key: cord-1011692-8tldrtcb authors: Jafari, Anya; Dadkhahfar, Sahar; Perseh, Sahra title: Considerations for interactions of drugs used for the treatment of COVID-19 with anti-Cancer treatments date: 2020-05-12 journal: Crit Rev Oncol Hematol DOI: 10.1016/j.critrevonc.2020.102982 sha: 105b3e6e0666802c9929e8734bbbd99d801f5bf0 doc_id: 1011692 cord_uid: 8tldrtcb SARS-CoV2 infection is an emerging issue worldwide. Cancer patient are at increased risk of infection compared to general population. On the other hand, these patients are at major risk of drug interactions caused by renal and hepatic impairment background. Because of the long-term use of chemotherapy drugs, drug interactions are important in these patients especially with SARS-CoV2 treatments now. This paper is review of reported drug interactions of current treatments for COVID-19 and anticancer agents. The novel coronavirus (SARS-CoV2) has caused a growing pandemic and global issue now (Zhou et al., 2020) . Cancer patients are at a greater risk of catastrophic outcomes of Coronavirus infectious disease 2019 because of the older age, immunosuppressive condition and combined comorbidity. Cancer patients may become infected by SARS-CoV2 during chemotherapy or may need to receive chemotherapy after the resolution of their disease and receiving coronavirus treatment (Wang and Zhang, 2020) . Here we reviewed drug interactions of current covid-19 drugs with antineoplastic agents. Montamat SC et al, said that the risk of drug interactions is higher in cancer patient due to their underlying disease, older age and consumption of multiple medications (Montamat et al., 1989) . The current paper is a review of the reported and expected drug interactions of current treatments for COVID-19 and anticancer agents. Drug-drug interactions (DDIs) commonly happen when two drugs with DDIs administered before 4-5 half-lives of one of them (Ito, 2011) . DDIs can cause three results: decreased therapeutic effect/adverse effects, enhanced therapeutic effect/adverse effects or a new side effect that does not occur with each drug separately. In pharmacodynamic interaction, both drugs affect the same physiologic pathway (Blower et al., 2005) . This effect can be inhibitory or inducible. Pharmacokinetic interaction happens when one drug influences other drug's absorption, distribution, metabolism or excretion (Blower et al., 2005) . Drugs may affect the GI motility or PH, serum albumin concentration which can affect another drug absorption or distribution (Blower et al., 2005) . Cytochrome P450 (CYP) with more than 50 isoenzymes is responsible for most of drug metabolism in liver. One drug can stimulate or inhibit its own CYP isoenzyme or other isoenzymes with further influencing the metabolism of other drugs that are metabolized with the same isoenzyme (Zhang et al., 2009 ). Another site of drug interactions occurs at P-glycoprotein that plays an important role in transporting drugs into cell on the cell membrane (Blower et al., 2005; Zhang et al., 2009 ). The most common proposed treatments for COVID-19 include chloroquine and hydroxychloroquine, azatinavir/ritonavir, lopinavir/ritonavir, J o u r n a l P r e -p r o o f remdesivir, tocilizumab and favipiravir (Baden, Lindsey R and Rubin, Eric J, 2020; Cascella et al., 2020; Dong et al., 2020; Guo et al., 2020) . Chloroquine (CQ) and hydroxychloroquine (HCQ) are both 4aminoquinoline agents that historically known as antimalaria drug from 1940s (Verbaanderd et al., 2017) . These drugs have been used for treatment of rheumatoid arthritis, lupus erythematous, AIDS and recently COVID-19 (Ito, 2011; Solomon and Lee, 2009 Leuprolide, Goserelin, Triptorelin, (Garnick, 2005) Eribulin (Perry, 2011) , Ribociclib (Syed, 2017) , Inotuzumab (Kebriaei et al., 2018) , Gemtuzumab (Selby et al., 2019) , Lenvatinib (Frampton, 2016) , Dasatinib (Keam, 2008) , Nilotinib (Kim et al., 2012) , Cabozantinib and Ceritinib (Shah and Morganroth, 2015) , Methadone (Barkin et al., 1998) Oxaliplatin (Chang et al., 2013) Ondansetron (Charbit et al., 2005) Increase Q-T prolongation probability (Haouala et al., 2011) , Abiraterone (Benoist et al., 2016) , Bicalutamide (Meulenbeld et al., 2013) , Aprepitant (Majumdar et al., 2003) , Imatinib (Majumdar et al., 2003) Increase the level of CQ Protease inhibitors (PIs) such as atazanavir, ritonavir, lopinavir have been for treatment of COVID-19 (Baden, Lindsey R. and Rubin, Eric J., 2020). Lopinavir is used in combination with ritonavir-Kaletra-to increase the lopinavir's bioavailability (Eckhardt and Gulick, 2017) . Reported half of lopinavir/ritonavir and atazanavir/ritonavir are 2-7/3-4 hours, 8-9/5-6 hours, respectively (Boffito et al., 2008; Chandwani and Shuter, 2008) . About 85-95% of these drugs bind to plasma proteins and metabolized in liver mainly by CYP3A4 isoenzyme (Makinson et al., 2010) . Lopinavir is metabolized by CYP3A4 and on the other hand ritonavir is a potent inhibitor of CYP3A4, so the coadministration of them leads an increase in the effect of lopinavir; therefore, lopinavir is not used alone (Berretta et al., 2016; Makinson et al., 2010; Rudek et al., 2011) . Atazanavir, lopinavir/ritonavir also associated with Q-T interval prolongation so should be prescribed with caution with drugs with the same side effect such as tamoxifen, anthracyclines, dasatninb, lapatinib, nilotinib and sunitinib (Table-2 Favipiravir is a pyrazine analog, originally made in Japan, oseltamivir resistant influenza (Furuta et al., 2013) . The drug inhibits RNA-dependent RNA polymerase enzymes leading to prevention of virus replication (Furuta et al., 2009 ). The elimination half-life is about 2-5.5 hours with a protein binding of 54% in plasma and metabolized by aldehyde oxidase (AO) and xanthine oxidase to its metabolite, T705M1, in liver and excreted to urine. (Du and Chen, 2020) Dose adjustment based on hepatic impairment is not needed however there is not enough humanized study about it (Du and J o u r n a l P r e -p r o o f Chen, 2020). The proposed dose for COVID-19 is the loading dose of 3200 mg on day 1 and maintenance dose of 1200 mg on day2-14. (Du and Chen, 2020 ) Main side effects of favipiravir include mild to moderate diarrhea, elevated liver enzymes, testicular toxicity, increased blood uric acid and decrease in neutrophil count (2011). The rate of Q-T prolongation is low (8%) (2011). There is limited clinical data about DDIs and metabolism of favipiravir. In vivo study showed inhibitory effect of favipiravir on CYP2C8 isoenzyme (2011). As well as, other study revealed favipiravir inhibits AO (Du and Chen, 2020) . So, more caution was necessary when used AO inhibitors such as tamoxifen or CYP2C8 substrates like paclitaxel with favipiravir (2011). Ivermectin is a broad spectrum antiparasitic agent that recently reported to have in vivo effect on SARS-CoV2 virus with 98% elimination rate of virus RNA in or out of cells (Caly et al., 2020) . It is used by oral or subcutaneous route and metabolized in liver by CYP3A4 isoenzyme (Canga et al., 2008; Zeng et al., 1998) . Ivermectin binds to plasma protein by rate of 93% and is mainly excreted in feces. (Klotz et al., 1990) . Its half-life based on administration route is around 12-20 hours (Canga et al., 2008) . The absorption, distribution and elimination of ivermectin is dependent on Pglycoprotein, on the other hand, it is a potent inhibitor of P-glycoprotein (Ménez et al., 2012) . The main interactions of this drug are caused by its effects on P-glycoprotein. Ivermectin may change the p-glycoprotein ABCB1 substrate (Ménez et al., 2012) . The most reported side effects are reported in the context of its use an antiparasitic drug as the result of immunologic response to parasite, including skin rash, fever, headache, nausea and dizziness (Juarez et al., 2018) . Drug interaction of Ivermectin and chemotherapy