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

Highlights

• Methadone has wide interindividual pharmacokinetics.

• Population pharmacokinetics identifies covariates influencing pharmacokinetics.

• Hmong ethnicity is associated with 30% reduction in methadone clearance.

• The rs2032582 (ABCB1 2677G > T/A) GG genotype is associated with 20% reduction in methadone clearance.

• The rs3745274 minor allele (CYP2B6 516G > T) is associated with 20% reduction in S-methadone clearance.

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.

Introduction

The misuse of and dependence on opiates is associated with significant morbidity and mortality through overdose and infectious diseases transmitted by injection drug use (Degenhardt et al., 2009). For more than 40 years, the long-acting synthetic opioid methadone has played a central role in the treatment of opiate dependence (Kleber, 2008).

Despite its effectiveness in the treatment of opiate use disorders, methadone is often difficult to use due to its highly variable pharmacokinetics. Estimates of methadone's clearance, volume of distribution, and half-life range from 5.9–13 l/h, 189–470 l, and 15–207 h, respectively (Eap et al., 2002). This difficulty is apparent in the significant rise in methadone associated mortality primarily seen when prescribed for pain by physicians who likely are less familiar with this variability than physicians within highly regulated methadone maintenance settings (Center for Substance Abuse Treatment, 2007). While training in safe prescribing strategies for methadone has resulted in reduced mortality, methadone remains a medication which has highly variable pharmacokinetics making it difficult to devise standard dosing regimens informed by therapeutic drug monitoring (Strang et al., 2010).

Methadone is a racemic mixture whose R-enantiomer provides the therapeutic effect at mu-opioid receptors, while both the R- and S-enantiomers are weak N-methyl-d-aspartate (NMDA) receptor antagonists (Eap et al., 2002). Most studies of methadone pharmacokinetics have evaluated only total methadone levels; however, it appears that there is also variability in pharmacokinetics within and between enantiomers (R-methadone: clearance 4–9.6 l/h, volume of distribution 96–469 l, half-life 24–48 h; S-methadone: clearance 7.7–20 l/h, volume of distribution 259–273 l, half-life 20–40 h), which may complicate interpretation of studies assessing the pharmacokinetics of total methadone only.

Population pharmacokinetics (POPPK) is a useful and valid approach toward quantifying drug exposure–clinical response relationships (Food and Drug Administration, 1999, Sheiner and Ludden, 1992). Unlike traditional pharmacokinetic studies, which gather dense data that assess individual variability in drug kinetics, POPPK can use sparse data to model measures of drug exposure and identify factors (e.g., ethnicity, gender, age, weight) that influence variability in drug concentrations across populations (Sheiner et al., 1977).

While the POPPK approach has been validated for methadone maintained individuals there are no studies from large or diverse populations (Foster et al., 2004, Rostami-Hodjegan et al., 1999, Wolff et al., 1997). In fact, over 90% of the subjects in previous POPPK studies of methadone were Caucasian and none of the studies were conducted within a United States population. With larger more diverse sample sizes, variables that contribute to methadone pharmacokinetics (e.g., ethnicity) and treatment outcome may be identified. Based on our previous observations that methadone maintained ethnic Hmong from Laos are on a lower mean dose of methadone yet achieve greater treatment response than do non-Hmong attending the same clinic (Bart et al., 2012), we hypothesized that POPPK could detect decreased methadone clearance in Hmong compared to non-Hmong.