Paul Gougis

and 6 more

To the editor,The rapid emergence of COVID-19 pandemics worldwide is of particular concern for fragile populations who are more at risk of acute respiratory distress syndrome and death. Patients treated for malignant hemopathy and solid cancers have a four times higher risk of hospitalization due to influenza infection, and a ten times higher risk of death. This fragility could be due to their age, multiple associated comorbidities, lymphopenia, or the immunosuppressive action of a broad spectrum of anticancer drugs.[1] Therefore, anticancer drugs should be used carefully in this population. Without further safety data, it might be unsafe to treat SARS-CoV-2 positive patients who have COVID-19 symptoms with anticancer drugs known to increase infections or harvesting immunosuppressive properties. We summarized in the table (part A) drug classes that have been reported to increase either neutropenia or infections. Regarding patients tested positive who have recovered from their symptoms, clinical data is missing. It is currently not clear if cancer treatments should be stopped, and if so, the time needed to resume it safely.In any of these settings, clinical trials and incoming standard of care could lead to the prescription of antiviral drugs concomitant to non-immunosuppressive anticancer treatments. Similar to previous works reporting interactions between HIV antiretrovirals and anticancer drugs,[2] these two classes of medications have a narrow therapeutic index and can have pharmacological interactions. Some of them are substrates or interact with hepatic cytochrome P450 cytochrome isoenzymes (CYP), particularly CYP3A4, and pharmacokinetic interactions could lead to supra or infratherapeutic concentrations. For example, enzalutamide, a nonsteroidal antiandrogen prescribed for prostate cancer, is both a CYP3A4 substrate and inducer. Ritonavir, on the other hand, is a pharmacokinetic booster of lopinavir contained in Kaletra, which is explored as a COVID-19 treatment. Ritonavir is a substrate and also a potent inhibitor of CYP3A4. Thus, enzalutamide and ritonavir could interfere with each other’s metabolism, decrease or increase each other’s clearance, and be responsible for severe toxicities or decreased efficacy. Favipiravir, an anti-EBOV drug, also a candidate for the COVID-19 treatment, is an inhibitor of CYP2C8,[3] and therefore may increase anticancer drug metabolized through this pathway, such as dabrafenib and enzalutamide. Furthermore, CYP3A4 induction could lead to sustained CYP3A4 increased activity for up to 1 week after discontinuation. Dabrafenib or enzalutamide, two CYP3A4 inducers, could significantly decrease hydroxychloroquine concentration during the first week of wash-out.Among pharmacodynamic interactions, QT interval prolongation could be of particular interest. Hydroxychloroquine, which is currently widely prescribed as an anti-coronavirus drug, or azithromycin, are two drugs known to prolong QT interval. Concomitant use of QT-prolonging anticancer drugs could lead to Torsade-de-Pointes and be fatal. Caution should be observed in this case, and electrocardiographic monitoring should be implemented to monitor QT interval duration during combination therapy.Similarly, anticancer drugs could potentiate nephrotoxicity and hepatotoxicity of antiviral treatments.The table (part B) summarizes pharmacokinetic and pharmacodynamics interactions between some currently tested drugs against COVID-19 and anticancer drugs.