Ribavirin and interferon alfa‐2b in chronic hepatitis C: assessment of possible pharmacokinetic and pharmacodynamic interactions

Abstract

AimsThe primary objective of this study was to determine whether pharmacokinetic interactions occurred between interferon a-2b (IFN) and ribavirin in patients with chronic hepatitis C infections. Additionally this study assessed the single and multiple-dose pharmacokinetics of ribavirin and IFN, and compared the safety, tolerability and antiviral pharmacodynamics of IFN plus ribavirin compared with either drug alone.Methods In this open label parallel group study, patients with chronic hepatitis C were randomized to receive IFN 3 million IU thrice weekly s.c. alone, ribavirin 600 mg twice daily p.o. alone or both drugs in combination over 6 weeks. Single and multiple dose pharmacokinetics and indices of antiviral pharmacodynamics were assessed during weeks 1 and 6, along with safety assessments during the study. Results The range of mean ribavirin terminal phase half-lives after single doses was 44-49 h. Comparison of week 1 and week 6 AUC(0,12h) values showed accumulation in plasma of approximately 6-fold. The range of mean washout halflives after week 6 was 274-298 h, reflecting release of ribavirin from deep compartment stores. The range of single and multiple dose IFN terminal phase halflives was 5-7 h. IFN demonstrated an increase in bioavailability (~2-fold) upon multiple dose administration. Ribavirin and IFN pharmacokinetic parameters for combined ribavirin and IFN were similar to those during monotherapy with either compound, although the power of this study to detect differences was low. Serum HCV-RNA titers and ALT concentrations were reduced by IFN alone, ribavirin alone reduced ALT concentrations only, and combined IFN plus ribavirin produced numerically greater falls in both measurements than either treatment alone. Serum concentrations of neopterin and activity of 2∞,5∞-oligoadenylate synthetase (2∞5∞-OAS) were increased by IFN alone and in combination with ribavirin, whereas serum 2∞5∞-OAS activity was decreased and neopterin concentrations unaltered by ribavirin monotherapy. IFN and ribavirin monotherapy produced characteristic changes in safety laboratory tests (IFN-reductions in white cells, neutrophils and platelets; ribavirin-reduced haemoglobin) and characteristic adverse event profiles (IFN-headache, flu-like symptoms, fatigue, anorexia, nausea, myalgia, and insomnia; ribavirin-headache, fatigue, myalgia, and pruritus). There was no additive effect of combination therapy on safety laboratory tests or reported adverse events. All changes were fully reversible upon treatment cessation. Conclusions There was no evidence of pharmacokinetic interactions between IFN and ribavirin in this study. There were numerical trends indicating that the combination of IFN and ribavirin reduced titers of HCV-RNA to a greater extent than did either treatment alone, and the safety profile of combination therapy was similar to those of both monotherapy treatments.

Viral Evolution and Interferon Resistance of Hepatitis C Virus RNA Replication in a Cell Culture Model

“…To determine if the HP replicon conferred differential regulation of ISG expression, we conducted a microarray analysis to evaluate global gene expression levels in cells cultured in the absence or presence of IFN-␣2a for 24 h. Pharmacological studies have determined that serum levels of IFN are approximately 10 to 12 U/ml within 2 h after the administration of IFN to patients undergoing therapy with recombinant IFN-␣ preparations (28); to maintain physiologic relevance, we treated cells with 10 U of IFN/ml. Our analyses included assessment of gene expression in the parental Huh7 control cells and Huh7-K2040, Huh7-L2198S,and Huh7-HP cells.…”

Study of pruritus in chronic hepatitis C patients

“…Comparison between PEG-IFN α2a and PEG-IFN α2b monotherapies would have been preferable; however, this was not possible because the Japanese health insurance system stipulates that PEG-IFN α2b must be administered with RBV. RBV itself has been reported to cause pruritus [13,19] . When combined with PEG-IFN, a synergistic effect may result in a delayed-type hypersensitivity reaction, with a shift in the helper T (Th) cell balance towards a Th1-dominant response due to the influence of IFN.…”

Targeting the “Cytokine Storm” for Therapeutic Benefit

“…One of the most widely used therapeutic cytokines is IFN-␣, a type 1 interferon which inhibits viral replication. It is used in combination with ribavirin for the treatment of chronic HCV, resulting in greater viral RNA clearance together than when administered alone (41,42).…”