A.Marsot, C. Audebert, L. Attolini, J. Micallef, O. Blin
Service de Pharmacologie Clinique et Pharmacovigilance, AP-HM, Pharmacologie intégrée et interface clinique et industriel, Institut des Neurosciences Timone – AMU-CNRS 7289, Aix Marseille Université, 13385 Marseille
Objectives: Cannabis is the most widely used illegal drug in the world. Delta-9-tetrahydrocannabinol (THC) is the main source of the pharmacological effect. Several studies have been carried out to determine pharmacokinetic parameters of cannabinoids in humans. These studies show significant variability in the described models as the values of the estimated pharmacokinetic parameters. The objective of this study was to develop a population pharmacokinetic model for THC in occasional cannabis smokers.
Methods: Twelve male volunteers (age: 20 to 28 years, body weight: 62.5 to 91.0 kg), tobacco (3-8 cigarette per day) and cannabis occasional smokers were recruited from the local community. Mean cannabis cigarette dose was 500 mg and contained 4% THC (20 mg of THC). After ad libitum smoking (maximum 30 min), participants provided 16 blood samples up to 72 h after smoking initiation. Population pharmacokinetic analysis was performed using a non-linear mixed effects model, with NONMEM version 7.3 software (ICON Development Solutions). The R version 3.1.2 software (www.r-project.org) was used for goodness-of-fit diagnostics. Demographic data (age and body weight) and biological data (creatinine, urea, glucose, AST and ALT) were investigated as covariates.
Results: A three-compartment model with first-order elimination fitted the data. The model was parameterized in terms of micro constants (k10, k12, k21, k23 and k32) and central volume of distribution (V1). Body weight demonstrated a correlation with k10 and V1 but did not significantly improve predictions. ALT concentration (6.0 to 45.0 UI/l) demonstrated a statistically significant correlation with k10. The mean values (%Relative Standard Error (RSE)) for k10, k12, k21, k23, k32 and V1 were 0.408 h-1 (48.8%), 4.070 h-1 (21.4%), 0.022 h-1 (27.0%), 1.070 h-1 (14.3%), 1.060 h-1 (16.7%) and 19.10 L (39.7%), respectively. The interindividual variability (%RSE) of k10 and V1, and residual variability (%RSE) were 49.4% (61.7%), 13.8% (fixed), and 53.9% (7.4%), respectively.
Conclusions: In the present study, we have developed a population pharmacokinetic model able to describe the quantitative relationship between administration of inhaled doses of THC and the observed plasma concentrations after smoking cannabis cigarette. Our study also provided an estimate of parameters variation between individuals. In addition, a linear relationship between ALT concentration and value of k10 has been described and request further investigation.
Reference: PAGE 25 (2016) Abstr 5739 [www.page-meeting.org/?abstract=5739]
Poster: Drug/Disease modeling - CNS