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

Wang, A. Q.; Hagen, N. R.; Padilha, E. C.; Yang, M.; Shah, P.; Chen, C. Z.; Huang, W.; Terse, P.; Sanderson, P.; Zheng, W.; Xu, X.

doi:10.1101/2022.02.07.478848

bioRxiv · 10.1101/2022.02.07.478848

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

Wang, A. Q.·Hagen, N. R.·Padilha, E. C.·Yang, M.·Shah, P.·Chen, C. Z.·Huang, W.·Terse, P.·Sanderson, P.·Zheng, W.·Xu, X.

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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.

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Wang, A. Q., Hagen, N. R., Padilha, E. C., Yang, M., Shah, P., Chen, C. Z., Huang, W., Terse, P., Sanderson, P., Zheng, W., Xu, X.. 2022-02-07. Preclinical Pharmacokinetics and In Vitro Properties of GS-441524, A Potential Oral Drug Candidate for COVID-19 Treatment. https://doi.org/10.1101/2022.02.07.478848

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