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

Gavin Bart, Scott Lenz, Robert J. Straka, Richard C. Brundage

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)185-193
Number of pages9
JournalDrug and alcohol dependence
Volume145
DOIs
StatePublished - Dec 1 2014
Externally publishedYes

Bibliographical note

Funding Information:
This project was supported by National Institutes of Health - National Institute on Drug Abuse mentored career-development award K23DA024663 (GB).

Publisher Copyright:
© 2014 Elsevier Ireland Ltd.

Keywords

  • Ethnicity
  • Genetics
  • Hmong
  • Methadone
  • Pharmacogenetics
  • Population pharmacokinetics

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