title: Pharmacokinetic/pharmaco-dynamic modelling and simulation of the effects of different cannabinoid receptor type 1 antagonists on Δ(9)-tetrahydrocannabinol challenge tests.
abstract: OBJECTIVE
  The severe psychiatric side effects of cannabinoid receptor type 1 (CB1 ) antagonists hampered their wide development but this might be overcome by careful management of drug development with pharmacokinetic/pharmacodynamic (PK/PD) analyses. PK/PD models suitable for direct comparison of different CB1 antagonists in Δ(9) -tetrahydrocannabinol (THC) challenge tests in healthy volunteer were constructed.
  
  
  METHODS
  The pharmacokinetic models of THC and four CB1 antagonists were built separately. THC-induced effects on heart rate and the visual analogue scale of feeling high in healthy volunteers and inhibitive effects of CB1 antagonists on THC-induced effects were modelled in PD models linked to the PK models. Simulations were then applied to evaluate the reduction rate of each antagonist on the reversal of the THC-induced effect in a unified simulation scenario.
  
  
  RESULTS
  The final PK model of THC and antagonists was a two compartment model. An Emax model and logistic regression model were used for effect measures and the antagonist effect was added in these models in a competitive binding manner. t1/2ke0 ranged from 0.00462 to 63.7 h for heart rate and from 0.964 to 150 h for VAS. IC50 ranged from 6.42 to 202 ng ml(-1) for heart rate and from 12.1 to 376 ng ml(-1) for VAS. Benchmark simulation showed different dose-efficacy profiles of two efficacy measures for each CB1 antagonist.
  
  
  CONCLUSIONS
  PK/PD modelling and simulation approach was suitable for describing and predicting heart rate and feeling high for CB1 antagonists in THC challenge tests. Direct comparison of four antagonists based on simulated efficacy profiles might be of benefit to guide future studies.
authors.affiliation: Centre for Human Drug Research, Leiden, the Netherlands.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Guan
authors.affiliation: Centre for Human Drug Research, Leiden, the Netherlands.
authors.forename: Linda E
authors.initials: LE
authors.lastname: Klumpers
authors.affiliation: Centre for Human Drug Research, Leiden, the Netherlands.
authors.forename: Olubukayo-Opeyemi
authors.initials: OO
authors.lastname: Oyetayo
authors.affiliation: Centre for Human Drug Research, Leiden, the Netherlands.
authors.forename: Jules
authors.initials: J
authors.lastname: Heuberger
authors.affiliation: Centre for Human Drug Research, Leiden, the Netherlands.
authors.forename: Joop M A
authors.initials: JM
authors.lastname: van Gerven
authors.affiliation: Centre for Human Drug Research, Leiden, the Netherlands.
authors.forename: Jasper
authors.initials: J
authors.lastname: Stevens
mesh_terms: D063387:Cannabinoid Receptor Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D055808:Drug Discovery; D064368:Healthy Volunteers; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D016015:Logistic Models; D008297:Male; D008954:Models, Biological; D011237:Predictive Value of Tests; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*
chemical_list: D063387:Cannabinoid Receptor Antagonists; D043884:Receptor, Cannabinoid, CB1; D013759:Dronabinol
keywords: CB1 antagonist; modelling and simulation; population pharmacokinetics and pharmacodynamics; Δ9-tetrahydrocannabinol