Using clinical, published and in vitro data, the authors developed and verified population and physiologically based pharmacokinetic models for MDMA which show that a high‑fat meal delays Tmax without changing overall exposure and that split dosing (2 h apart) lowers early AUC and delays Tmax compared with a single dose. The models further indicate MDMA is a potent CYP2D6 inhibitor but is unlikely to cause clinically meaningful drug–drug interactions via renal transporters, supporting model‑informed predictions of clinically relevant dosing regimens.
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.
Papers cited by this study that are also in Blossom
Nichols, D. E. · Frontiers in Psychiatry (2022)
de la Torre, R., Farré, M., Roset, P. N. et al. · Annals of the New York Academy of Sciences (2006)
Greer, G. R. · Journal of Psychoactive Drugs (1986)
Huestis and colleagues situate this work in the context of MDMA (3,4-methylenedioxymethamphetamine) development for post‑traumatic stress disorder (PTSD). Earlier clinical trials indicate MDMA-assisted therapy can be effective and generally well tolerated, and pharmacokinetic (PK) properties of MDMA include nonlinear behaviour, primary hepatic elimination via CYP2D6, and rapid mechanism‑based inhibition (MBI) of CYP2D6 that can limit its own metabolism. The proposed clinical regimen for therapeutic sessions uses split dosing (two portions given 1.5–2 h apart) at maximum split doses of 120 mg (80 + 40 mg) and 180 mg (120 + 60 mg), with sessions spaced weeks apart rather than daily dosing.
Simulations used a Simcyp Caucasian healthy volunteer population with default CYP2D6 metaboliser frequencies (56.8% extensive, 32.5% intermediate, 8.2% poor, 2.5% ultra‑rapid). Virtual trials matched clinical demographics: for dose regimen comparisons, 10 virtual trials of 10 volunteers (50% female) aged 20–50 years were run to derive Cmax, AUC0‑44 (approximate five half‑lives) and AUC0‑4 (acute exposure). Sensitivity analyses varied fm CYP2D6 from 0.05 to 0.95 using atomoxetine as a representative sensitive CYP2D6 substrate to probe DDI magnitude. Metformin was chosen as a victim probe to evaluate potential transporter‑mediated DDIs; simulations included uncertainty scenarios reducing in vitro Ki values by up to 3‑fold for MATE1 and up to 15‑fold for OCT1/OCT2.
DDI simulations using atomoxetine as a sensitive CYP2D6 substrate found an fm CYP2D6 value of 0.85 best recovered observed clinical interactions and was used in modelling. Sensitivity analysis predicted a mild interaction (AUC ratio ≥1.25) beginning at fm CYP2D6 = 0.05, a moderate interaction (≥2‑fold) at fm CYP2D6 = 0.20, and a strong interaction (≥5‑fold) at fm CYP2D6 ≥ 0.75, illustrating substantial potential for MDMA to increase exposure of CYP2D6 substrates depending on their dependence on that pathway. For metformin, using in vitro Ki values for OCT1, OCT2 and MATE1 yielded no predicted interaction; however, reducing Ki values in sensitivity scenarios (3‑fold for MATE1 and 15‑fold for OCTs) produced a weak interaction with predicted AUC and Cmax elevations >1.5‑fold but <2‑fold. The data indicate less than 20% of MDMA and MDA are excreted unchanged renally.
The PBPK simulations captured observed data within accepted predictive limits and provided insight into split‑dosing dynamics and drug‑drug interaction (DDI) risk. Simulated split dosing produced similar overall exposure to single doses while lowering early exposure (AUC0‑4) and modestly delaying Tmax, an outcome the authors link to clinical rationale for split dosing: more gradual onset and extended peak effects without increasing total duration, and potential mitigation of early dose‑dependent physiological adverse effects such as elevated blood pressure and heart rate. PBPK DDI analyses reinforced MDMA's role as a potent CYP2D6 mechanism‑based inhibitor and indicated that co‑administration with CYP2D6 substrates, even those with low fm CYP2D6, can lead to clinically meaningful increases in exposure depending on substrate dependence and therapeutic index. Regarding renal transporters, the authors report that in vitro inhibition constants exceed expected clinical MDMA concentrations and that only conservative reductions in Ki produced weak interactions with metformin; therefore, transporter‑mediated DDIs are unlikely to be broadly clinically meaningful. The investigators acknowledge the observed study effect may reflect differences in washout periods, prior drug use history or other unmeasured factors between MPKF and NIDA datasets, and they note some parameter estimates had large uncertainty, warranting cautious interpretation.
The authors conclude that MDMA can be administered without regard to food because a high‑fat/high‑calorie meal did not alter Cmax or AUC, only delayed Tmax. PopPK modelling identified no covariates that necessitate clinically meaningful dose adjustments in the target population. PBPK simulations indicate split dosing reduces exposure during the first 4 h while maintaining overall exposure, which may facilitate a gentler onset and reduce severity of early adverse events. Finally, MDMA's principal DDI liability is as a precipitant via potent CYP2D6 inhibition; transporter‑mediated interactions are unlikely to be broadly meaningful but could be weak under conservative in vitro‑to‑in vivo assumptions.