Pharmacokinetics of digoxin in healthy subjects receiving taranabant, a novel cannabinoid-1 receptor inverse agonist.

Abstract

INTRODUCTION:

Interaction studies with digoxin (Lanoxin; GlaxoSmithKline, Research Triangle Park, NC, USA), a commonly prescribed cardiac glycoside with a narrow therapeutic index and a long half-life, are typically required during the development of a new drug, particularly when it is likely that digoxin may be given to patients also treated with the new agent, taranabant--a cannabinoid-1 receptor inverse agonist--for weight loss. This study was designed to establish if this combination of therapy has the potential of a significant pharmacokinetic interaction.

METHODS:

This open-label, fixed-sequence, two-period study investigated whether taranabant, administered to steady state, affects the well-described single-dose pharmacokinetics of digoxin. During the first period, 12 healthy men and women ranging in age from 21 to 35 years received a single oral dose of digoxin 0.5 mg. Following a 10-day wash out, they started a 19-day taranabant dosing regimen (6 mg once daily from day -14 to day 5) designed to establish and maintain steady-state levels of taranabant. On study day 1, subjects received a single oral dose of digoxin 0.5 mg. The plasma levels of digoxin were followed for an additional 4 days while the dosing of taranabant continued.

RESULTS:

The geometric mean ratio and 90% confidence intervals for digoxin AUC(0-infinity) were 0.91 (0.83, 0.99), falling within the prespecified comparability intervals (CI) of (0.8, 1.25), which is within the usually allowed interval for bioequivalence. The geometric mean ratio and 90% CI for digoxin maximum plasma concentration (C(max)) were 1.23 (1.09, 1.40). The median time to C(max) was the same for both treatments.

CONCLUSION:

Multiple doses of 6 mg taranabant do not have a clinically meaningful effect on the pharmacokinetics of a single oral dose of digoxin.

• Authors: Andrew E Denker, Gaetano Morelli, Laura K Vessey, Susie Li, Jinyu Yuan, Stephanie Dunbar, Nicole M Lewis, William Taggart, John A Wagner
• Journal: Advances in therapy (Adv Ther) Vol. 26 Issue 2 Pg. 230-40 (Feb 2009) ISSN: 1865-8652 [Electronic] United States
• PMID: 19219408 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amides
• Cardiotonic Agents
• Pyridines
• Digoxin
• N-(3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl)-2-methyl-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)propanamide

Topics

• Administration, Oral
• Adult
• Amides (administration & dosage)
• Analysis of Variance
• Area Under Curve
• Cardiotonic Agents (metabolism, pharmacokinetics)
• Digoxin (metabolism, pharmacokinetics)
• Dose-Response Relationship, Drug
• Drug Evaluation
• Drug Interactions
• Drug Monitoring
• Drug Therapy, Combination
• Female
• Half-Life
• Humans
• Least-Squares Analysis
• Linear Models
• Male
• Middle Aged
• Pyridines (administration & dosage)
• Safety
• Weight Loss (drug effects)