Safety, Tolerability, and Pharmacokinetics of Intravenous Doses of PF-07304814, a Phosphate Prodrug Protease Inhibitor for the Treatment of SARS-CoV-2, in Healthy Adult Participants.

Abstract

Studies on targeted antivirals for treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of the ongoing pandemic, are limited. PF-07304814 (lufotrelvir) is the phosphate prodrug of PF-00835231, a protease inhibitor targeting the 3C-like protease of SARS-CoV-2. This phase 1 study evaluated the safety, tolerability, and pharmacokinetics (PK) of single ascending intravenous doses of lufotrelvir (continuous 24-hour infusion of 50, 150, 500, or 700 mg) versus placebo in healthy volunteers (2 interleaving cohorts: 1, n = 8; 2, n = 7). Each dosing period was separated by a washout interval (≥5 days). Treatment-emergent adverse events, PK, and biomarker concentrations were estimated from plasma/urine samples. Lufotrelvir was administered to 15 volunteers (mean [SD] age 39.7 [11.8] years). No serious adverse events, discontinuations, or deaths were reported. Mean maximum observed concentration of PF-00835231 (active moiety; 97.0 ng/mL to 1288 ng/mL) were observed between median time to maximum concentration of 14 to 16 hours after the start of the lufotrelvir infusion. Near-maximum plasma concentrations of PF-00835231 were observed ≈6 hours after infusion start and sustained until infusion end. PF-00835231 plasma concentrations declined rapidly after infusion end (mean terminal half-life: 500 mg, 2.0 hours; 700 mg, 1.7 hours). Approximately 9%-11% of the dose was recovered in urine as PF-00835231 across doses. A continuous, single-dose, 24-hour infusion of lufotrelvir (50-700 mg) was rapidly converted to PF-00835231 (active moiety), with dose-proportional PK exposures and no significant safety concerns. A daily, 24-hour continuous infusion of 270 to 350 mg is expected to maintain PF-00835231 concentration at steady state/above effective antiviral concentrations. Further studies exploring lufotrelvir efficacy in patients with coronavirus disease 2019 are ongoing.

• Authors: Tong Zhu, Sylvester Pawlak, Sima S Toussi, Frances Hackman, Kimberly Thompson, Wei Song, Joanne Salageanu, Erica Winter, Haihong Shi, Jennifer Winton, Michael Binks
• Journal: Clinical pharmacology in drug development (Clin Pharmacol Drug Dev) Vol. 11 Issue 12 Pg. 1382-1393 (12 2022) ISSN: 2160-7648 [Electronic] United States
• PMID: 36285536 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2022, The American College of Clinical Pharmacology.

Chemical References

• Antiviral Agents
• Indoles
• Organophosphates
• Phosphates
• Prodrugs
• Protease Inhibitors
• Pyrrolidinones

Topics

• Adult
• Humans
• Antiviral Agents (adverse effects)
• COVID-19 Drug Treatment
• Healthy Volunteers
• Indoles
• Organophosphates
• Phosphates
• Prodrugs (adverse effects)
• Protease Inhibitors (adverse effects)
• Pyrrolidinones
• SARS-CoV-2