Methadone population pharmacokinetics: toward understanding the dose-response relationship in the treatment of opiate addiction

University of Minnesota Ph.D. dissertation. January 2013. Major: Experimental & Clinical Pharmacology. Major: Richard Brundage, PharmD, PhD. 1 computer file (PDF); viii, 209 pages, appendices A-D.Methadone is a synthetic opiate agonist that is highly effective in the treatment of opiate addiction. When given as a long-term therapy, methadone maintenance reduces morbidity and mortality associated with opiate addiction. It is thus considered an “essential” medication by the World Health Organization. The benefits of methadone maintenance in the treatment of opiate addiction are well established. Predicting treatment response for a given individual, however, remains difficult. While methadone dose is generally associated with treatment outcome, large interstudy and interindividual variability in plasma concentrations of methadone have made it difficult to link dose response to pharmacokinetic parameters. This thesis explores characteristics of methadone maintained patients and develops a population pharmacokinetic model that identifies variables associated with methadone pharmacokinetic parameters. Chapter 1 provides a general review of the three Food and Drug Administration approved pharmacotherapeutic agents for the treatment of opiate dependence. Chapter 2 reviews the clinical pharmacology of methadone as used in the treatment of opiate dependence. Chapter 3 introduces us to the Hmong and their paradoxically exceptional treatment outcome in methadone maintenance on lower doses of methadone than their non-Hmong counterparts. This retrospective study helps form the hypothesis that their better treatment outcome is related to greater methadone exposure.The results of this population pharmacokinetic study and the psychosocial differences between Hmong and non-Hmong are presented in Chapters 4 and 5, respectively. We found that the lower methadone dose requirement is explained by higher apparent bioavailability of methadone in Hmong. Other influences on methadone pharmacokinetics, more specifically clearance, include age, body mass index, and single nucleotide polymorphisms in the ABCB1 and CYP2B6 genes. While the potential for culture to influence methadone treatment outcome is acknowledged, there remain sufficient grounds to hypothesize a significant biological (i.e., pharmacokinetic and/or pharmacodynamic) influence