J Clin Pharmacol
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PHARMACOKINETICS AND PHARMACODYNAMICS

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Properties of Taranabant, a Novel Selective Cannabinoid-1 Receptor Inverse Agonist, for the Treatment of Obesity: Results From a Double-Blind, Placebo-Controlled, Single Oral Dose Study in Healthy Volunteers

Carol Addy, MD, MMSc, Susie Li, PhD, Nancy Agrawal, PhD, Julie Stone, PhD, Anup Majumdar, PhD, Ling Zhong, PhD, Hankun Li, MS, Jinyu Yuan, PhD, Andrea Maes, PhD, Paul Rothenberg, MD, PhD, Josee Cote, BS, Kim Rosko, BS, Corinne Cummings, PhD, Steven Warrington, MD, FRCP, FFPM, Malcolm Boyce, FRCP, FFPM, FBPharmacolS, Keith Gottesdiener, MD, Aubrey Stoch, MD and John Wagner, MD, PhD

From Merck Research Laboratories, Boston, Massachusetts (Dr Addy); Merck Research Laboratories, West Point, Pennsylvania (Dr Li, Dr Agrawal, Dr Stone, Dr Majumdar, Dr Zhong, Mr Li); Merck Research Laboratories, Rahway, New Jersey (Dr Yuan, Dr Maes, Dr Rothenberg, Ms Cote, Ms Rosko, Dr Gottesdiener, Dr Stoch, Dr Wagner); Merck Research Laboratories, Harlow, Essex, United Kingdom (Dr Cummings); and Hammersmith Medicines Research, Central Middlesex Hospital, Park Royal, London, United Kingdom (Dr Warrington, Dr Boyce). Dr Rothenberg's current affiliation is Johnson & Johnson, Raritan, New Jersey.

Taranabant is a novel cannabinoid CB-1 receptor (CB1R) inverse agonist in clinical development for the treatment of obesity. This double-blind, randomized, placebo-controlled, single oral dose study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of taranabant (0.5-600 mg) in 24 healthy male volunteers. Single-dose AUC0-{infty} and Cmax values for taranabant increased approximately linearly with dose up to 200 mg, with slightly less than dose-proportional increases in AUC0-{infty} and Cmax values for doses >200 mg. Plasma taranabant had a biphasic disposition, with a median tmax of 1 to 2.5 hours and a terminal elimination t1/2 of 38 to 69 hours. Coadministration of taranabant with a high-fat meal led to a 14% increase in Cmax and a 74% increase in AUC0-{infty}. Clinical adverse experiences associated with single doses of taranabant were generally mild and transient. Of the 198 clinical adverse experiences reported, the most common drug-related ones were nausea (36), headache (22), drowsiness (14), abdominal discomfort/abdominal pain/stomachache (14), hiccups (9), dizziness (8), decreased appetite (7), increased bowel movement (7), mood change (6), tiredness (4), vomiting (4), and sweating increased (4). Taranabant has pharmacokinetic characteristics suitable for a once-daily dosing regimen.

Key Words: MK-0364 • taranabant • cannabinoid-1 receptor inverse agonist • obesity • appetite • satiety

Address for correspondence: Carol Addy, MD, MMSc, Director, Clinical Pharmacology, Merck Research Laboratories, 33 Avenue Louis Pasteur, HB3-429, Boston, MA 02115; e-mail: carol_addy{at}merck.com.


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