TY - JOUR
T1 - The Use of the Methadone/Metabolite Ratio (MMR) to Identify an Individual Metabolic Phenotype and Assess Risks of Poor Response and Adverse Effects
T2 - Towards Scientific Methadone Dosing
AU - McCarthy, John J.
AU - Graas, Joseph
AU - Leamon, Martin H.
AU - Ward, Coburn
AU - Vasti, Ernest J.
AU - Fassbender, Catherine
N1 - Copyright:
This record is sourced from MEDLINE/PubMed, a database of the U.S. National Library of Medicine
PY - 2020/9/1
Y1 - 2020/9/1
N2 - 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.
AB - 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.
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U2 - 10.1097/ADM.0000000000000620
DO - 10.1097/ADM.0000000000000620
M3 - Article
C2 - 32032212
AN - SCOPUS:85088264285
VL - 14
SP - 431
EP - 436
JO - Journal of Addiction Medicine
JF - Journal of Addiction Medicine
SN - 1932-0620
IS - 5
ER -