MDMA pharmacokinetics: A population and physiologically based pharmacokinetics model-informed analysis.

Midomafetamine (3,4-methylenedioxymethamphetamine [MDMA]) is under the U.S. Food and Drug Administration review for treatment of post-traumatic stress disorder in adults. MDMA is metabolized by CYP2D6 and is a strong inhibitor of CYP2D6, as well as a weak inhibitor of renal transporters MATE1, OCT1, and OCT2. A pharmacokinetic phase I study was conducted to evaluate the effects of food on MDMA pharmacokinetics. The results of this study, previously published pharmacokinetic data, and in vitro data were combined to develop and verify MDMA population pharmacokinetic and physiologically based pharmacokinetic models. The food effect study demonstrated that a high-fat/high-calorie meal did not alter MDMA plasma concentrations, but delayed Tmax. The population pharmacokinetic model did not identify any clinically meaningful covariates, including age, weight, sex, race, and fed status. The physiologically based pharmacokinetic model simulated pharmacokinetics for the proposed 120 and 180 mg MDMA HCl clinical doses under single- and split-dose (2 h apart) conditions, indicating minor differences in overall exposure, but lower AUC within the first 4 h and delayed Tmax when administered as a split dose compared to a single dose. The physiologically based pharmacokinetic model also investigated the drug-drug interaction magnitude by varying the fraction metabolized by a representative CYP2D6 substrate (atomoxetine) and evaluated inhibition of renal transporters. The simulations confirm MDMA is a potent CYP2D6 inhibitor, but likely has no meaningful impact on the pharmacokinetics of drugs sensitive to renal transport. This model-informed drug development approach was employed to inform drug-drug interaction potential and predict pharmacokinetics of clinically relevant dosing regimens of MDMA.