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Pharmacokinetic and Pharmacodynamic Interactions Between Anticancer and Antiviral Drugs

More safety data is needed in terms of treatment of symptomatic COVID-19 patients with anticancer drugs
25 Jun 2020

In an article published on 10 June 2020 in the European Journal of Cancer, a group of French investigators led by Paul Gougis of the Department of pharmacology, Hôpital Pitié-Salpêtrière in Paris, France summarised classes of immunosuppressive anticancer drugs. Furthermore, they provided a summary of pharmacokinetic and pharmacodynamic interactions between anticancer drugs and some of antiviral drugs that are currently tested against COVID-19. The context is very relevant in the era of COVID-19, as more safety data is needed to support decisions for treatment of symptomatic COVID-19 patients with anticancer drugs.

The authors wrote that the patients treated for haematological malignancies and solid tumours have a four times higher risk of hospitalisation due to influenza infection, and a ten times higher risk of death. This could be due to their age, comorbidities, lymphopenia, or the immunosuppression caused by anticancer drugs.

They emphasised that safety data are lacking, and it might not be safe to treat symptomatic COVID-19 patients with immunosuppressive anticancer drugs which increase infections. Anticancer drugs that increase either neutropenia or infections are cytotoxic chemotherapy, proteasome inhibitors, histone deacetylase inhibitors, anti-CD20 therapy, PI3K-AKT-mTOR pathway inhibitors, BCR-ABL inhibitors, FLT3 inhibitors, MEK inhibitors, JAK inhibitors, BTK inhibitors, CDK4-6 inhibitors, PARP inhibitors, and multikinase inhibitors.

In particular, the authors underlined that it is not clear yet, if in case of COVID-19, anticancer treatments should be stopped. And it is also not known, if the treatment is interrupted, what is a safe time to resume it. Therefore, it is difficult at present time to decide on prescription of antiviral drugs concomitantly with non-immunosuppressive anticancer therapy.

Comparing the situation with antiretroviral drugs for treatment of HIV, the authors underlined that anticancer drugs and antiviral drugs have a narrow therapeutic index and pharmacological interactions are possible.

Pharmacokinetic-and-Pharmacodynamic-Interactions-Between-Anticancer-and-Antiviral-Drugs

Panel A: Classes of immunosuppressive anticancer drugs. Panel B: Summary of pharmacokinetic and pharmacodynamics interactions between non-immunosuppressive anticancer drugs and some of the drugs currently tested for COVID-19 treatment.

*Tamoxifen is a prodrug and the reported effect is on the active metabolite endoxifen CQ: chloroquine; GnRH: gonadotrophin-releasing hormone; HCQ: hydroxychloroquine; Id: cytochrome inducer; Ih: cytochrome inhibitor; Lopinavir/r: lopinavir/ritonavir association (KALETRA®); S: substrate

© Reprinted with permission from Elsevier

They wrote that some of them are substrates or interact with CYP3A4. As an example they stated enzalutamide which is a non-steroidal antiandrogen for the treatment of prostate cancer. In particular, it is both a CYP3A4 substrate and inducer. Ritonavir is a pharmacokinetic booster of lopinavir investigated in the treatment of COVID-19. Ritonavir is a substrate and a potent CYP3A4 inhibitor. Therefore, enzalutamide and ritonavir could interfere in terms of metabolism, decreasing or increasing each other’s clearance, and cause severe side effects or be responsible for decreased efficacy.

Favipiravir is also investigated for the treatment of COVID-19. It is a CYP2C8 inhibitor, and may increase anticancer drugs that are metabolised through this pathway, in particular dabrafenib and enzalutamide. Furthermore, dabrafenib and enzalutamide are CYP3A4 inducers and could significantly decrease hydroxychloroquine concentration during the first week of wash-out.

In terms of pharmacodynamic interactions, prolongation of QT interval is of particular clinical importance. Hydroxychloroquine and azithromycin prolong QT interval. Concomitant use of anticancer drugs that prolong QT interval could lead to Torsade-de-Pointes and consequently be fatal. The authors warned that electrocardiographic monitoring should be implemented to monitor duration of QT interval during such combination therapy.

Anticancer drugs could also potentiate nephrotoxicity and hepatotoxicity of antiviral drugs.

Reference

Gougis P, Fenioux C, Funck-Brentano C, et al. Anticancer drugs and COVID-19 antiviral treatments in cancer patients: what can we safely use? European Journal of Cancer, Published online 10 June 2020. DOI: https://doi.org/10.1016/j.ejca.2020.05.027.

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