Population Pharmacokinetics of Intravenous Methadone Enantiomers in Adults: A Comprehensive Model

Methadone is a utilitarian opioid with growing use for anesthesia and postoperative pain. Methadone pharmacokinetic models have evolved over time; however, there is no comprehensive population pharmacokinetic model. This investigation developed a population model for R(-)- and S(+)-enantiomers of methadone and the primary metabolite 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) in plasma and urine, incorporating enantiomeric disposition, metabolism, genetics, renal elimination, and frequent and long-duration sampling, to adequately describe both distribution and elimination. In this secondary analysis of previously obtained data from 64 adults sampled for 96 hours, a compartmental model utilizing eight distinct measurement categories of drug and metabolite concentration that unified enantiomer kinetics was developed using nonlinear mixed effects techniques. Potential model covariates for weight, race, sex, CYP2B6 genetics, and CYP2C19 genetics were tested. The final unified three-compartment population model accounted for significant and systematic enantiomer-specific differences in volumes of distribution, intercompartmental and elimination clearances between R(-)- and S(+)-methadone, by estimating S(+)/R(-) ratios. The model incorporated weight and CYP2B6 genotype but not CYP2C19 genotype, sex or race as covariates. Intersubject variability was consistent with that of other intravenous opioids. S(+)/R(-) ratios were consistent with known enantiomeric differences in α₁-acid glycoprotein binding and in vitro biotransformation, and disposition was explainable by enantiomeric restrictive plasma protein binding effects on drug distribution, pharmacokinetic flow, and intrinsic hepatic clearance (CYP2B6-catalyzed metabolism). The population model may be applicable to pharmacokinetically guided intravenous methadone dosing and CYP2B6-mediated drug interactions in perioperative and critical care settings.