Effect of peginterferon alfa-2a (40KD) on cytochrome P450 isoenzyme activity

Hoffmann-La Roche Inc, Nutley, NJ, USA.
British Journal of Clinical Pharmacology (Impact Factor: 3.69). 07/2012; 75(2). DOI: 10.1111/j.1365-2125.2012.04373.x
Source: PubMed

ABSTRACT AIM: Pegylated interferon-based therapy is recommended for treatment of hepatitis C virus (HCV) infection. Because interferons are known to downregulate hepatic cytochrome P450 (CYP) enzymes, which are involved in drug metabolism and clearance, there is a need to investigate the effect of peginterferon (PEG-IFN) alfa-2a (40KD) on the activity of these enzymes in the CYP system. METHODS: Fourteen healthy, male volunteers aged 18 to 45 years were recruited into an open-label, two-period, single-centre study in which CYP enzyme activity was measured by administration of the selectively metabolised probe drugs theophylline (CYP1A2), tolbutamide (CYP2C9), mephenytoin (CYP2C19), debrisoquine (CYP2D6) and dapsone (CYP3A4) on day 1 of the study. Peginterferon alfa-2a (40KD) 180 μg was given subcutaneously each week from day 15 to 36, and probe drugs were re-administered on day 37. Probe drugs and metabolites were quantified in plasma or urine samples and used to derive enzyme activity and pharmacokinetic parameters. RESULTS: Peginterferon alfa-2a (40KD) significantly increased the area under the serum drug concentration versus time curve (AUC(0-∞) ) for theophylline by 24%, with a reduction in the mean oral clearance of theophylline of 20%. There were no effects on the pharmacokinetics of any of the other probe drugs. The incidence of adverse events was as expected in subjects receiving pegylated interferons. CONCLUSION: These results suggest there may be an inhibitory effect of PEG-IFN alfa-2a (40KD) on CYP1A2. Peginterferon alfa-2a (40KD) had no effect on CYP2C9, CYP2C19, CYP2D6 or CYP3A4 in healthy patients.

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