Relevance of CYP2B6 and CYP2D6 genotypes to methadone pharmacokinetics and response in the OPAL study

Abstract

Aims: Our study aimed to evaluate the impacts of the cytochrome P450 (CYP) 2B6-G516T and CYP2D6 genetic polymorphisms on pharmacokinetic and clinical parameters in patients receiving methadone maintenance treatment. Methods: Opioid PhArmacoLogy (OPAL) was a clinical survey of the sociodemographic characteristics, history and consequences of pathology associated with methadone maintenance treatment response and current addictive comorbidities. A subgroup of 72 methadone patients was genotyped. Results: When comparing the three CYP2B6 genotype groups, the methadone (R)and (S)-methadone enantiomer concentrations/doses (concentrations relative to doses) were different (P = .029, P = .0019). The CYP2D6 phenotypes did not seem to be relevant with regard to methadone levels. On multivariate analysis, neither the CYP2B6 genotype nor the CYP2D6 phenotype explained the (R)-methadone concentration/dose values (P = .92; P = .86); the (S)-methadone concentration/dose values (P = .052; P = .95 [although there was a difference between the TT group and GT and GG groups {P = .019}]); or opiate cessation (P = .12; P = .90).Conclusion: The genotyping of CYP2B6 G516T could be an interesting tool to explore methadone intervariability.

Biomarkers to predict staging and treatment response in opioid dependence: A narrative review

“…Mouly et al, 2015; Victorri‐Vigneau et al, 2019; Crist, Clarke, & Berrettini, 2018; Eap et al, 2002; Fonseca & Torrens, 2018…”

“…On the other hand, Methadone, the most anciently prescribed opioid use disorder treatment (Kleber, 2008), is widely affected by variability in the dose required to achieve adequate treatment response, due to a fairly inducible hepatic metabolism but also to several genetic polymorphisms affecting its absorption, blood–brain barrier passage, and hepatic disposition. These complex and interacting phenomena lead to a great importance of associated medical conditions, polypharmacy and individual genetic polymorphisms in the personalized prescription of methadone (for recent examples see (Mouly et al, 2015; Victorri‐Vigneau et al, 2019), for a more general review see (Crist, Clarke, & Berrettini, 2018; Eap et al, 2002; Fonseca & Torrens, 2018)). Of note, specific genetic polymorphisms have also been associated with methadone‐induced side‐effects, such as QT length enlargement measures on ECG (for a recent example see [Zerdazi et al, 2019]).…”

Prevalence of Coaddictions and Rate of Successful Treatment Among a French Sample of Opioid-Dependent Patients With Long-Term Opioid Substitution Therapy: The OPAL Study

“…OPAL (NCT01847729) was an observational, cross-sectional, multicenter study involving 10 centers located in the Western region of France. It combined both a clinical evaluation and a prespecified ancillary pharmacogenetic study (34). OPAL was conducted in accordance with the Good Clinical Practice Guidelines and the Declaration of Helsinki and was approved by the local ethics committee.…”

CYP2B6 Functional Variability in Drug Metabolism and Exposure Across Populations—Implication for Drug Safety, Dosing, and Individualized Therapy

“…In vitro studies demonstrate differential metabolism and clearance of methadone by CYP2B6 variants ranging from CYP2B6 * 4 ≥ CYP2B6 * 1 > CYP2B6 * 5 > CYP2B6 * 9 ≥ CYP2B6 * 6 (Gadel et al, 2015 ). CYP2B6 genotype influences the plasma levels of both enantiomers (Victorri-Vigneau et al, 2019 ). Also, decreased clearance and high plasma concentration of methadone enantiomers was observed in patients with CYP2B6 * 1/ * 6 and CYP2B6 * 6/ * 6 compared to controls (Eap et al, 2007 ; Kharasch et al, 2015 ; Kringen et al, 2017 ; Talal et al, 2020 ).…”