A Phase I, Single- and Multiple-dose Study to Evaluate the Pharmacokinetics of Elbasvir and Grazoprevir in Healthy Chinese Participants

Abstract Purpose This study evaluated the single- and multiple-dose pharmacokinetic (PK) variables of elbasvir and grazoprevir in healthy Chinese individuals. Methods This study was a 2-part, parallel-arm, open-label trial. In part 1, single-dose PK variables of elbasvir 10/50/100 mg and grazoprevir 50/100/200 mg were evaluated in 10 participants per drug. In part 2, 10-day multiple-dose PK variables of elbasvir 50 mg and grazoprevir 100 mg administered once daily alone and in combination were evaluated in 12 participants. Summary and inferential statistics of the PK parameters are reported. Elbasvir and grazoprevir PK parameters were also compared between Chinese participants and historical data from white participants. Findings Single-dose elbasvir and grazoprevir median T max were 2.9 to 4.0 and 1.9 to 3.0 hours after administration, respectively. Elbasvir AUC 0–∞ and C max increased in a dose-proportional manner (slope estimate [90% CI], 0.92 [0.84–1.01] and 0.98 [0.86–1.09], respectively), whereas grazoprevir AUC 0–∞ and C max increased in a greater-than-dose-proportional manner (slope estimate [90% CI], 1.42 [1.27–1.57] and 1.96 [1.64–2.29]). After repeated administration, the accumulation ratios for AUC 0–24 , 24-hour concentration, and C max were 1.55, 1.57, and 1.38 for elbasvir and 2.03, 1.23, and 2.51 for grazoprevir. Co-administration of elbasvir 50 mg and grazoprevir 100 mg once daily did not have a clinically relevant effect on the PK variables of either drug. Median T max after co-administration versus alone was 3.0 hours versus 3.0 hours for elbasvir and 3.1 hours versus 3.0 hours for grazoprevir. Geometric mean ratios (90% CI) for elbasvir and grazoprevir AUC 0–24 (Chinese/white participants) were 1.58 (1.03–2.42) and 1.21 (0.76–1.92). Elbasvir and grazoprevir, administered alone or concomitantly, were well tolerated. Implications In healthy Chinese individuals, administration of elbasvir and grazoprevir, alone or concomitantly, was generally well tolerated, with a thoroughly characterized PK profile. Elbasvir and grazoprevir exposures may trend higher in Chinese healthy participants relative to white healthy participants. Protocol number MK-5172 PN022.