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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

Zhu et al., Clinical Pharmacology in Drug Development, doi:10.1002/cpdd.1174, NCT04627532
Oct 2022  
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Phase 1 randomized, double-blind, placebo-controlled study of 15 healthy participants showing safety and tolerability of single ascending 24-hour IV infusions of lufotrelvir (PF-07304814), a phosphate prodrug protease inhibitor targeting the 3CL protease of SARS-CoV-2, at doses of 50 to 700 mg. No serious adverse events, treatment discontinuations or deaths were reported, and all adverse events were mild. Dose-proportional pharmacokinetics of the active moiety PF-00835231 were observed, with rapid conversion from the prodrug and sustained plasma concentrations during the infusion period. The results suggest a daily dose of 270-350 mg administered as a 24-hour continuous infusion is expected to maintain the steady-state concentration of PF-00835231 at potentially therapeutic levels.
Zhu et al., 26 Oct 2022, Double Blind Randomized Controlled Trial, placebo-controlled, USA, peer-reviewed, 11 authors, study period 23 October, 2020 - 17 December, 2020, trial NCT04627532 (history). Contact:
This PaperLufotrelvirAll
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
PhD Tong Zhu, Sylvester Pawlak, Sima S Toussi, Frances Hackman, Kimberly Thompson, Wei Song, Joanne Salageanu, Erica Winter, Haihong Shi, Jennifer Winton, Michael Binks
Clinical Pharmacology in Drug Development, doi:10.1002/cpdd.1174
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.
After Dosing (h) After Dosing (h) Conflicts of Interest All authors are employees of Pfizer, Inc. and may hold stock/stock options in Pfizer.
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Dn, dose normalized AUC last ; C 24 , concentration at 24 hours; C max , maximum observed concentration; C ss , concentration at steady state; dn, dose normalized; N, number of participants in the treatment group contributing to summary statistic; NC, not calculated; NR, not reported; PK, pharmacokinetics; SD, standard deviation; t 1/2 , terminal half-life; t max , time to maximum concentration. a Geometric mean (geometric % coefficient of variation) and arithmetic mean
Dn, h/mL/mg NC, NC NC
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Ss, mL/mg 1, 1
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