Drug Metab Dispos. 2021 May 5:DMD-AR-2020-000322. doi: 10.1124/dmd.120.000322. Online ahead of print.
Conducting clinical trials to understand the exposure-risk/benefit relationship of cannabis use is not always feasible. Alternatively, physiologically-based pharmacokinetic (PBPK) models can be used to predict exposure of the psychoactive cannabinoid, THC, and its active metabolite 11-OH-THC. Here, we first extrapolated in vitro mechanistic PK information previously quantified to build a linked THC/11-OH-THC PBPK model, and verified the model with observed data after intravenous and inhalation administration of THC in a healthy, non-pregnant population. The in vitro to in vivo extrapolation (IVIVE) of both THC and 11-OH-THC disposition was successful. The bioavailability (Finh) of THC after inhalation was higher in chronic versus casual cannabis users (Finh = 0.35 and 0.19, respectively). Sensitivity analysis demonstrated that 11-OH-THC but not THC exposure was sensitive to alterations in hepatic intrinsic clearance of the respective compound. Next, we extrapolated the linked THC/11-OH-THC PBPK model to pregnant women. Simulations showed that THC plasma AUC does not change during pregnancy, but 11-OH-THC plasma AUC decreases by up to 41%. Using a maternal-fetal PBPK model, maternal and fetal THC serum concentrations were simulated and compared to the observed THC serum concentrations in pregnant women at term. In order to recapitulate the observed THC fetal serum concentrations, active placental efflux of THC needed to be invoked. In conclusion, we built and verified a linked THC/11-OH-THC PBPK model in healthy non-pregnant population and demonstrated how this mechanistic physiological and pharmacokinetic platform can be extrapolated to a special population, such as pregnant women. Significance Statement While the pharmacokinetics of cannabinoids has been extensively studied clinically, there are limited mechanistic PK models. Here we present the development and verification of a physiologically-based pharmacokinetic (PBPK) model for (-)-Δ9-tetrahydrocannabinol (THC) and its active metabolite, 11-OH-THC. The PBPK model was verified in healthy non-pregnant population after intravenous and inhalation administration of THC, and then extrapolated to pregnant women. The THC/11-OH-THC PBPK model can be used to predict exposure in special populations, predict drug-drug interactions, or impact of genetic polymorphism.
Source: ncbi 2