Multiple-dose pharmacokinetics, pharmacodynamics, and safety of taranabant, a novel selective cannabinoid-1 receptor inverse agonist, in healthy male volunteers.
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 t(max) of 1.0 to 2.0 hours and a t(1/2) of approximately 74 to 104 hours. Moderate accumulation was observed in C(max) (1.18- to 1.40-fold) and AUC(0-24 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 AUC(0-24 h) and C(max) 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.
Addy
Carol
C
Clinical Pharmacology, Merck Research Laboratories, 33 Avenue Louis Pasteur, HB3-429, Boston, MA 02115, USA. carol_addy@merck.com
Rothenberg
Paul
P
Li
Susie
S
Majumdar
Anup
A
Agrawal
Nancy
N
Li
Hankun
H
Zhong
Ling
L
Yuan
Jinyu
J
Maes
Andrea
A
Dunbar
Stephanie
S
Cote
Josee
J
Rosko
Kim
K
Van Dyck
Kristien
K
De Lepeleire
Inge
I
de Hoon
Jan
J
Van Hecken
Anne
A
Depré
Marleen
M
Knops
Annemie
A
Gottesdiener
Keith
K
Stoch
Aubrey
A
Wagner
John
J
D000328:Adult; D000577:Amides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019440:Anti-Obesity Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D054314:Drug Inverse Agonism; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000188:drug therapy; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects*
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