All patients participated in either a sparse population-pharmacokinetic (PK) cohort or in an optional intensive-PK cohort, which involved a more intensive schedule of sample collection. Patients who participated in the population-PK cohort were stratified based on HCV genotype (i.e., 1a versus other genotype 1 subtypes). Plasma concentrations of vaniprevir were determined Ixazomib in vitro using liquid-liquid extraction, followed by high-performance liquid chromatography/tandem mass

spectrometry analysis. The lower limit of quantitation (LOQ) for the plasma assay was 1 ng/mL (1.32 nM) and the linear calibration range was 1-1,000 ng/mL. Sparse population PK samples were collected on selected days up to week 72. In addition, samples were also collected at multiple time points over the 12- or 24-hour dosing period for the subset of patients (∼4-8 patients per treatment group) included in the intensive-PK cohort. For all patients, the concentration

of drug in the plasma at 2 hours after dose and the trough concentration of drug in the plasma (Ctrough: concentration of drug in the plasma at 12 hours after dose for BID regimens and concentration of drug in the plasma at 24 hours after dose [C24h] for QD regimens) were assessed. The following additional plasma PK parameters were assessed for the intensive-PK cohort: area under the plasma-concentration versus time curve (AUC0-12h see more for the BID regimens and AUC0-24h for the QD regimens), time to reach maximum concentration (Cmax) (Tmax), and accumulation ratio, as appropriate. The accumulation of vaniprevir was determined by calculating the ratio of the PK parameter value (i.e., AUC, Cmax, and Ctrough) on days 28 and 1. WinNonlin (Pharsight Corporation, Mountain

View, CA) was used to determine PK parameters. The primary efficacy endpoint was the proportion of patients achieving RVR, defined as plasma HCV RNA below the limit of detection (LOD) at week 4. Exploratory efficacy endpoints included the proportion of patients achieving EVR (defined as plasma HCV RNA below the LOD at week 12) and the proportion of patients achieving SVR Thymidine kinase (defined as plasma HCV RNA below the LOD 24 weeks after completing treatment with Peg-IFN and RBV). The per-protocol (PP) population was predefined as the primary efficacy-analysis population. This excluded patients who had important deviations from the protocol, such as those taking prohibited medications or who fell below predetermined levels of compliance required for each component of the treatment. Only patients with HCV RNA results at week 4 were included in the analysis of RVR using the predefined missing primary data approach of data as observed (i.e., missing data were not replaced).