A possible interaction between favipiravir and methotrexate: Drug-induced hepatotoxicity in a patient with osteosarcoma

Abstract

Introduction Favipiravir is an antiviral agent that is recently used for SARS-CoV2 infection. The drug-drug interactions of favipiravir especially with chemotherapeutic agents in a patient with malignancy are not well known. Case report The patient diagnosed with metastatic osteosarcoma was given high dose methotrexate treatment, and favipiravir was started on the third day of the treatment with suspicion of SARS-CoV2 infection. Grade 3 hepatotoxicity developed after favipiravir. Management & outcome: The acute viral hepatitis panel and autoimmune liver disease panel were negative. The ultrasound of the abdomen was unremarkable for any hepatobiliary pathology. The all viral and hepatobiliary possible etiological factors were ruled out. The patient’s liver enzymes increased just after (12 hours later) the initiation of favipiravir, and we diagnosed toxic hepatitis caused by favipiravir-methotrexate interaction. Therefore, methylprednisolone 1 mg/kg dose was started for a presumed diagnosis of toxic hepatitis. Hepatotoxicity completely regressed after favipiravir was discontinued. Discussion Favipiravir may inhibit methotrexate elimination by inhibiting aldehyde oxidase and its sequential use may cause hepatotoxicity in this case. The clinicians should keep in mind possible drug interactions while using new antiviral agents against SARS-CoV2 like favipiravir.

Drug-Drug Interaction of Aldehyde Oxidase Inhibitor and Xanthine Oxidase Inhibitor with Favipiravir

“…Therefore, it can be thought that the inhibitory effect against AO decreases depending on the decrease in blood concentrations of drugs that inhibit AO (4). Demir et al suggested that favipiravir may inhibit methotrexate elimination by inhibiting aldehyde oxidase (13). Contrary to expectations, we found that when favipiravir was coadministered with verapamil, an AO inhibitor, Cl increased and t 1/2 , MRT, C max, and AUC values decreased.…”

“…Favipiravir is extensively metabolized to an inactive metabolite favipiravir-M1 (F-M1) by AO and lesser extent by XO in the liver and excreted by the renal route (11)(12)(13). Cytochrome P450 isoenzymes do not contribute to the metabolism of favipiravir (4,11).…”

Dissecting Parameters Contributing to the Underprediction of Aldehyde Oxidase-Mediated Metabolic Clearance of Drugs

“…Failure to sufficiently characterize AO mediated metabolism has led to inaccurate predictions of clearance resulting in either toxicity or poor exposure in humans, leading to discontinuation of compounds such as carbazeran, BIBX1382, FK3453, LuAF09535, and RO1 (Akabane et al, 2011;Dittrich et al, 2002;Jensen et al, 2017;Kaye et al, 1984. Recent reports such as methotrexate-induced liver toxicity due to inhibition of its metabolism following co-administration of an AO substrate and inhibitor, favipiravir (Demir et al, 2022) also indicate the possible role of AO in clinically significant drug-drug interactions (DDIs). AO shows wide species differences which makes the translation of toxicological data challenging.…”

Ontogeny of Human Liver Aldehyde Oxidase: Developmental Changes and Implications for Drug Metabolism

“…Recent reports such as methotrexateinduced liver toxicity due to inhibition of its metabolism following coadministration of an AO substrate and inhibitor, favipiravir, also indicate the possible role of AO in clinically significant drug−drug interactions (DDIs). 37 Anti-infective agents like famciclovir are approved for the treatment of opportunistic infections (herpes simplex virus, varicella zoster) in HIV-infected adolescents and are also recommended for HIV-infected children. 38 Low therapeutic index oncology drugs such as 6-mercaptopurine and methotrexate are metabolized partly by AO and are administered to children.…”