Our objective was to quantify the pharmacokinetics of methadone and the pharmacokinetics and pharmacodynamics of peginterferon alfa-2a (40 kd) in patients with chronic hepatitis C undergoing methadone maintenance therapy.
Adults with chronic hepatitis C who had been receiving a consistent methadone maintenance regimen for at least 3 months were eligible for this open-label, multicenter, nonrandomized drug interaction study. All patients received 180 microg subcutaneous peginterferon alfa-2a once weekly for 4 weeks and continued their methadone regimen. Serial blood samples were collected at baseline and immediately before and for up to 168 hours after study drug administration for the purposes of quantifying methadone and peginterferon alfa-2a serum concentrations, measuring serum 2',5'-oligoadenylate synthetase activity, and determining hepatitis C virus ribonucleic acid levels.
Twenty-four patients were enrolled. Methadone exposure, as measured by maximum serum concentration (C(max)) and area under the concentration-time curve (AUC) normalized to a 100-mg/d dose, after 4 doses of peginterferon alfa-2a increased by 10% to 15% when compared with baseline. The week 4/baseline ratio of the mean C(max) was 1.11 (90% confidence interval [CI], 1.02-1.22), and for AUC from time 0 to 24 hours, the week 4/baseline ratio was 1.15 (90% CI, 1.08-1.23). The mean accumulation ratios (week 4/first dose) for C(max) and AUC from time 0 to 168 hours of peginterferon alfa-2a were 2.1 and 2.3, respectively.
Peginterferon alfa-2a does not appreciably alter the pharmacokinetics of methadone.
[Show abstract][Hide abstract] ABSTRACT: Hepatitis C virus (HCV) infected patients often take multiple co-medications to treat adverse events related to HCV therapy, or to manage other co-morbidities. Drug-drug interactions associated with this polypharmacy are relatively new to the field of HCV pharmacotherapy. With the advent of the direct-acting antivirals telaprevir and boceprevir, which are both substrates and inhibitors of the cytochrome P450 (CYP) 3A iso-enzyme, knowledge and awareness of drug-drug interactions have become a cornerstone in the evaluation of patients starting and continuing HCV combination therapy. In our opinion, an overview of conducted drug-drug interaction studies and a list of contra-indicated medications is not enough for the clinical management of these drug-drug interactions. Knowledge of pharmacokinetic profiles and concentration-effect relationships is key for the interpretation of these data, and insight how to manage these interactions (e.g., dose adjustments, safe alternatives and therapeutic drug monitoring) is of equal importance. This review provides a practical overview of the safe and effective management of these clinical challenges.
Journal of Hepatology 11/2012; 58(4). DOI:10.1016/j.jhep.2012.10.027 · 11.34 Impact Factor
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