agents is an important issue both in treatment of cancer or COVID-19 (Canga et al., 2008 ). There are not enough clinical data about ivermectin drug interactions. It is reasonable to cautiously administer this drug with drugs that are metabolized by CYP3A4 and induce or inhibit P-glycoproteins (Table-3 (Kim, 2002) Mitoxantrone (Kim, 2002) Paclitaxel (Lin, 2003) Vinblastine (Lin, 2003) Vincristine (Kim, 2002) Ivermectin (Lin, 2003) Lapatinib (Cidon, 2017) Lenvatinib (Cidon, 2017) Sorafenib (Cidon, 2017) Actinomycine D (Zhou, 2008) Docetaxel (Zhou, 2008) Imatinib (Zhou, 2008) Irinotecan (Zhou, 2008) Mitomycine C (Zhou, 2008) Topotecan (Zhou, 2008) Etoposide (Kim, 2002) Tamoxifen (Kim, 2002) Ivermectin (Ménez et al., 2012) Methadone (Kim, 2002) Vinblastin (Zhou, 2008) Cisplatin (Zhou, 2008) Daunorubicin (Zhou, 2008) Doxorubicin (Zhou, 2008) Vinblastine (Zhou, 2008) Vincristine (Zhou, 2008) Etoposide (Zhou, 2008) Remdisivir (RDV) is a new investigational antiviral agent, that have been used against coronavirus. RDV inhibits the RNA-dependent RNA polymerase (Al-Tawfiq et al., 2020; Gordon et al., 2020; Tchesnokov et al., 2019) . Its oral bioavailability is very low, so it is used intravenously (Mealey et al., 2003) .Unfortunately, there are not any data about the drug pharmacokinetic J o u r n a l P r e -p r o o f and drug-drug interaction. In a phase II trial on remdesivir, 9 cases of sideeffects were reported but 8 cases of them were not related to remdesivir (Tchesnokov et al., 2019) . While waiting for more definite evidence, physicians should prescribe this drug with caution in cases of multiple medications. Tocilizumab (TCZ, Actemra) is an Ig G recombinant humanized monoclonal antibody that blocks the receptor of IL-6. TCZ has been used for treatment of rheumatoid arthritis (Zhang and Brennan, 2010) . As the result of the cytokine storm the increased level of IL-6 is observed in the course of COVID-19, based on this finding, TCZ is currently used for treatment of this condition (Coomes and Haghbayan, 2020) . There is no information regarding the metabolism and plasma protein binding of tocilizumab. Its half-life depending on administration dose and routes is 11-13 days. Reported adverse effects are upper respiratory tract infection, neutropenia, headache, hypertension, ALT elevation and lipid profile changes. Mild reaction in infusion site is common (Oldfield et al., 2009; Sheppard et al., J o u r n a l P r e -p r o o f 2017). One study showed that TCZ has no effect on QT interval. Among the drugs that has concurrently used with TCZ, It seems that coadministration of TCZ has no effect on MTX pharmacokinetic (Schmitt et al., 2012) .Increasing the level of IL-6 is the consequence of blocking IL-6 receptors by TCZ. Elevated IL-6 reduces CYP450 activity, TCZ may reverse this reduced activity of CYPA50. This issue must be kept in mind when we want to administer TCZ with other agents that metabolized by CYP450. TCZ is an immunosuppressive agent; therefore, there is a concern toward its administration in cancer patients who are already immunosuppressed as the result of chemotherapy (26). It should also be noted that due to the long half-life of TCZ monitoring of this interaction may be necessary for 1 to 2 months after the discontinuation of TCZ (Roche Pharma, 2013). In conclusion, there are limited data about the metabolism or drug interactions some of the current COVID-19 treatments. But some of them have been studied more. Knowing of the metabolism, half-life and drug J o u r n a l P r e -p r o o f interactions of the current covid-19 treatments help physicians to make a better and quick decisions and manage correctly. Anya Jafari: Data curation, Writing-Original draft preparation. Sahar Dadkhahfar: Writing-Reviewing and Editing Sahra Perseh: Data curation, Writing This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. 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