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

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

JOURNAL=Frontiers in Pharmacology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.918083

DOI=10.3389/fphar.2022.918083

ISSN=1663-9812

ABSTRACT=<p>Preclinical pharmacokinetics (PK) and <italic>In Vitro</italic> ADME properties of GS-441524, a potential oral agent for the treatment of Covid-19, were studied. GS-441524 was stable <italic>in vitro</italic> 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 <italic>in vitro</italic> 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 (CL<sub>p</sub>), ranging from 4.1 mL/min/kg in dogs to 26 mL/min/kg in mice; the steady state volume distribution (Vd<sub>ss</sub>) ranged from 0.9 L/kg in dogs to 2.4 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.</p>