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Methadone & Pegasys Interactions, Safety and Tolerability
Reported by Jules Levin
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At the DDW (Digestive Disease Week) Conference in Orlando May 17-22, 2003 Mark Sulkowski, MD, Johns Hopkins University Medical School) reported on a 4-week study evaluating interactions between methadone and Pegasys (abstract 231). He found methadone exposure (levels) increased by 10% to 15% during the first 4 weeks of taking them together, although no patient reduced their methadone dose during this 4-week study. He concluded that the combination was safe and well tolerated. In this study, methadone did not have an impact on the pharmacokinetics (drug levels) of Pegasys nor the pharmacodynamics (PD) of Pegasys. Therfore dose modifications of Pegasys are not required.
As background information Sulkowski reported that intravenous drug use is the single most important risk factor for HCV infection. Up to 90% of intravenous drug users are chronically infected with HCV. There has been concern that methadone might suppress interferon antiviral activity.
The aim of the study was to evaluate the pharmacokinetics (PK) and PD of PEG-IFN were evaluated after single and multiple weekly 180 µg doses of Pegasys in 24 patients with chronic hepatitis C on methadone maintenance; to assess the effects of multiple doses of Pegasys (40KD) on methadone pharmacokinetics (drug levels) in patients with chronic hepatitis C; to assess the safety and tolerability of multiple doses of peginterferon alfa-2a (40KD) in patients with chronic hepatitis C receiving methadone maintenance. This study is prospective, open-label (patients knew what they were taking), non-randomized, and was a multi-center trial. The study is a single and multiple dose pharmacokinetics and pharamacodynamics study.
PEG-IFN's effect on methadone pharmacokinetics was assessed by the comparison of methadone's PK before and after multiple doses of PEG-IFN. The PD effects of PEG-IFN were assessed by measuring 2',5'-oligoadenylate synthetase (2',5'-OAS) serum activity and HCV kinetics. Noncompartmental PK and PD analyses, including descriptive statistics and an ANOVA, were completed.
Study participants were 18 years or older, were HCV-antibody positive with detectable HCV-RNA, and on a consistent methadone maintenance regimen (formulation, dose, frequency) for at least 3 months. The majority of patients enrolled were male (63%), Caucasian (63%), 120 to 270 lbs (average 180 lbs), and 34 to 57 years old (mean age 47 yrs). Patients received stable daily methadone doses of 30 to 150 mg (mean dose 80 mg/day0 Mean body mass index was 29.7. 12 patients (50%) had concomitant psychiatric disorders.
Patients were excluded from the study if they had received treatment with interferon within 6 months of study enrollment, if they had coinfection with hepatitis A, B or with HIV, if they had serious concomitant illness, or if they had positive urine for amphetamines, cannabis, cocaine, opiates, and/or other drugs without a valid medical indication.
This was a 4-week study with a 29-57 day follow-up period. Patients receive 4 weekly injections of Pegasys. Pegasys PK (drug levels) at week 1 and week 4 was similar to Pegasys PK (drug levels) determined from previous studies and experience in chronic hepatitis C patients not receiving methadone maintenance. Methadone Cmax (the peak level of methadone after taking a dose) was increased about 10% from 701 ng/mL to 774 ng/mL. The AUC (area under the curve: total drug level in the blood) increased from about 10,670 to 12,670 ng/mL. Sulkowski said on average methadone exposure increased 10% to 15%. 64% of patients had an increased Cmax on therapy. 76% of patients had an increase in AUC from baseline to week 4. One subject had Cmax increase 2-fold and AUC increased 1.5-fold. No adverse events were noted. Peginterferon (Pegasys)-induced 2',5'-OAS activity (biologic activity) after a single dose and after 4 weeks was similar to that seen in healthy subjects. 12 patients experienced a 2 log reduction in HCV-RNA (viral load) and 4 patients had a 1 log reduction, suggesting no interaction of methadone with the antiviral activity of Pegasys.
The safety profile of peginterferon alfa-2a was similar to that reported in previous studies. The most common adverse events were headache, rigors, fatigue, pyrexia, mylagia, and arthralgia, and were mild or moderate in severity. No patients reduced their methadone dose during the four week study.
Editorial note from Jules Levin: These results raise an interesting point. Some individuals taking methadone report withdrawal symptoms after starting peginterferon plus ribavirin therapy. The side effects of the therapy for hepatitis C are similar to symptoms of methadone withdrawal (fatigue, fever, rigors, flu-like symptoms). In response some doctors raise the dose of methadone for these patients. Raising the methadone dose serves to provide incentive for patients to remain on HCV therapy.
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