]This was a Phase 1, single-center, open-label, drug interaction study conducted in 24 healthy male and female subjects.

[0235]After providing informed consent, subjects were screened for eligibility to participate in the study. Screening started 21 days before Day 1 (the first day of study drug administration). Subjects who met the eligibility criteria were admitted to the research unit on Day −1 (the day prior to dosing) and remained at the study center until the end of the study (Day 10 or early termination). On Day −1, a blood sample was collected to determine cytochrome P450 2D6 (CYP2D6) status.

[0236]All subjects received the same treatment. Subjects received a single dose of 50 mg NBI-98854 on Days 1 and 6 at approximately 0800 hours. In addition, subjects received 200 mg ketoconazole twice daily (bid) on Days 5 through 9 at approximately 0800 and 2000 h...

example 2

Pharmacologic Characterization of Valbenazine, Tetrabenazine, and Metabolite Thereof

[0297]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-11β), which could hypothetically result in eight stereoisomers. However, because the C-3 and C-11β carbons have fixed relative configurations, only four stereoisomers are possible: (R,R,R-DHTBZ or (+)-α-DHTBZ (alternate nomenclature) or NBI-98782 (laboratory nomenclature); S,S,S-DHTBZ or (−)-α-DHTBZ or NBI-98771; S,R,R-DHTBZ or (+)-β-DHTBZ or NBI-98795; and R,S,S-DHTBZ or (−)-β-DHTBZ or NBI-98772.

[0298]The affinity of each compound was measured by inhibition of [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 calculati...

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Abstract

Provided are methods of administering a vesicular monoamine transport 2 (VMAT2) inhibitor chosen from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-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 administered a strong cytochrome P450 3A4 (CYP3A4) inhibitor.

Description

[0001]This application 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, whic...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4375A61K31/4745A61P25/14
CPCA61K31/4745A61K31/4375A61P25/14A61K31/473A61P25/00A61P25/18A61P1/16C07D455/06A61K9/0053A61K9/48A61K31/4525A61K31/4709A61K31/495
Inventor O`BRIEN, CHRISTOPHER F.BOZIGIAN, HAIG P.
Owner NEUROCRINE BIOSCI INC
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