Methods for the administration of certain VMAT2 inhibitors
Inventors
O'Brien, Christopher F. • Bozigian, Haig P.
Assignees
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Publication Number
US-11654142-B2
Publication Date
2023-05-23
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-1,3,4,6,7,1 1b-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 digoxin.
Core Innovation
The described invention relates to co-administration of a vesicular monoamine transporter 2 (VMAT2) inhibitor to a patient who is also being co-administered digoxin, where digoxin is adjusted based on increased digoxin exposure observed with the VMAT2 inhibitor. The disclosure specifies oral administration of a VMAT2 inhibitor chosen from a defined (S)-2-amino-3-methyl-butyric acid-based hexahydro-2H-pyrido[2,1-a]isoquinoline ester structure and pharmaceutically acceptable salts, isotopic variants, and related forms including valbenazine.
The problem addressed is that, when a VMAT2 inhibitor is administered to a patient also receiving digoxin, digoxin exposure in the patient's blood can be increased compared with digoxin administered alone. The document associates increased digoxin exposure with exposure-related adverse reactions and provides that the digoxin concentration in the patient's blood is monitored so that the dose of digoxin is reduced when increased exposure is detected.
The disclosure further explains that co-administration is associated with increased digoxin exposure and links this effect to inhibition of intestinal P-glycoprotein (P-gp) efflux. A Phase 1 open-label one-sequence crossover study in healthy subjects is described showing increased digoxin pharmacokinetic exposure parameters when digoxin is co-administered with a VMAT2 inhibitor form (NBI-98854, a valbenazine ditosylate form), together with reported safety/tolerability and pharmacokinetic methodology and results.
Claims Coverage
The only independent claim identified in the provided claims list is directed to treating a patient with chorea associated with Huntington's disease using an orally administered VMAT2 inhibitor while co-administering digoxin, with digoxin blood-level monitoring and dose reduction when exposure increases. The claim set includes dependent refinements that specify additional adverse-reaction monitoring and additional pharmacokinetic and mechanism-related details.
Treating chorea associated with Huntington's disease with an oral VMAT2 inhibitor while co-administering digoxin
A method for treating a patient with a hyperkinetic movement disorder, wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease, and wherein the patient is also being co-administered digoxin.
Orally administering a specified VMAT2 inhibitor structure or pharmaceutically acceptable salts
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 pharmaceutically acceptable salts thereof.
Monitoring digoxin concentration in blood
Monitoring the digoxin concentration in the patient's blood.
Reducing digoxin dose when blood exposure increases versus digoxin alone
Reducing the dose of digoxin when the digoxin exposure in the patient's blood is increased as compared with the digoxin level in a patient who is administered digoxin alone.
Overall claim coverage centers on co-therapy: an oral VMAT2 inhibitor is used to treat chorea associated with Huntington's disease in patients receiving digoxin, while digoxin blood concentration is monitored and digoxin dose is reduced when exposure increases versus digoxin alone. Dependent claims further cover pharmacokinetic metrics for guiding adjustment, monitoring for exposure-related adverse reactions, and linking increased exposure to intestinal P-gp inhibition.
Stated Advantages
Reduces the dose of digoxin when digoxin exposure is increased compared with digoxin alone.
Supports monitoring of digoxin concentration in blood when co-administered with a VMAT2 inhibitor.
Associates increased digoxin exposure with intestinal P-glycoprotein (P-gp) efflux inhibition and provides a basis for dose reduction guided by increased exposure.
Documented Applications
Treatment of a patient with a hyperkinetic movement disorder, wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease, where the patient is also being co-administered digoxin.
Phase 1 open-label one-sequence crossover pharmacokinetic evaluation in healthy subjects assessing digoxin pharmacokinetic exposure when co-administered with a VMAT2 inhibitor form (NBI-98854, a valbenazine ditosylate form).
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