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.

Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Intravenous Infusions of PF-07304814 (Lufotrelvir) in Participants Hospitalized With COVID-19

“…Subsequently, good laboratory practice data from 2-week continuous infusion toxicology studies in rats and monkeys became available to support the enrollment of participants in MAD. A study in healthy volunteers was also initiated (C4611007) that provided data to inform a starting MAD dose for C4611001 [ 21 ]. The notable finding in the monkey study was an exacerbation at higher doses of commonly observed infusion procedure‒related effects of inflammation and thromboemboli.…”

“…After a single 500-mg dose of lufotrelvir, the maximum plasma concentration, C ss , and area under the curve for PF-00835231 were higher among participants in this study compared with healthy volunteers, whereas t ½ was similar between healthy participants and patients [ 21 ]. However, the small number of participants in this study preclude definitive comparisons between the studies.…”

“…Evaluation of the plasma PK of the prodrug lufotrelvir and the active moiety PF-00835231 was a secondary endpoint. Plasma samples obtained at prespecified time points were analyzed with a validated, sensitive, and specific method of liquid chromatography‒tandem mass spectrometry [ 21 ]. In the SAD group, plasma samples were collected before treatment was started and then at 6, 24, 28, and 48 hours of the start of infusion.…”