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

Aims The primary objective of this study was to determine whether pharmacok inetic interactions occurred between interferon alpha-2b (IFN) and ribaviri n 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 I FN plus ribavirin compared with either drug alone. Methods In this open label parallel group study, patients with chronic hepa titis C were randomized to receive IFN 3 million IU thrice weekly s.c. alon e, ribavirin 600 mg twice daily p.o. alone or both drugs in combination ove r 6 weeks. Single and multiple dose pharmacokinetics and indices of antivir al pharmacodynamics were assessed during weeks 1 and 6, along with safety a ssessments 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 half-lives after week 6 was 274-298 h, reflecting release of ribavirin from deep compartment stores. The range of single and multiple dose IFN termina l phase half-lives was 5-7 h. IFN demonstrated an increase in bioavailabili ty (similar to 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 s tudy to detect differences was low. Serum HCV-RNA titers and ALT concentrat ions 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 neo pterin and activity of 2',5'-oligoadenylate synthetase (2'5'-OAS) were incr eased by IFN alone and in combination with ribavirin, whereas serum 2'5'-OA S activity was decreased and neopterin concentrations unaltered by ribaviri n monotherapy. IFN and ribavirin monotherapy produced characteristic change s in safety laboratory tests (IFN-reductions in white cells, neutrophils an d platelets; ribavirin-reduced haemoglobin) and characteristic adverse even t profiles (IFN-headache, flu-like symptoms, fatigue, anorexia, nausea, mya lgia, and insomnia; ribavirin-headache, fatigue, myalgia, and pruritus). Th ere was no additive effect of combination therapy on safety laboratory test s or reported adverse events. All changes were fully reversible upon treatm ent cessation. Conclusions There was no evidence of pharmacokinetic interactions between I FN and ribavirin in this study. There were numerical trends indicating that the combination of IFN and ribavirin reduced titers of HCV-RNA to a greate r extent than did either treatment alone, and the safety profile of combina tion therapy was similar to those of both monotherapy treatments.