Population Pharmacokinetic Model of THC Integrates Oral, Intravenous, and Pulmonary Dosing and Characterizes Short- and Long-term Pharmacokinetics
- 747 Downloads
Δ9-Tetrahydrocannobinol (THC), the main psychoactive compound of Cannabis, is known to have a long terminal half-life. However, this characteristic is often ignored in pharmacokinetic (PK) studies of THC, which may affect the accuracy of predictions in different pharmacologic areas. For therapeutic use for example, it is important to accurately describe the terminal phase of THC to describe accumulation of the drug. In early clinical research, the THC challenge test can be optimized through more accurate predictions of the dosing sequence and the wash-out between occasions in a crossover setting, which is mainly determined by the terminal half-life of the compound. The purpose of this study is to better quantify the long-term pharmacokinetics of THC. A population-based PK model for THC was developed describing the profile up to 48 h after an oral, intravenous, and pulmonary dose of THC in humans. In contrast to earlier models, the current model integrates all three major administration routes and covers the long terminal phase of THC. Results show that THC has a fast initial and intermediate half-life, while the apparent terminal half-life is long (21.5 h), with a clearance of 38.8 L/h. Because the current model characterizes the long-term pharmacokinetics, it can be used to assess the accumulation of THC in a multiple-dose setting and to forecast concentration profiles of the drug under many different dosing regimens or administration routes. Additionally, this model could provide helpful insights into the THC challenge test used for the development of (novel) compounds targeting the cannabinoid system for different therapeutic applications and could improve decision making in future clinical trials.
KeywordsTerminal Phase Administration Route Cannabis User Visual Predictive Check Nose Clip
The authors would like to acknowledge the contribution of Jasper Stevens for his review of the manuscript and advice during manuscript development.
Conflict of interest
The authors would like to declare the following conflicts of interest; Study CHDR0828 was sponsored by ECHO Pharmaceuticals. TLB is an employee of ECHO Pharmaceuticals; Support for Dr. Paul Morrison was from the MRC (UK).
- 2.Hazekamp A, Grotenhermen F. Review on clinical studies with cannabis and cannabinoids 2005–2009. Cannabinoids. 2010;5:1–21.Google Scholar
- 6.Klumpers LE, Roy C, Ferron G, Turpault S, Poitiers F, Pinquier JL, et al. Surinabant, a selective cannabinoid receptor type 1 antagonist, inhibits delta 9-tetrahydrocannabinol-induced central nervous system and heart rate effects in humans. Br J Clin Pharmacol. 2013;76:65–77.PubMedCentralPubMedCrossRefGoogle Scholar
- 7.Grotenhermen F. Clinical pharmacokinetics of cannabinoids. J Cannabis Ther. 2003;3:3–51.Google Scholar
- 25.Hunault CC, van Eijkeren JC, Mensinga TT, de VI, Leenders ME, Meulenbelt J. Disposition of smoked cannabis with high delta(9)-tetrahydrocannabinol content: a kinetic model. Toxicol Appl Pharmacol. 2010;246:148–53.Google Scholar
- 26.Strougo A, Zuurman L, Roy C, Pinquier JL, van Gerven JM, Cohen AF, et al. Modelling of the concentration-effect relationship of THC on central nervous system parameters and heart rate: insight into its mechanisms of action and a tool for clinical research and development of cannabinoids. J Psychopharmacol. 2008;22:717–26.PubMedCrossRefGoogle Scholar
- 27.Klumpers LE, Beumer TL, van Hasselt JG, Lipplaa A, Karger LB, Kleinloog HD, et al. Novel delta(9)-tetrahydrocannabinol formulation Namisol(R) has beneficial pharmacokinetics and promising pharmacodynamic effects. Br J Clin Pharmacol. 2011;74:42–53.Google Scholar
- 35.Promasys 6.1 version. Leiden: Promasys BV; 2011.Google Scholar
- 36.Beal SL, Sheiner LB, Boeckmann A, Bauer RJ. NONMEM User’s Guides (1989–2009). SSLBBA&BRJ. 2009.Google Scholar
- 37.R Development Core Team. R: a language and environment for statistical computing. RFfSCVA. 2011.Google Scholar
- 39.Litterst CL, Flora KP, Cradock JC. Bioavailability of delta-9-tetrahydrocannabinol-derived radioactivity following intramuscular administration of delta-9-11-C-14-tetrahydrocannabinol to rabbits. Res Commun Subst Abuse. 1982;3:453–65.Google Scholar