Preclinical Pharmacokinetics and In Vitro Properties of GS-441524, A Potential Oral Drug Candidate for COVID-19 Treatment

Authors: Wang AQ, Hagen NR, Padilha EC, Yang M, Shah P, Chen CZ, Huang W, Terse P, Sanderson P, Zheng W, Xu X
Publication: bioRxiv
Keywords: dose slection, fih, FIHSimulator, first-in-human, gastroplus, IVIVE, mechanistic absorption, PBPK modeling, physiologically based pharmacokinetics
Software: GastroPlus®

Abstract

Preclinical pharmacokinetics (PK) and in vitro ADME properties of GS-441524, a potential oral agent for the treatment of Covid-19, were studied. GS-441524 was stable in vitro in liver microsomes, cytosols, and hepatocytes of mice, rats, monkeys, dogs, and humans. The plasma free fractions of GS-441524 were 62-78% across all studied species. The in vitro transporter study results showed that GS-441524 was a substrate of MDR1, BCRP, CNT3, ENT1, and ENT2; but not a substrate of CNT1, CNT2, and ENT4. GS-441524 had a low to moderate plasma clearance (CLp), ranging from 4.1 mL/min/kg in dogs to 26 mL/min/kg in mice; the steady state volume distribution (Vdss) ranged from 0.9 L/kg in dogs to 2.2 L/kg in mice after IV administration. Urinary excretion appeared to be the major elimination process for GS-441524. Following oral administration, the oral bioavailability was 8.3% in monkeys, 33% in rats, 39% in mice, and 85% in dogs. The PK and ADME properties of GS-441524 support its further development as an oral drug candidate.

By Amy Q. Wang, Natalie R. Hagen, Elias C. Padilha, Mengbi Yang, Pranav Shah, Catherine Z. Chen, Wenwei Huang, Pramod Terse, Philip Sanderson, Wei Zheng, Xin Xu