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

Abstract

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.

Development of a Population Pharmacokinetic Model for Taranabant, a Cannibinoid-1 Receptor Inverse Agonist

“…Maximum taranabant concentration (C max ) demonstrates similar increases with dose (4). Following multiple-dose administration of taranabant, the plasma concentration-time curve from 0 to 24 h (AUC 0-24 ) and C max increase in a dose-proportional manner over the dose range of 5 to 10 mg, but increases are somewhat less than dose proportional at 25 mg, possibly due to autoinduction (5). Accumulation of plasma taranabant concentrations is approximately twofold after multiple-dose administration.…”

“…Its primary active metabolite, M1, circulates in plasma with concentrations generally two to three times higher than taranabant and with a comparable apparent terminal half-life, suggesting formation rate-limited elimination (5).…”

“…The analytical methods for determination of taranabant plasma concentrations have been described previously (4,5). The process included cohesive high-turbulence liquid chromatography for online extraction from plasma using turbulent flow chromatography, high-performance liquid chromatography for separation, and tandem mass spectrometry for detection in the positive ionization mode using a TurboIonSpray interface and monitoring the precursor-product ion in combination with multiple-reaction monitoring mode.…”

“…Metabolite concentrations were not modeled, as M1 is formation rate-limited and thus the concentrations always parallel parent concentrations with a high degree of correlation (5). All data preparation and presentation were performed using SAS® Version 9 (6) and/or S-PLUS Server Version 7.0 (7).…”

“…Pharmacokinetic (PK) data in humans indicate that taranabant is rapidly absorbed with the time of maximum plasma concentration occurring between 1 and 2.5 h. Taranabant plasma concentrations then decrease in a multiphasic manner, with an initial rapid decline followed by a slower decline with an apparent terminal half-life of ∼70 to 100 h following single-or multiple-dose administration (4,5).…”