Abstract
Purpose
To examine the effect of pegylated interferon (PEG-IFN) alfa-2b on the activity of major drug-metabolizing enzymes.
Methods
This nonrandomized, open-label, multiple-dose study examined the effects of PEG-IFN alfa-2b on the activity of CYP450 1A2, 2 C8/9, 2D6, and 3A4 enzymes and N-acetyltransferase in subjects with chronic hepatitis C. Eligible subjects received PEG-IFN alfa-2b 1.5 μg/kg subcutaneously once weekly for 4 weeks (days 3, 10, 17, and 24). Oral probe substrates (dextromethorphan hydrobromide 45 mg, caffeine 200 mg, tolbutamide 500 mg, and dapsone 100 mg) were administered after a 10-h fast on days 1 and 25. Midazolam 4 mg was administered orally on days 2 and 26. Enzyme activity for each CYP450 isozyme and for N-acetyltransferase was estimated based on the ratios of the observed concentrations of the substrates and metabolites in plasma or urine samples.
Results
Twenty-six subjects enrolled in the study. Mean age was 44.3 years, mean weight was 78.9 kg, and mean body mass index was 26.3 kg/m2. Multiple doses of PEG-IFN alfa-2b inhibited CYP1A2 activity to a limited extent (point estimate = 84.2%, 90% confidence interval [CI] 79–90), increased CYP2C8/9 activity to a limited extent (point estimate = 127.6%, 90% CI 115–142), increased CYP2D6 activity (point estimate = 167%, 90% CI 125–223), and had no effect on the activity of CYP3A4 or N-acetyltransferase.
Conclusion
Weekly administration of PEG-IFN alfa-2b to subjects with chronic hepatitis C increased CYP2C8/9 and CYP2D6 activity in some individuals.
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Acknowledgements
The authors thank Steven Schenker, MD and Jerry Herron MD for their assistance in conduct of the study. The authors also thank Tim Ibbotson, PhD, and Claudette Knight, PharmD, for writing assistance, which was funded by Schering-Plough Corporation, now Merck & Co., Inc., Whitehouse Station, NJ, USA.
Financial disclosure
The study was funded Schering-Plough Corporation, now Merck & Co., Inc., Whitehouse Station, NJ, USA.
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Gupta, S.K., Kolz, K. & Cutler, D.L. Effects of multiple-dose pegylated interferon alfa-2b on the activity of drug-metabolizing enzymes in persons with chronic hepatitis C. Eur J Clin Pharmacol 67, 591–599 (2011). https://doi.org/10.1007/s00228-010-0972-5
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DOI: https://doi.org/10.1007/s00228-010-0972-5