Z.Guan, L.E.Klumpers, B.Oyetayo, J.Heuberger, J.M.A.van Gerven, J.Freijer
Centre for Human Drug Research, Leiden, The Netherlands
Objectives: To explore the PK/PD relationships of 4 cannabinoid receptor antagonists after a Δ9-tetrahydrocannabinol (THC) challenge. To compare the inhibition potential and target site equilibration of these antagonists in the THC challenge test.
Methods: 4 different CB1 antagonists (drinabant (AVE1625), surinabant, rimonabant, and TM38837) were studied in volunteers after multiple administrations of THC. First, the PK models of THC after multiple dosing and of the 4 antagonists after single dose were developed separately. Next, the THC-induced effects, including changes in heart rate (HR), body sway (BS) and visual analogue scale for feeling high (FH) were modeled by a PK/PD link model. Then, the reversal of the THC-induced effects by the antagonists was also quantified by incorporating terms representing the inhibition effect in the model.
Results: Two-compartment models were selected to describe the THC and antagonists’ PK profile. For the PD model, HR and BS were modeled using an Emax model. FH was first translated into binary data, and then modeled applying logistic regression. The delay between drug concentration and drug effect was described using a biophase compartment [1] [2]. The inhibition potential (IC50) to reverse the effects of the THC challenge was compared based on the differences in THC EC50 shifts and equilibration half-lifes among the antagonists. The compounds showed marked differences in their IC50 and penetration half-life for the PD variables. The estimated IC50 of HR, BS and FH for the 4 antagonists varied from 9.13 to 438ng/ml, 12.7 to7560ng/ml and 12.1 to 376ng/ml respectively.
Conclusions: PK/PD models could be used to predict the concentrations and HR, BS, and FH profiles of THC alone and with antagonists. Modeling also provided quantitative insights for understanding the target site equilibration and antagonizing potency of antagonists working on the cannabinoid system.
References:
[1]. Strougo A., 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 22.7 (2008): 717-26.
[2]. Zuurman, L., et al. Inhibition of THC-induced effects on the central nervous system and heart rate by a novel CB1 receptor antagonist AVE1625. J Psychopharmacol (2008).
Reference: PAGE 21 () Abstr 2330 [www.page-meeting.org/?abstract=2330]
Poster: CNS