Population pharmacokinetic modeling of plasma Δ9-tetrahydrocannabinol and an active and inactive metabolite following controlled smoked cannabis administration

Aims Population pharmacokinetic models of Delta 9-tetrahydrocannabinol (THC) have been developed for THC plasma and blood concentration data. Often, only the metabolites of THC are measurable when blood samples are obtained. Therefore, we performed a population pharmacokinetic analysis of THC, 11-OH-THC and THCCOOH plasma concentration data from a Phase I clinical trial of THC smoking. Methods Frequently obtained plasma THC, 11-OH-THC and THCCOOH concentration data were obtained over 168 h from 6 subjects who smoked low (15.8 mg) and high dose (33.8 mg) THC cigarettes on 2 occasions. Bayesian estimates of the THC pharmacokinetic model from each individual for each dose were fixed prior to the sequential pharmacokinetic analysis of the metabolites. Results A 3-compartment model of THC was developed that has a steady-state volume of distribution (Vd(SS)) of 3401 +/- 788 L and a clearance of 0.72 +/- 0.10 L/min. 11-OH-THC was characterized by 50 +/- 6% of the THC being directly cleared to a 3-compartment model with a Vd(SS) of 415.2 +/- 4.3 L and clearance of 0.78 +/- 0.05 L/min. The THCCOOH model shared the central compartment of the 11-OH-THC model with a Vd(SS) of 29.1 +/- 0.05 L and a clearance of 0.12 +/- 0.02 L/min. First order kinetics were observed for THC and THCCOOH between the low and high doses, but a nonlinear pattern was observed for 11-OH-THC. Conclusion We describe the pharmacokinetics of THC, 11-OH-THC and THCCOOH including inter- and intraindividual variability of the parameter estimates of the model.