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

Area of Science:

• Pharmacology
• Drug Metabolism
• Clinical Pharmacology

Background:

• Midomafetamine (MDMA) is under FDA review for PTSD treatment.
• MDMA is metabolized by CYP2D6 and inhibits CYP2D6, MATE1, OCT1, and OCT2.
• Understanding MDMA pharmacokinetics is crucial for safe and effective clinical use.

Purpose of the Study:

• To evaluate the effect of food on MDMA pharmacokinetics.
• To develop and verify population pharmacokinetic (PopPK) and physiologically based pharmacokinetic (PBPK) models for MDMA.
• To predict drug-drug interactions (DDIs) and pharmacokinetics for clinical dosing regimens.

Main Methods:

• A pharmacokinetic phase I study assessed food effects.
• PopPK and PBPK models were developed and verified using study data, published data, and in vitro data.
• PBPK simulations investigated food effects, dosing regimens, and DDIs.

Main Results:

• A high-fat meal did not alter MDMA plasma concentrations but delayed Tmax.
• PopPK analysis found no clinically significant covariates.
• PBPK models predicted minor exposure differences for single vs. split doses, with delayed Tmax for split doses.
• MDMA is a potent CYP2D6 inhibitor, with minimal predicted impact on renal transporter substrates.

Conclusions:

• Food does not significantly alter MDMA pharmacokinetics.
• MDMA's pharmacokinetic profile is predictable across clinical doses.
• MDMA is a strong CYP2D6 inhibitor, but unlikely to cause clinically relevant DDIs via renal transporters.