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Hepatotoxicity and rhabdomyolysis in kidney transplant patient with COVID-19: possible role of remdesivir and atorvastatin drug-drug-gene interactions

Introduction: Because of very variable clinical presentation of COVID-19 and polypharmacy in elderly, sometimes is difficult to distinguish between the drug-drug, disease-drug or drug- druggene induced side effects. Description: A 63–year old Caucasian woman with kidney transplant, was hospitalized due to COVID-19 infection. She was treated with remdesivir for 10 days along with meropenem and methylprednisolone. Mycophenolate was excluded for 10 days. Tacrolimus, atorvastatin, ramipril and ezetimibe were continued and furosemide and pantoprazole were added. After discharge, she started to feel muscle weakness in her extremities and laboratory results at admission showed elevated value of creatinine kinase (CK-MM 6975 U/L), AST (455 U/L), ALT (516 U/L). CK returned to the normal range and liver damage was resolved in two weeks following the cessation of atorvastatin and ezetimibe. Discussion: In this case atorvastatin and remdesivir were the most prominent candidates for drug-drug and drug-drug-gene interactions resulting in elevated CK and rhabdomyolysis as well as liver damage. Pharmacogenetic analysis showed that patient was a carrier of inactivating alleles of CYP2D6*1/*4, CYP3A4*1/*22, SLCO1B1 *5/*5. Remdesivir is substrate of CES1, CYP2D6, CYP3A4, OATP1B1(SLCO1B1) and inhibitor of CYP3A4 and SLCO1B1. Atorvastatin is substrate of CYP3A4 and OATP1B1 and can moderately inhibit the CES1 enzyme, the main metabolic pathway of remdesivir. Other concomitantly prescribed medicines, such as ezetimibe, furosemide and proton pump inhibitors could have added to the drug-drug-gene interactions. Conclusions: The pharmacogenetic profiling along with the assessment of drug interactions and pharmacokinetics in polypharmacy can significantly contribute to the minimization of the risk of developing side effects especially in a vulnerable subpopulation of patients such are the kidney transplant patient.

drug safety ; interactions ; multidisciplinary ; pharmacogenetic ; risk factors

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