Cannabidiol: in vitro drug metabolism, pharmacodynamics, and PBPK modelling

Abstract

Cannabidiol (CBD) oral oil solution is approved as add-on treatment for the management of severe childhood epileptic syndromes. Clinical pharmacokinetic studies are few and especially so in the pediatric population. CBD exhibits dose-dependent oral absorption and high pharmacokinetic variability. Therapeutic concentrations are not well established. Potential drug-drug interactions between CBD and antiseizure medications (ASMs) require further study. Any pharmacokinetic algorithm which could predict CBD exposure after varying dosage regimens could be helpful for their optimization, especially in children. A HPLC-MS/MS assay for quantifying CBD, 7-OH-CBD and 7-COOH-CBD was developed and validated. The impact of concomitant ASMs on CBD intrinsic clearance was studied in vitro in pooled human liver microsomes (HLMs). Effective and neurotoxic CBD concentrations were examined in human iPSC-derived neuronal culture models by microelectrode array techniques. Finally, a physiologically-based pharmacokinetic (PBPK) model for exposure prediction was developed bottom-up for CBD and its active metabolite 7-OH-CBD and validated based on its predictive performance against available clinical literature data. The bioanalytical assay was shown to be both rapid and sensitive. In HLM incubations, most tested ASM combinations had marginal to moderate effects on CBD hepatic intrinsic clearance with the exception of stiripentol which caused a marked reduction. CYP3A4 substrates reduced the metabolism of 7-OH-CBD. Results in human neuronal in vitro cultures indicated preliminary values for effective antiseizure and neurotoxic CBD concentrations. The PBPK model showed good predictive performance in adults and also fair prediction in children and was used for simulation of exposure in children of varying ages as well as effects of combination regimens.