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

Abstract

AIMPegylated 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. METHODSFourteen 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 mg 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. RESULTSPEG-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. CONCLUSIONThese 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. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Interferons are known to down-regulate the hepatic cytochrome P450 (CYP) system thereby reducing drug metabolism.• Several studies have evaluated the interactions between interferon and drugs metabolized by various CYP isoenzymes and the data suggest that interferon may reduce the activity of CYP1A2. WHAT THIS STUDY ADDS• This study examines the effect of PEG-IFN alfa-2a on drugs metabolized by the CYP450 system, including theophylline (CYP1A2).• Previous studies have examined the effect of standard IFN or PEG-IFN alfa-2b on the activity of the CYP450 drug metabolizing enzymes. However, PEG-IFN alfa-2a has different pharmacokinetics, dosing and pegylated moiety as compared with standard IFN and PEG-IFN-alfa-2b.• Any effects on the CYP enzyme system by PEG-IFN alfa-2a (40KD) could have important consequences for patients with hepatits C virus receiving concomitant drug treatments.

Microarray Analysis of Differentially-Expressed Genes Encoding CYP450 and Phase II Drug Metabolizing Enzymes in Psoriasis and Melanoma

“…Since suppression of CYP3A4 gene expression in inflammatory diseases can lead to improper drug metabolism and poor efficacy of therapeutic drugs, it is important to determine the effects of new therapies on CYP3A4 and other DME genes. Notably, biological therapies which target specific interferons (Pegasys; peginterferon α-2a) and the therapeutic monoclonal antibody targeting IL-6 receptor (tocilizumab), could de-repress the CYP3A34, CYP2C9, and CYP2C19 enzymes in vitro and in clinical studies [ 48 , 49 ] . Other biological therapies such as TNF-α antagonists did not suppress these CYP450 genes, but were reported to increase the risk of infections and other skin diseases [ 50 ].Therefore, conventional therapies (glucocorticoid therapy, vitamin D analogs) for psoriasis will continue to remain clinically relevant.…”

Contribution of Major Metabolites toward Complex Drug-Drug Interactions of Deleobuvir: In Vitro Predictions and In Vivo Outcomes

“…However, there had been reports of PEG-interferon a-2b inhibiting CYP1A2, albeit very mildly. These studies had assessed the effect of PEG-interferon a-2b after approximately 1 month of treatment (Gupta et al, 2011;Brennan et al, 2013), which is much longer than the duration reported for our study. Further, in a parallel arm to our study, PEG-interferon a-2b and ribavirin were administered in an identical regimen in combination with faldaprevir and had no effect on CYP1A2 and CYP2C9 activities .…”

Regulation of drug-metabolizing enzymes in infectious and inflammatory disease: implications for biologics–small molecule drug interactions

“…Presently, PEGylated interferons, made by addition of poly-ethylene glycol side chain to the interferon, are being used in combination therapies for diseases such as hepatitis B and hepatitis C. As mentioned in the Table. 2, clinically significant drug interaction studies with PEGylated interferons have not been carried out to a large extent, however, studies have shown that its treatment was associated with increase in AUC of theophylline [27] and methadone [16]. …”

“…Likewise, in healthy volunteers, PEG-IFN alfa-2a increased the AUC 0-∞ of theophylline that paralleled with reduction in its clearance [27]. In vitro , interferon-α was found to down-regulate CYP1A2 gene, which probably explains the decreased theophylline clearance by interferon.…”