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


CONCLUSIONS
Multiple doses of 6 mg taranabant do not have a clinically meaningful effect on the pharmacokinetics of a single oral dose of digoxin.
Denker
Andrew E
AE
Merck Research Laboratories Boston, BMB3-431, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. andrew_denker@merck.com
Morelli
Gaetano
G
Vessey
Laura K
LK
Li
Susie
S
Yuan
Jinyu
J
Dunbar
Stephanie
S
Lewis
Nicole M
NM
Taggart
William
W
Wagner
John A
JA
D000284:Administration, Oral; D000328:Adult; D000577:Amides / Q000008:administration & dosage*; D000704:Analysis of Variance; D019540:Area Under Curve; D002316:Cardiotonic Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D004077:Digoxin / Q000378:metabolism / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D004347:Drug Interactions; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D005260:Female; D006207:Half-Life; D006801:Humans; D016018:Least-Squares Analysis; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000008:administration & dosage*; D012449:Safety; D015431:Weight Loss / Q000187:drug effects
D000577:Amides; D002316:Cardiotonic Agents; D011725:Pyridines; D004077:Digoxin; C521311:N-(3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl)-2-methyl-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)propanamide