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 480 mg following single and up to 400 mg following multiple once‐daily doses. The half‐life ranged from 52 to 83 hours, and steady state was reached between 8 and 13 days. 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 1.5 hour 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 600 mg following single and up to 200 mg following multiple once‐daily doses. Considering a therapeutic dose of 100 mg once‐daily, pritelivir demonstrated a favorable safety and tolerability and pharmacokinetic profile in healthy subjects to support further development.

Mass Balance and Metabolite Profile after Single and Multiple Oral Doses of Pritelivir in Healthy Subjects

“…The oral loading dose was used to reach steady state more quickly as pritelivir is known to have a long halflife (52-83 hours). 10 The dose on day 8 was spiked with 14 C-pritelivir labeled at the pyridinyl phenyl acetic moiety. The second trial (Trial 2) was performed using a single oral dose of 100 mg pritelivir spiked with 14 Cpritelivir labeled at the pyridinyl phenyl acetic moiety and 14 C-pritelivir labeled at the amino thiazole sulfonamide moiety.…”

“…Blood samples (3 mL at each time point) for PK analysis of total radioactivity (TRA) were collected predose on day 1 and day 8, and at 0.25, 0.5, 0.75, 1, 1. 5,2,3,4,5,6,8,10,24,48,96,144,192,240,288,336,384,432,480,528,576, and 624 hours postdose on day 8. Blood samples (10 mL each time point) for metabolite profiling were collected at 2,4,24,48,96,144,192,240,288,336,384,432,480, and 624 hours postdose on day 8.…”

“…Blood samples for PK analysis of TRA in plasma and blood (4 mL for plasma and 2 mL for blood) were collected predose on day 1 and postdose at 0.25, 0.5, 0.75, 1, 1. 5,2,3,4,5,6,8,10,24,48,60,72,96,120,144,168,192,216,240,288,336,384,432,480,528,576, and 624 hours. Additional blood samples of 4 mL were collected for metabolite profiling on day 1 postdose at 2, 4, 24, 480, and 624 hours.…”

“…This formation was mainly mediated by cytochrome P450 (CYP)3A4, which was concluded based on experiments using inhibitors and recombinant CYP enzymes. Approximately half of the loss of parent drug in suspended human hepatocytes was attributed to nonenzymatic hydrolysis as examined in the presence and absence of 1‐aminobenzotriazole (1‐ABT), an inactivator of most CYP enzymes 10 . Metabolite identification studies conducted in mice, rats, minipigs, and monkeys showed that pyridinyl phenyl acetic acid (PPA) was the main circulating metabolite in plasma.…”

“…Approximately half of the loss of parent drug in suspended human hepatocytes was attributed to nonenzymatic hydrolysis as examined in the presence and absence of 1-aminobenzotriazole (1-ABT), an inactivator of most CYP enzymes. 10 Metabolite identification studies conducted in mice, rats, minipigs, and monkeys showed that pyridinyl phenyl acetic acid (PPA) was the main circulating metabolite in plasma. Hydroxylated pritelivir, formed by oxidation at the methyl-1,3-thiazole moiety (catalyzed by CYP3A4), was also detected.…”