The Use of the Methadone/Metabolite Ratio (MMR) to Identify an Individual Metabolic Phenotype and Assess Risks of Poor Response and Adverse Effects: Towards Scientific Methadone Dosing.

OBJECTIVES: Significant genetic variability of metabolism confounds reliable clinical use of methadone because physicians have no way of identifying individual patient metabolism. The methadone/metabolite ratio (MMR), the numerical ratio of serum methadone to its inactive metabolite ethylidine-dimethyl-diphenypyrrolidine (EDDP), represents the net expression of the genes controlling metabolism. The MMR has been adapted to four established pharmacogenetic metabolic categories: ultra-rapid (URM), extensive (EM, normal), intermediate (IM), and ultra-slow (USM). METHODS: This study reports on the analysis of 1700 paired peak and trough serum samples for methadone and EDDP. The MMR data were stratified by metabolic category. The reliability of these categories and the relationship of the MMR to 2 other laboratory assessments, a peak/trough ratio (PTR) and a methadone half-life, was tested. Additionally, peak and trough serum levels were analyzed by MMR category. RESULTS: Each category of MMR identified significantly different mean serum levels (peak and trough), peak/trough ratios, and half-lives. When serum levels were analyzed, evidence of subtherapeutic serum levels were found, predominantly in the URM and EM categories. Seventeen percent of peak serum levels were greater than 1000 ng (a level indicating potential toxicity) with a range up to 2384 ng, predominantly in the IM and USM categories. CONCLUSIONS: The MMR measures an individual's phenotype for methadone metabolism. The data suggested underdosing in the URM category, as well as evidence of excessive dosing in IM and USM categories. The MMR provides a guide to safe and effective dosing, an alternative to the pharmacokinetically 'blind' dosing algorithms currently in use.

The Use of Serum Methadone/Metabolite Ratios to Monitor Changing Perinatal Pharmacokinetics.

OBJECTIVES: Pregnancy profoundly alters drug metabolism, accelerating clearance and confounding medication management, primarily through induction of CYP450 enzymes. Methadone is a CYP450 substrate with altered pharmacokinetics during pregnancy. We report on the use of serum methadone/metabolite ratios (MMRs) to monitor changes in methadone metabolism through the perinatal period and to objectively guide methadone dosing. Previous research found average MMRs in nonpregnant populations of between 11.3 and 12.7. METHODS: Serum methadone and its major metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine concentrations were analyzed in 67 samples from 23 pregnant patients treated for opioid use disorder, and their calculated ratio was used to document changes in methadone clearance across trimesters and postpartum. Lower ratios indicate increased clearance. RESULTS: The average MMR during pregnancy was 6.1. Ratios declined significantly from trimester 1 to trimester 3 (P = 0.007), and then rose significantly from trimester 3 to postpartum (P = 0.001). The per cent of ratios that were 4 or less, indicating ultrarapid metabolism, increased from 8% to 30% to 38% across trimesters, and decreased to 5% postpartum. Forty-four per cent of individual patients had at least 1 prepartum ratio of 4 or less. CONCLUSIONS: This study documents significant metabolic changes occurring perinatally, which indicate the need for both changes in methadone dose and dose frequency to maintain maternal/fetal stability, and also dose reductions as hypermetabolism reverses postpartum. MMRs provide an objective tool to more efficiently improve the safety and efficacy of methadone dosing perinatally.