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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, Tong; Pawlak, Sylvester; Toussi, Sima S; Hackman, Frances; Thompson, Kimberly; Song, Wei; Salageanu, Joanne; Winter, Erica; Shi, Haihong; Winton, Jennifer; Binks, Michael.
  • Zhu T; Pfizer Worldwide Research, Development and Medical, Cambridge, Massachusetts, USA.
  • Pawlak S; Pfizer Clinical Research Unit, New Haven, Connecticut, USA.
  • Toussi SS; Pfizer Worldwide Research, Development and Medical, Pearl River, New York, USA.
  • Hackman F; Pfizer Worldwide Research, Development and Medical, Cambridge, UK.
  • Thompson K; Pfizer Clinical Research Unit, New Haven, Connecticut, USA.
  • Song W; Pfizer Worldwide Research, Development and Medical, Groton, Connecticut, USA.
  • Salageanu J; Pfizer Global Product Development, Groton, Connecticut, USA.
  • Winter E; Pfizer Global Product Development, Groton, Connecticut, USA.
  • Shi H; Pfizer Global Product Development, Groton, Connecticut, USA.
  • Winton J; Pfizer Global Product Development, Groton, Connecticut, USA.
  • Binks M; Pfizer Worldwide Research, Development and Medical, Cambridge, Massachusetts, USA.
Clin Pharmacol Drug Dev ; 11(12): 1382-1393, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-2085007
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Prodrugs / COVID-19 Drug Treatment Type of study: Cohort study / Experimental Studies / Observational study / Prognostic study / Randomized controlled trials Topics: Vaccines Limits: Adult / Humans Language: English Journal: Clin Pharmacol Drug Dev Year: 2022 Document Type: Article Affiliation country: Cpdd.1174

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Prodrugs / COVID-19 Drug Treatment Type of study: Cohort study / Experimental Studies / Observational study / Prognostic study / Randomized controlled trials Topics: Vaccines Limits: Adult / Humans Language: English Journal: Clin Pharmacol Drug Dev Year: 2022 Document Type: Article Affiliation country: Cpdd.1174