Pharmacokinetics, Safety, and Tolerability Following Single and Multiple Doses of Pibrentasvir in a First-in-Human Study.

This first-in-human dose-ascending study investigated pharmacokinetics, safety, and tolerability of pibrentasvir following single and multiple doses in healthy volunteers. Additionally, the effects of food and ritonavir on pibrentasvir were assessed in a crossover study design. The starting dose of pibrentasvir was selected based on the no-observed-adverse-effect-level exposure from preclinical studies. Dose escalations of subsequent cohorts were dependent on reviews of the safety, tolerability, and pharmacokinetic data from previous dose cohorts. Pibrentasvir exposures increased in a greater than dose-proportional manner across the 1.5- to 120-mg dose range and became linear across the 120- to 600-mg dose range. Following multiple dosing, pibrentasvir steady state was attained by day 5 with an accumulation ratio of 25% to 35%. Pibrentasvir harmonic mean terminal half-life ranged from 20 to 22 hours. Food had minimal effect (<14%) on pibrentasvir bioavailability, but ritonavir increased pibrentasvir peak concentration and area under the concentration-time curve by 60% and 89%, respectively. All adverse events were assessed by the investigator as mild, and no clinically significant vital signs, electrocardiogram, or clinical laboratory values were observed. The pharmacokinetic results from this study support once-daily dosing and administration of pibrentasvir without regard to food. A maximum tolerated dose was not attained in the single- and multiple-ascending-dose assessments for pibrentasvir.