title: 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.
abstract: 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 AUC(0-infinity) and C(max) values for taranabant increased approximately linearly with dose up to 200 mg, with slightly less than dose-proportional increases in AUC(0-infinity) and C(max) values for doses >200 mg. Plasma taranabant had a biphasic disposition, with a median t(max) of 1 to 2.5 hours and a terminal elimination t((1/2)) of 38 to 69 hours. Coadministration of taranabant with a high-fat meal led to a 14% increase in C(max) and a 74% increase in AUC(0-infinity). 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.
authors.affiliation: Clinical Pharmacology, Merck Research Laboratories, 33 Avenue Louis Pasteur, HB3-429, Boston, MA 02115, USA. carol_addy@merck.com
authors.forename: Carol
authors.initials: C
authors.lastname: Addy
authors.forename: Susie
authors.initials: S
authors.lastname: Li
authors.forename: Nancy
authors.initials: N
authors.lastname: Agrawal
authors.forename: Julie
authors.initials: J
authors.lastname: Stone
authors.forename: Anup
authors.initials: A
authors.lastname: Majumdar
authors.forename: Ling
authors.initials: L
authors.lastname: Zhong
authors.forename: Hankun
authors.initials: H
authors.lastname: Li
authors.forename: Jinyu
authors.initials: J
authors.lastname: Yuan
authors.forename: Andrea
authors.initials: A
authors.lastname: Maes
authors.forename: Paul
authors.initials: P
authors.lastname: Rothenberg
authors.forename: Josee
authors.initials: J
authors.lastname: Cote
authors.forename: Kim
authors.initials: K
authors.lastname: Rosko
authors.forename: Corinne
authors.initials: C
authors.lastname: Cummings
authors.forename: Steven
authors.initials: S
authors.lastname: Warrington
authors.forename: Malcolm
authors.initials: M
authors.lastname: Boyce
authors.forename: Keith
authors.initials: K
authors.lastname: Gottesdiener
authors.forename: Aubrey
authors.initials: A
authors.lastname: Stoch
authors.forename: John
authors.initials: J
authors.lastname: Wagner
mesh_terms: D000293:Adolescent; D000328:Adult; D000577:Amides / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000494:pharmacology; D000704:Analysis of Variance; D019440:Anti-Obesity Agents / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D011725:Pyridines / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists*
chemical_list: D000577:Amides; D019440:Anti-Obesity Agents; D011725:Pyridines; D043884:Receptor, Cannabinoid, CB1; C521311:N-(3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl)-2-methyl-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)propanamide