A. Strougo(1), L. Zuurman(1), C. Roy(2), J.-L. Pinquier(2), A.F. Cohen(1), J.M.A. van Gerven(1), R. Schoemaker(1)
(1)Centre for Human Drug Research, Leiden, The Netherlands, (2)Aventis-Pharma Recherche-Développement, Paris, France.
Introduction: Delta9-tetrahydrocannabinol (THC) is the most well known pharmacologically active cannabinoid, acting as a CB1 and CB2 agonist. Currently a large number of newly developed cannabinoid agonists and antagonists are under investigation as therapeutic agents. The clinical development of these is hampered by the lack of quantitative information regarding the pharmacokinetic/pharmacodynamic (PK/PD) properties of THC. We aimed to develop a model to investigate the potency and efficacy of agonists as well as to provide a framework to predict and quantify the pharmacological action of antagonists.
Aim: The purpose of this investigation was to develop a PK/PD model for the characterization of different central nervous system effects (CNS) and heart rate effects of THC in humans. This model should be capable to assist in the quantification of the PD interaction between THC and antagonists.
Methods: Inhaled rising doses of THC were administered using a Volcano® vaporizer (Storz-Bickel GmbH, Tuttlingen, Germany) to 12 subjects in a randomised order according to a placebo-controlled, two-way crossover design. The consecutive doses of THC (2, 4, 6 and 8 mg) were administered with 1½ hour intervals and pharmacodynamic measurements were frequently obtained after each dose. Parameters demonstrating a clear dose-dependent THC effect were used in PK/PD modelling including visual analogue scales (VAS) for subjective effects on alertness, “feeling high” and external perception. Postural stability was assessed using body sway and cardiovascular effect were characterised using heart rate. Plasma THC and its major metabolites 11-OH-THC and 11-nor-9-COOH-THC were measured frequently after each consecutive dose. An integrated PK/PD model was used to analyse the data. Parameter estimation was performed using NONMEM (Version V, GloboMax, LLC, Hanover, MD).
Results: A four-compartment model simultaneously described the PK of THC and 11-OH-THC and of THC and 11-nor-9-COOH-THC. Both models revealed Michaelis Menten elimination for THC. The effects of THC lagged behind the plasma concentration, revealing hysteresis which indicated a slow equilibrium between blood and effect compartment. VAS “feeling high”, VAS external perception, body sway and heart rate were best described using an Emax model, while VAS alertness was best described by a linear model. Equilibration half-lives varied from 7.68 min for heart rate and from 39.2 to 84.8 min for the CNS parameters.
Conclusion: Suitable PK models were developed for THC and its major metabolites 11-nor-9-COOH-THC and 11-OH-THC. The PK/PD model developed was found to successfully predict the time course of VAS alertness, “feeling high”, external perception, body sway and heart rate after non-steady state rising consecutive doses of THC. The difference in equilibration half-lives between heart rate and CNS effects, suggests two different physiological compartments, perhaps in combination with different mechanisms of action. This PK/PD model will be of value in the quantitative analysis of CB1 agonist and antagonist studies.
Reference: PAGE 14 (2005) Abstr 706 [www.page-meeting.org/?abstract=706]
Poster: poster