Pharmacokinetic/pharmaco–dynamic modelling and simulation of the effects of different cannabinoid receptor type 1 antagonists on Δ⁹‐tetrahydrocannabinol challenge tests

Aim

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 Δ⁹‐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 E_max model and logistic regression model were used for effect measures and the antagonist effect was added in these models in a competitive binding manner. t_1/2ke0 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.

DOI: 10.1111/bcp.12852

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