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

作者：Amy Q. Wang, Natalie R. Hagen, Elias Carvalho Padilha, Mengbi Yang, Pranav Shah, Catherine Z. Chen, Wenwei Huang, Pramod Terse, Philip E.J. Sanderson, Wei Zheng, Xin Xu · 发表于：Frontiers in Pharmacology · 年份：2022 · DOI：10.3389/fphar.2022.918083 · 被引用次数：31 · 研究领域：COVID-19 Clinical Research Studies、Pharmacological Receptor Mechanisms and Effects、Drug-Induced Hepatotoxicity and Protection

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 (CL p ), ranging from 4.1 mL/min/kg in dogs to 26 mL/min/kg in mice; the steady state volume distribution (Vd ss ) 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.