Explore the vast range of titles available.

Faldaprevir (FDV) is a novel NS3/NS4A inhibitor used in the treatment of hepatitis C infection in an interferon-free regimen. This study evaluated the safety, tolerability, and pharmacokinetics of FDV following a single dose in healthy male subjects and assessed the effect of food on FDV bioavailability. In the placebo-controlled, randomized, single-blind, single-increasing-dose part of the study (Part 1), 64 healthy male subjects were randomized to receive FDV in PEG/TRIS/meglumine solution at one of eight dose levels (4–1,200 mg, n = 6 per dose group) or placebo (n = 2 per dose group). In Part 2, the effect of food on the relative bioavailability (rBA) of 480 mg FDV in solution was evaluated in an open-label, crossover comparison, with and without a high-fat breakfast, in an additional 10 subjects (8 FDV and 2 placebo). Following single doses of 4–1,200 mg FDV, geometric mean (gMean) C max and AUC 0-inf were 3.57–16500 ng/mL and 254–402000 h*ng/mL, respectively, displaying more than dose-proportional increases in exposure. FDV was slowly absorbed, with gMean t 1/2 and median t max of 15.5–39.2 h and 4.0–14.0 h, respectively; both were dose dependent. The urinary excretion of FDV was less than 0.1% of the dose. A high-fat breakfast increased systemic exposure to FDV in solution by 14%. FDV was generally well tolerated; subjects who experienced adverse events (AEs) recovered without sequelae, and no serious AEs were reported. Indirect (unconjugated) bilirubin of >3.0 mg/dL was observed in two subjects at 480 mg and five subjects at 1,200 mg. In conclusion, at single doses of 4–1,200 mg in healthy male subjects, FDV showed dose-dependent pharmacokinetics and was generally considered safe and well tolerated. Food had no clinically relevant effect on the rBA of FDV.

Nevirapine (NVP) is a widely used non-nucleoside reverse transcriptase inhibitor. A once-daily extended-release (XR) formulation would potentially increase adherence and thus efficacy. The aim of this study was to investigate the steady-state bioavailability of 2 once-daily tablet formulations of NVP XR (containing 25% or 20% hypromellose; NVP XR25 and NVP XR20, respectively) in 400- or 300-mg tablets compared with twice-daily immediate-release (IR) NVP 200-mg tablets. This Phase Ib multinational, multicenter, open-label trial was conducted in patients aged 18 to 60 years, infected with HIV-1 (viral load, ≤50 copies/mL), and treated for ≥12 weeks with twice-daily NVP IR 200 mg. Patients were switched to NVP XR25 400 or 300 mg or NVP XR20 400 or 300 mg for 19 days. Plasma samples were collected over 24-hour periods at steady state. Primary end points were AUC 0–24,ss, C max,ss, and C min,ss, analyzed using an ANOVA statistical model on the logarithmic scale and 2-sided 90% CI. Sample size was determined assuming an intrasubject %CV of 20% for C max. Adverse events (AEs) and viral loads were monitored. Ninety-two patients were enrolled (NVP XR25 400 mg, 24 patients; NVP XR20 400 mg, 24; NVP XR25 300 mg, 21; NVP XR20 300 mg, 23). Compared with NVP IR, the AUC 0–24,ss values of the NVP XR formulations were lower (test/reference ratios: 79.5% [90% CI, 73.0–86.7; P = 0.544], 71.0% [90% CI, 63.3–79.7; P = 0.956], 90.3% [90% CI, 80.4–101.4; P = 0.044], and 83.7% [90% CI, 77.9–89.9; P = 0.148] with NVP XR25 400 mg, NVP XR20 400 mg, NVP XR25 300 mg, and NVP XR20 300 mg, respectively). The relative bioavailability of NVP XR25 was greater compared with that of NVP XR20. C max,ss values were lower with all NVP XR formulations compared with NVP IR. For C min,ss, NVP XR25 400 and 300 mg were not significantly different from NVP IR, with 90% CIs within the range of 80% to 125% ( P = 0.039 and P = 0.017, respectively). All AEs were mild or moderate, with no significant differences between treatment groups. No virologic failures (viral load, >50 copies/mL over 2 consecutive readings) were observed. Extent of bioavailability was lower and t max,ss was delayed with all NVP XR formulations compared with NVP IR. The bioavailability of the NVP XR25 formulations was greater than that of the NVP XR20 formulations. C min,ss with NVP XR25 was similar to that with NVP IR. All of the NVP XR formulations were well tolerated. The 400-mg NVP XR25 formulation was selected for further development.

Hepatitis C virus (HCV) infection is a serious cause of chronic liver disease worldwide with more than 170 million infected individuals at risk of developing significant morbidity and mortality 1 , 2 , 3 . Current interferon-based therapies 4 are suboptimal especially in patients infected with HCV genotype 1, and they are poorly tolerated, highlighting the unmet medical need for new therapeutics 5 , 6 . The HCV-encoded NS3 protease is essential for viral replication 7 , 8 and has long been considered an attractive target for therapeutic intervention in HCV-infected patients. Here we identify a class of specific and potent NS3 protease inhibitors and report the evaluation of BILN 2061, a small molecule inhibitor biologically available through oral ingestion and the first of its class in human trials. Administration of BILN 2061 to patients infected with HCV genotype 1 for 2 days resulted in an impressive reduction of HCV RNA plasma levels, and established proof-of-concept in humans for an HCV NS3 protease inhibitor. Our results further illustrate the potential of the viral-enzyme-targeted drug discovery approach for the development of new HCV therapeutics.