First-in-Human, Single- and Multiple-Ascending-Dose, Food-Effect, and Absolute Bioavailability Trials to Assess the Pharmacokinetics, Safety, and Tolerability of Pritelivir, a Nonnucleoside Helicase-Primase Inhibitor Against Herpes Simplex Virus in Healthy Subjects.

Abstract

The pharmacokinetics and safety of the novel herpes simplex virus helicase-primase inhibitor pritelivir were evaluated in 5 phase 1 trials: a single-ascending-dose trial, 2 multiple-ascending-dose trials, a food-effect trial, and an absolute bioavailability trial in healthy male subjects. One cohort of healthy female subjects was included in the single-ascending-dose trial. Pritelivir pharmacokinetics were linear up to 480mg following single and up to 400mg following multiple once-daily doses. The half-life ranged from 52 to 83hours, and steady state was reached between 8 and 13days. Maximum plasma concentration and area under the plasma concentration-time curve from time 0 to the last quantifiable concentration were 1.5- and 1.1-fold higher in female compared to male subjects. Absolute bioavailability was 72% under fasted conditions. Following a fatty diet, pritelivir time to maximum concentration was 1.5hour delayed and maximum plasma concentration and area under the plasma concentration-time curve from time 0 to the last quantifiable concentration were 33% and 16% higher, respectively. Pritelivir was safe and well tolerated up to 600mg following single and up to 200mg following multiple once-daily doses. Considering a therapeutic dose of 100mg once-daily, pritelivir demonstrated a favorable safety and tolerability and pharmacokinetic profile in healthy subjects to support further development.