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PHARMACOKINETICS AND PHARMACODYNAMICS

Multiple-Dose Pharmacokinetics, Pharmacodynamics, and Safety of Taranabant, a Novel Selective Cannabinoid-1 Receptor Inverse Agonist, in Healthy Male Volunteers

Carol Addy, MD, MMSc, Paul Rothenberg, MD, PhD, Susie Li, PhD, Anup Majumdar, PhD, Nancy Agrawal, PhD, Hankun Li, MS, Ling Zhong, PhD, Jinyu Yuan, PhD, Andrea Maes, PhD, Stephanie Dunbar, PhD, Josee Cote, BS, Kim Rosko, BS, Kristien Van Dyck, PhD, Inge De Lepeleire, PharmD, Jan de Hoon, MD, PhD, Anne Van Hecken, PhD, Marleen Depré, PhD, Annemie Knops, MD, Keith Gottesdiener, MD, Aubrey Stoch, MD and John Wagner, MD, PhD

From Merck Research Laboratories, Boston, Massachusetts (Dr Addy); Merck Research Laboratories, Rahway, New Jersey (Dr Rothenberg, Dr Yuan, Dr Maes, Dr Dunbar, Ms Cote, Ms Rosko, Dr Gottesdiener, Dr Stoch, Dr Wagner); Merck Research Laboratories, West Point, Pennsylvania (Dr S. Li, Dr Majumdar, Dr Agrawal, Mr H. Li, Dr Zhong); MSD (Europe), Brussels, Belgium (Dr Van Dyck, Dr De Lepeleire); Center for Clinical Pharmacology, University Hospital, Leuven, Belgium (Dr de Hoon, Dr Van Hecken, Dr Depré); and SGS Life Science Services, Antwerp, Belgium (Dr Knops). Paul Rothenberg's current affiliation is Johnson & Johnson, Raritan, New Jersey. Jinyu Yuan's current affiliation is Pfizer, New York, NY. Annemie Knops' current affiliation is CM Limburg, Hasselt, Belgium.

Taranabant is a cannabinoid-1 receptor inverse agonist for the treatment of obesity. This study evaluated the safety, pharmacokinetics, and pharmacodynamics of taranabant (5, 7.5, 10, or 25 mg once daily for 14 days) in 60 healthy male subjects. Taranabant was rapidly absorbed, with a median tmax of 1.0 to 2.0 hours and a t1/2 of approximately 74 to 104 hours. Moderate accumulation was observed in Cmax (1.18- to 1.40-fold) and AUC0-24 h (1.5- to 1.8-fold) over 14 days for the 5-, 7.5-, and 10-mg doses, with an accumulation half-life ranging from 15 to 21 hours. Steady state was reached after 13 days. After multiple-dose administration, plasma AUC0-24 h and Cmax of taranabant increased dose proportionally (5-10 mg) and increased somewhat less than dose proportionally for 25 mg. Taranabant was generally well tolerated up to doses of 10 mg and exhibited multiple-dose pharmacokinetics consistent with once-daily dosing.

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

Address for reprints: 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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