Verifying in vitro-determined enzyme contributions to cannabidiol clearance for exposure predictions in human through physiologically-based pharmacokinetic modeling.

Cannabidiol (CBD) is approved for treatment of seizures associated with two forms of epilepsy that become apparent in infancy or early childhood. To consider an adult physiologically-based pharmacokinetic (PBPK) model for pediatric scaling, we assessed in vitro-derived cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT) enzyme contributions to CBD clearance in human. An i.v. PBPK model was constructed using CBD physicochemical properties and knowledge of disposition. The i.v. datasets were used for model building and evaluation. Oral PBPK models for CBD administered in fasted and fed states were developed using single dose oral datasets and parameters optimized from the i.v. model and evaluated with multiple dose datasets. Relative contributions of CBD metabolizing enzymes were partitioned according to in vitro studies. Clinical drug-drug interaction (DDI) studies were simulated using CBD fed state, itraconazole, fluconazole, and rifampicin PBPK models. Linear mixed effect modeling was used to estimate area under the concentration-time curve from zero to infinity (AUC ) perpetrator + CBD versus CBD alone. The i.v. and oral datasets used in model evaluation produced acceptable average fold error (AFE) of 1.28 and absolute AFE of 1.65. Relative contributions of drug-metabolizing enzymes to CBD clearance were proposed from in vitro data: UGT1A7 4%, UGT1A9 16%, UGT2B7 10%, CYP3A4 38%, CYP2C19 21%, and CYP2C9 11%. The simulated DDI studies using the in vitro-derived values produced AUC treatment ratios comparable to observed: itraconazole 1.24 versus 1.07, fluconazole 1.45 versus 1.22, and rifampicin 0.49 versus 0.69. The constructed CBD PBPK models can predict adult exposures and have potential for use in pediatrics where exposure estimates are limited.