title: Effect of peginterferon alfa-2a (40KD) on cytochrome P450 isoenzyme activity.
abstract: OBJECTIVE
  Pegylated interferon-based therapy is recommended for treatment of hepatitis C virus (HCV) infection. Because interferons are known to down-regulate 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 vivo.
  
  
  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 metabolized probe drugs theophylline (CYP1A2), tolbutamide (CYP2C9), mephenytoin (CYP2C19), debrisoquine (CYP2D6) and dapsone (CYP3A4) on day 1 of the study. PEG-IFN 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 pharmacokinetic parameters.
  
  
  RESULTS
  PEG-IFN alfa-2a (40KD) significantly increased the area under the serum drug concentration vs. 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 interferon.
  
  
  CONCLUSIONS
  These results suggest there may be an inhibitory effect of PEG-IFN alfa-2a (40KD) on CYP1A2. PEG-IFN alfa-2a (40KD) had no effect on CYP2C9, CYP2C19, CYP2D6 or CYP3A4 in healthy subjects.
authors: Department of Clinical Pharmacology, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. barbara.brennan@roche.com
authors: Barbara J
authors: BJ
authors: Brennan
authors: Zhi-Xin
authors: ZX
authors: Xu
authors: Joseph F
authors: JF
authors: Grippo
mesh_terms: D000293:Adolescent; D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology; D019540:Area Under Curve; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D003577:Cytochrome P-450 Enzyme System; C100416:peginterferon alfa-2a