Nucleoside analog GS-441524: pharmacokinetics in different species, safety, and potential effectiveness against Covid-19
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Nucleoside analog GS-441524 : pharmacokinetics in different species, safety, and potential effectiveness against Covid-19. / Rasmussen, Henrik Berg; Thomsen, Ragnar; Hansen, Peter Riis.
In: Pharmacology Research and Perspectives, Vol. 10, No. 2, e00945, 2022.Research output: Contribution to journal › Review › Research › peer-review
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TY - JOUR
T1 - Nucleoside analog GS-441524
T2 - pharmacokinetics in different species, safety, and potential effectiveness against Covid-19
AU - Rasmussen, Henrik Berg
AU - Thomsen, Ragnar
AU - Hansen, Peter Riis
N1 - Publisher Copyright: © 2022 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.
PY - 2022
Y1 - 2022
N2 - GS-441524, the parent nucleoside of remdesivir, has been proposed to be effective against Covid-19 based on in vitro studies and studies in animals. However, randomized clinical trials of the agent to treat Covid-19 have not been conducted. Here, we evaluated GS-441524 for Covid-19 treatment based on studies reporting pharmacokinetic parameters of the agent in mice, rats, cats, dogs, monkeys, and the single individual in the first-in-human trial supplemented with information about its activity against severe acute respiratory syndrome coronavirus 2 and safety. A dosing interval of 8 h was considered clinically relevant and used to calculate steady-state plasma concentrations of GS-441524. These ranged from 0.27 to 234.41 μM, reflecting differences in species, doses, and administration routes. Fifty percent maximal inhibitory concentrations of GS-441524 against severe acute respiratory syndrome coronavirus 2 ranged from 0.08 μM to above 10 μM with a median of 0.87 μM whereas concentrations required to produce 90% of the maximal inhibition of the virus varied from 0.18 µM to more than 20 µM with a median of 1.42 µM in the collected data. Most of these concentrations were substantially lower than the calculated steady-state plasma concentrations of the agent. Plasma exposures to orally administered GS-441524, calculated after normalization of doses, were larger for dogs, mice, and rats than cynomolgus monkeys and humans, probably reflecting interspecies differences in oral uptake with reported oral bioavailabilities below 8.0% in cynomolgus monkeys and values as high as 92% in dogs. Reported oral bioavailabilities in rodents ranged from 12% to 57%. Using different presumptions, we estimated human oral bioavailability of GS-441524 at 13% and 20%. Importantly, doses of GS-441524 lower than the 13 mg/kg dose used in the first-in-human trial may be effective against Covid-19. Also, GS-441524 appears to be well-tolerated. In conclusion, GS-441524 has potential for oral treatment of Covid-19.
AB - GS-441524, the parent nucleoside of remdesivir, has been proposed to be effective against Covid-19 based on in vitro studies and studies in animals. However, randomized clinical trials of the agent to treat Covid-19 have not been conducted. Here, we evaluated GS-441524 for Covid-19 treatment based on studies reporting pharmacokinetic parameters of the agent in mice, rats, cats, dogs, monkeys, and the single individual in the first-in-human trial supplemented with information about its activity against severe acute respiratory syndrome coronavirus 2 and safety. A dosing interval of 8 h was considered clinically relevant and used to calculate steady-state plasma concentrations of GS-441524. These ranged from 0.27 to 234.41 μM, reflecting differences in species, doses, and administration routes. Fifty percent maximal inhibitory concentrations of GS-441524 against severe acute respiratory syndrome coronavirus 2 ranged from 0.08 μM to above 10 μM with a median of 0.87 μM whereas concentrations required to produce 90% of the maximal inhibition of the virus varied from 0.18 µM to more than 20 µM with a median of 1.42 µM in the collected data. Most of these concentrations were substantially lower than the calculated steady-state plasma concentrations of the agent. Plasma exposures to orally administered GS-441524, calculated after normalization of doses, were larger for dogs, mice, and rats than cynomolgus monkeys and humans, probably reflecting interspecies differences in oral uptake with reported oral bioavailabilities below 8.0% in cynomolgus monkeys and values as high as 92% in dogs. Reported oral bioavailabilities in rodents ranged from 12% to 57%. Using different presumptions, we estimated human oral bioavailability of GS-441524 at 13% and 20%. Importantly, doses of GS-441524 lower than the 13 mg/kg dose used in the first-in-human trial may be effective against Covid-19. Also, GS-441524 appears to be well-tolerated. In conclusion, GS-441524 has potential for oral treatment of Covid-19.
KW - coronavirus disease 2019
KW - GS-441524
KW - in vitro–in vivo extrapolation
KW - nucleoside analog
KW - pharmacokinetics
U2 - 10.1002/prp2.945
DO - 10.1002/prp2.945
M3 - Review
C2 - 35396928
AN - SCOPUS:85127818768
VL - 10
JO - Pharmacology Research & Perspectives
JF - Pharmacology Research & Perspectives
SN - 2052-1707
IS - 2
M1 - e00945
ER -
ID: 306591860