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.
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.
Addy
Carol
C
Clinical Pharmacology, Merck Research Laboratories, 33 Avenue Louis Pasteur, HB3-429, Boston, MA 02115, USA. carol_addy@merck.com
Li
Susie
S
Agrawal
Nancy
N
Stone
Julie
J
Majumdar
Anup
A
Zhong
Ling
L
Li
Hankun
H
Yuan
Jinyu
J
Maes
Andrea
A
Rothenberg
Paul
P
Cote
Josee
J
Rosko
Kim
K
Cummings
Corinne
C
Warrington
Steven
S
Boyce
Malcolm
M
Gottesdiener
Keith
K
Stoch
Aubrey
A
Wagner
John
J
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*
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