PK and PK/PD modeling of CB1 blocker antagonism of THC induced CNS and Heart Rate effect
G. Ferron (a), L. Klumpers (b), Joop van Gerven(b), and C. Roy (a)
(a) Sanofi-Aventis and (b) Centre for Human Drug Research
Objectives: The purpose of this study was to develop a pharmacokinetic / pharmacodynamic (PK/PD) model for the characterization of the inhibition of CNS and heart rate effects of delta9-tetrahydrocannabinol (THC) by surinabant, a selective cannabinoid receptor type 1 (CB1) blocker, in healthy male subjects.
Methods: This is a double blind, placebo-controlled, randomised, six-treatment, four-period six-sequence incomplete balanced cross-over study. Thirty healthy young male occasional cannabis users (< 1/week) were included. Single oral dose of surinabant (5, 20 or 60 mg) or placebo was administered followed 1.5 hours later by four increasing doses of THC (2, 4, 6 and 6 mg) inhaled at 1 h intervals. PD measurements were: body sway, "alertness"factor from Bond and Lader visual analogue scales (VAS), item "feeling high", and composite factors "internal perception" and "external perception" from Bowdle VAS, and heart rate. THC and surinabant PK were obtained in each period. An integrated population PK/PD model was initially built describing the effect of THC on the PD end-points and, in a second step, the antagonism of these effects by surinabant. NONMEM V (Globomax, LLC, Hanover, MD) was used for the analysis.
Results: A two-compartment model with intra-individual variability on the absorption and linear elimination adequately described THC PK. A two-compartment model with first order absorption and elimination and a lag-time was used for CB1 blocker PK. The PK/PD model describing THC effect on PD measures was comprised of an effect compartment, an Emax or linear model and intra-individual variability on baseline PD. CB1 antagonism effect was included using a competitive binding equation.
Conclusions: The PK/PD model adequately described the time-course of PK and PD effects of THC and the antagonism of these PD effects by the CB1 blocker. This model could be of value to differentiate CB1 blockers and possibly get further knowledge into CB1 receptor physiopathology .