The Effect of Multiple Doses of Peginterferon alfa‐2b on the Steady‐State Pharmacokinetics of Methadone in Patients With Chronic Hepatitis C Undergoing Methadone Maintenance Therapy

Abstract

This multicenter, open-label study evaluated the effects of multiple doses of peginterferon alfa-2b on the steadystate pharmacokinetics of methadone in 20 adults with hepatitis C virus infection who were enrolled in a methadone maintenance program. All subjects received peginterferon alfa-2b 1.5 mug/kg/wk for 4 weeks and maintained their normal methadone regimen. Serial blood samples were collected immediately before the first and after the fourth peginterferon alfa-2b dose (day 23). At day 23, exposure to the active methadone R-enantiomer increased by approximately 15% following administration of peginterferon alfa-2b, with 90% confidence intervals just outside the bioequivalence criteria (range, 80%-125%). Similar increases in exposure (C(max), AUC(0-24), and AUC(last)) were observed with S-methadone and total methadone. Peginterferon alfa-2b was well tolerated. Peginterferon alfa-2b is associated with minor increases in exposure to methadone in individuals with hepatitis C virus infection; however, these increases are unlikely to be clinically meaningful and are not associated with any safety concerns.

Pharmacotherapy in the Treatment of Addiction: Methadone

“…These interactions are usually via the CYP3A4 system and can have effects on the level of either methadone or the antiretroviral medication, which can then have actual clinical effects (reviewed in 54). Alfa-2b interferon given as treatment for hepatitis C, which is common in intravenous drug users (IVDUs), does not appear to have any clinically significant interaction in terms of subjective or objective effects, as noted in three studies55, 56, 57; however, in all patients interferon produces flu-like symptoms which may mimic opioid withdrawal.…”

Drug Interactions of Clinical Importance among the Opioids, Methadone and Buprenorphine, and Other Frequently Prescribed Medications: A Review

“…No clinically significant interaction 40 Not studied in human pharmacokinetics studies Hepatitis C Interferon No clinically significant interaction 45,46 Not studied in human pharmacokinetics studies Ribavirin Not studied in human pharmacokinetics studies Not studied in human pharmacokinetics studies Other infections Fluconazole Increased methadone plasma concentrations 47 Not studied in human pharmacokinetics studies Voriconizole…”

“…To date, two studies have been reported in the literature and both have shown no significant drug interactions be-tween methadone and interferon. 45,46 No studies of drug interactions between ribavirin and methadone have been completed at this time.…”

Immunological Response as a Source to Variability in Drug Metabolism and Transport

“…Several studies have been performed with administration of IFN-α-2b and IFN-α-2a and possible interaction with methadone, which is predominantly metabolized by CYP3A4. A minor increase in methadone exposure in hepatitis C patients after multiple doses of peginterferon-α-2b or peginterferon-α-2a have been reported, but the authors conclude that this may not be of any clinical relevance (Sulkowski et al, 2005; Gupta et al, 2007). However several reports indicate that IFN could cause a clinically relevant interaction when administered with drugs that are CYP substrates, but there might be different effect on the individual CYPs.…”