Ethnic and genetic factors in methadone pharmacokinetics: a population pharmacokinetic study

Abstract

Background: Treatment of opiate use disorders with methadone is complicated by wide interindividual variability in pharmacokinetics. To identify potentially contributing covariates in methadone pharmacokinetics, we used population pharmacokinetic modeling to estimate clearance (CL/F) and volume of distribution (V/F) for each methadone enantiomer in an ethnically diverse methadone maintained population.

Methods: Plasma levels of the opiate-active R-methadone and opiate-inactive S-methadone were measured in 206 methadone maintained subjects approximately two and twenty-three hours after a daily oral dose of rac-methadone. A linear one-compartment population pharmacokinetic model with first-order conditional estimation with interaction (FOCE-I) was used to evaluate methadone CL/F and V/F. The influence of covariates on parameter estimates was evaluated using stepwise covariate modeling. Covariates included ethnicity, gender, weight, BMI, age, methadone dose, and 21 single nucleotide polymorphisms in genes implicated in methadone pharmacokinetics.

Results: In the final model, for each enantiomer, Hmong ethnicity reduced CL/F by approximately 30% and the rs2032582 (ABCB1 2677G>T/A) GG genotype was associated with a 20% reduction in CL/F. The presence of the rs3745274 minor allele (CYP2B6 515G>T) reduced CL/F by up to 20% for S-methadone only. A smaller effect of age was noted on CL/F for R-methadone.

Conclusion: This is the first report showing the influence of the rs2032582 and rs3745274 variants on methadone pharmacokinetics rather than simply dose requirements or plasma levels. Population pharmacokinetics is a valuable method for identifying the influences on methadone pharmacokinetic variability.

Keywords: Ethnicity; Genetics; Hmong; Methadone; Pharmacogenetics; Population pharmacokinetics.

Fig 1

Goodness of fit plots for R-methadone. Upper panels are the observed individual (left) and population (right) concentrations (ng/ml) versus predicted concentrations (ng/ml). Lower panels are the conditional weighted residuals (CWRES) versus the predicted concentration (ng/ml) (left) and conditional weighted residuals versus time after dose (h) (right).

Fig 2

Visual predictive check. Information from the VPC is presented as 5th, 50th (median), and 95th percentile of methadone concentrations (ng/ml) ((a) R-methadone; (b) S-methadone). The raw observed data are presented as open circle symbols. The median of the observations within each of the three bins is presented as the heavy solid line. The dashed lines represent the 5th and 95th percentiles of the observed data in that bin. The gray bars represent the 95% prediction intervals around the 50th (darker) and 5th and 95th (lighter) percentiles of the predicted concentrations in each bin from 500 simulations in the VPC.

Fig 3

Goodness of fit plots for S-methadone. Upper panels are the observed individual (left) and population (right) concentrations (ng/ml) versus predicted concentrations (ng/ml). Lower panels are the conditional weighted residuals (CWRES) versus the predicted concentration (ng/ml) (left) and conditional weighted residuals versus time after dose (h) (right).