Faldaprevir

Faldaprevir (FDV), a substrate of CYP3A/P-glycoprotein (P-gp), is a selective inhibitor of the hepatitis C virus (HCV) NS3/4 protease. FDV is currently under clinical development for application in interferon-free treatment regimens for patients with chronic HCV infection. Understanding the drug-drug interaction potential of FDV is critical, as certain drug combinations may facilitate the more rapid achievement of steady-state-that is, the ideal drug concentration and balanced metabolic cycle of absorption and elimination that optimize drug efficacy. We thus conducted this study to investigate the effect of itraconazole (ICZ), a strong inhibitor of CYP3A and a moderate inhibitor of P-gp, on the pharmacokinetics (PK) of FDV. Eighteen healthy male and female volunteers participated in this open-label, fixed-sequence study. FDV 120 mg twice daily (BID) was administered on Day 1, followed by 120 mg once daily (QD) from Day 2 until the end of the 10-day study; after 6 days of FDV alone, ICZ 200 mg was added to FDV for an additional 4 days (BID on Day 7 and QD from Day 8 to Day 10). Intensive PK sampling was performed after 6 days of FDV treatment and again after 4 days of combined FDV/ICZ treatment. The adjusted geometric mean (gMean) ratios (%) of area under the concentration curve over dosing interval at steady-state (AUC_{τ, ss}) and maximal concentration at steady-state (C_{max, ss}) for combined FDV/ICZ treatment vs. FDV treatment alone were 198.6% and 180.6%, respectively, with 90% confidence intervals (CIs) of 182.4-216.1 and 165.7-196.9. Administration of FDV alone or in combination with ICZ was observed to be safe and well-tolerated. Co-administration with ICZ, however, resulted in an approximately two-fold increase in FDV steady-state exposure. Furthermore, FDV required no dosage adjustment when co-administered with ICZ.

Faldaprevir (FDV) is a potent, orally administered inhibitor of hepatitis C virus. In this single‐centre, open‐label, fixed‐sequence, crossover study of 32 healthy adult male and female volunteers, subjects received either a single dose of cyclosporine (CsA) 50 mg (N = 16) or tacrolimus (TAC) 0.5 mg (N = 16), followed by a washout of at least 14 days. Each subject then received a loading dose of FDV 240 mg followed by 120 mg FDV once daily for 6 days. FDV 120 mg was then co‐administered with an additional single dose of CsA (50 mg) or TAC (0.5 mg), followed by an additional 6 days of FDV 120 mg once daily. Intensive blood sampling was performed to assess the PK interaction potential. Assessment of relative BA indicated that exposure to CsA co‐administered with FDV was similar to CsA alone. However, the AUCτ,ssandCmax,ssof FDV were increased by 23% and 41%, respectively, when FDV was co‐administered with CsA. Exposure to TAC was slightly increased (AUC0‐∞increased by 27%, no change inCmax) when TAC was co‐administered with FDV. In contrast, exposure to FDV co‐administered with TAC was similar to FDV alone. No unexpected safety findings arose from the trial. The limitations of the study (use of single, low dose of TAC and CsA, and only healthy volunteers in the trial) are discussed.