Stéphane Mouly1,2,3,4, Vanessa Bloch1,2,3, Katell Peoc'h1,2,3,5, Pascal Houze6, Laurence Labat1,2,3, Kamilia Ksouda7, Guy Simoneau4, Xavier Declèves1,2,3, Jean Francois Bergmann1,2,3,4, Jean-Michel Scherrmann1,2,3, Jean-Louis Laplanche1,2,3,5, Jean-Pierre Lepine1,2,3,7, Florence Vorspan1,2,3,7. 1. Inserm, U1144, Paris, F-75006, France. 2. Université Paris Descartes, UMR-S1144, Paris, F-75006, France. 3. Université Paris Diderot, UMR-S1144, Paris, F-75010, France. 4. Unit of Therapeutic Research & Internal Medicine Department, Lariboisière-Saint Louis Hospital, Paris, France. 5. Laboratory of Biochemistry and Molecular Biology, Lariboisière-Saint Louis Hospital, Paris, France. 6. Laboratory of Pharmacology, Lariboisière-Saint Louis Hospital, Paris, France. 7. Psychiatric Unit, Assistance Publique-Hôpitaux de Paris (APHP), Lariboisière-Saint Louis Hospital, Paris, France.
Abstract
AIMS: Methadone is characterized by wide intersubject variability regarding the dose needed to obtain full therapeutic response. We assessed the influence of sociodemographic, ethnic, clinical, metabolic and genotypic variables on methadone maintenance dose requirement in opioid-dependent responder patients. METHODS: Eighty-one stable patients (60 men and 21 women, 43.7 ± 8.1 years old, 63.1 ± 50.9 mg day(-1) methadone), divided into quartiles with respect to the median daily dose, were enrolled and underwent clinical examination, treatment history and determination of liver/intestinal cytochrome P450 (CYP) 3A4 activity measured by the midazolam test, R,S-methadone trough concentration and clinically significant polymorphisms of the OPRM1, DRD2, COMT, ABCB1, CYP2B6, CYP3A5, CYP2C19 and CYP2D6 genes. RESULTS: Methadone maintenance dose was correlated to the highest dose ever used (r(2) = 0.57, P < 0.0001). Fractioned methadone intake (odds ratio 4.87, 95% confidence interval 1.27-18.6, P = 0.02), bodyweight (odds ratio 1.57, 95% confidence interval 1.01-2.44, P = 0.04), history of cocaine dependence (80 vs. 44 mg day(-1) in never-addict patients, P = 0.005) and ethnicity (Asian > Caucasian > African, P = 0.04) were independently associated with high-dose methadone in multiple regression analysis. A modest correlation was observed between liver/intestinal CYP3A4 activity and methadone dose at steady state (Spearman rank correlation coefficient [rs ] = 0.21, P = 0.06) but not with highest dose ever used (rs = 0.15, P = 0.18) or dose-normalized R,S-methadone trough concentrations (rs = -0.05, P = 0.64). Concomitant CYP3A4 inhibitors only affected the relationship between methadone dose and R,S-methadone trough concentration. None of the genetic polymorphisms explored was predictive of the methadone maintenance dose. CONCLUSIONS: Methadone maintenance dose was predicted by sociodemographic and clinical variables rather than genetic polymorphisms or liver/intestinal CYP3A4 activity in stable patients.
AIMS: Methadone is characterized by wide intersubject variability regarding the dose needed to obtain full therapeutic response. We assessed the influence of sociodemographic, ethnic, clinical, metabolic and genotypic variables on methadone maintenance dose requirement in opioid-dependent responder patients. METHODS: Eighty-one stable patients (60 men and 21 women, 43.7 ± 8.1 years old, 63.1 ± 50.9 mg day(-1) methadone), divided into quartiles with respect to the median daily dose, were enrolled and underwent clinical examination, treatment history and determination of liver/intestinal cytochrome P450 (CYP) 3A4 activity measured by the midazolam test, R,S-methadone trough concentration and clinically significant polymorphisms of the OPRM1, DRD2, COMT, ABCB1, CYP2B6, CYP3A5, CYP2C19 and CYP2D6 genes. RESULTS:Methadone maintenance dose was correlated to the highest dose ever used (r(2) = 0.57, P < 0.0001). Fractioned methadone intake (odds ratio 4.87, 95% confidence interval 1.27-18.6, P = 0.02), bodyweight (odds ratio 1.57, 95% confidence interval 1.01-2.44, P = 0.04), history of cocaine dependence (80 vs. 44 mg day(-1) in never-addict patients, P = 0.005) and ethnicity (Asian > Caucasian > African, P = 0.04) were independently associated with high-dose methadone in multiple regression analysis. A modest correlation was observed between liver/intestinal CYP3A4 activity and methadone dose at steady state (Spearman rank correlation coefficient [rs ] = 0.21, P = 0.06) but not with highest dose ever used (rs = 0.15, P = 0.18) or dose-normalized R,S-methadone trough concentrations (rs = -0.05, P = 0.64). Concomitant CYP3A4 inhibitors only affected the relationship between methadone dose and R,S-methadone trough concentration. None of the genetic polymorphisms explored was predictive of the methadone maintenance dose. CONCLUSIONS:Methadone maintenance dose was predicted by sociodemographic and clinical variables rather than genetic polymorphisms or liver/intestinal CYP3A4 activity in stable patients.
Authors: Jörn Lötsch; Carsten Skarke; Johannes Wieting; Bruno Georg Oertel; Helmut Schmidt; Jürgen Brockmöller; Gerd Geisslinger Journal: Clin Pharmacol Ther Date: 2006-01 Impact factor: 6.875
Authors: Senthil Packiasabapathy; Blessed W Aruldhas; Pengyue Zhang; Brian R Overholser; Sara K Quinney; Senthilkumar Sadhasivam Journal: Pharmacogenomics Date: 2021-06-08 Impact factor: 2.533