Association between CES1, CYP3A genetic polymorphisms and remdesivir hepatotoxicity in patients with COVID-19

Temirbulatov I.I., Abdullaev Sh.P., Denisenko N.P., Kryukov A.V., Tuchkova S.N., Mirzaev K.B., Averkov O.V., Vechorko V.I., Sychev D.A.

1) Russian Medical Academy of Continuous Professional Education, Moscow, Russia; 2) City Clinical Hospital No. 15 n.a. O.M. Filatov, Moscow, Russia

Background. Hepatotoxicity is the most common adverse event associated with remdesivir treatment. Carboxylesterases (CES1 and CES2) and CYP3A are involved in remdesivir metabolism. Carriage of CES and CYP3A genetic polymorphisms may affect the pharmacokinetics and safety of drugs metabolized by these enzymes.
Objective. Assessment of the impact of CES1, CES2, CYP3A4*22 and CYP3A5*3 gene polymorphism carriage on the hepatotoxicity of remdesivir in hospitalized patients with COVID-19.
Methods. The study included 139 hospitalized patients. We determined the carriage of different allelic variants of the CES1 gene (rs2244613, rs2244614, rs8192950, rs8192935, rs2307240), CES2 (rs11075646), CYP3A4*22 (rs35599367) and CYP3A5*3 (rs776746) using real-time polymerase chain reaction. To assess liver damage, the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels before and after treatment were recorded. The incidence of hepatoxicity with remdesivir was compared between carriers of different polymorphisms of the studied genes.
Results. The AA genotype rs2244614, GG genotype rs8192950 and GG genotype rs8192935 of CES1 were associated with a three-fold increase in AST levels above the upper limit of normal. Carriage of the CYP3A5*3 (rs776746) GA genotype was associated with an increase in both ALT and AST levels 2-3 times above the upper limit of normal.
Conclusion. Carriage of homozygous polymorphic variants of CES1 and CYP3A5*3 can be considered as a potential marker of hepatotoxicity during remdesivir therapy in patients with COVID-19.

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About the Authors

Corresponding author: Ilyas I. Temirbulatov, Department of Clinical Pharmacology and Therapy n.a. Academician B.E. Votchal, Russian Medical Academy of Continuous Professional Education, Moscow, Russia; temirbulatov.ilyas@gmail.com

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