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

This pharmacokinetic study (n=16 + n=51 data from earlier study) investigates the effects of food on MDMA pharmacokinetics and uses population and physiologically based pharmacokinetic models to simulate clinical dosing regimens. Results show that a high-fat/high-calorie meal delays Tmax but does not alter plasma concentrations, with no clinically meaningful covariates identified. Simulations reveal MDMA is a potent CYP2D6 inhibitor but has negligible impact on drugs sensitive to renal transport, informing drug–drug interaction potential and dosing strategies.

Abstract of MDMA pharmacokinetics

“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.”

Authors: Marilyn A. Huestis, William B. Smith, Cathrine Leonowens, Rebecca Blanchard, Aurélien Viaccoz, Erin Spargo, Nicholas B. Miner & Berra Yazar-Klosinski

Summary of MDMA pharmacokinetics

MDMA, chemically known as 3,4-methylenedioxymethamphetamine, is being reviewed by the U.S. Food and Drug Administration (FDA) for its potential to treat post-traumatic stress disorder (PTSD) in adults. Used alongside psychological interventions, MDMA-assisted therapy has shown promise in Phase III trials for PTSD treatment, demonstrating significant efficacy and tolerability. MDMA operates as an entactogen, influencing neurotransmitter levels by inhibiting their reuptake and inducing release. Its pharmacokinetics are complex; MDMA is primarily metabolised in the liver via the cytochrome P450 2D6 enzyme (CYP2D6) and acts as a potent self-inhibitor of this enzyme.

The standard clinical regimen proposed involves three split-dose administrations spaced at least 21 days apart. The dose increases across sessions, with a maximum split dose of 180 mg administered in two portions two hours apart. This phased dosing strategy allows for therapeutic effects without necessitating continuous plasma levels.

Earlier studies have characterised single-dose pharmacokinetics, but limited data exists for split dosing. This study incorporated new and existing data, utilising population pharmacokinetic (PopPK) and physiologically based pharmacokinetic (PBPK) models. These models assessed MDMA’s pharmacokinetics under various scenarios, including food consumption and drug-drug interactions (DDIs), to optimise its clinical application.

Materials and Methods

Pharmacokinetic Studies

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