key: cord-0803656-s5ogsswm
authors: Campesi, Ilaria; Montella, Andrea; Franconi F, Flavia
title: Letter to the Editor in response to the article ‘Candidate drugs against SARS-CoV-2 and COVID-19’
date: 2020-11-04
journal: Pharmacol Res
DOI: 10.1016/j.phrs.2020.105285
sha: b18293f4e4c9deeeaf815bd748c7fadbae0ae799
doc_id: 803656
cord_uid: s5ogsswm

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. COVID-19 constitutes a worldwide wartime-like health, societal and economic emergency and many drugs, including biological ones, have been repurposed for the treatment of this disease [1] .

Drugs repurposing reduces discovery and development times and decreases overall costs, as well as most preclinical and clinical tests including safety and pharmacokinetic profiles, which were already performed.

One of the most severe complications of COVID-19 consists in sepsis-like inflammation that may evolve into "hyperinflammation" [2] . Inflammation and immunological make-up of men and women present numerous and relevant sexual dimorphisms [2] . Interestingly, ageing affects women's and men's immune systems differently, as old men exhibit a "stronger inflammatory"

response than old women [2] . In line with the above observations, COVID-19 has more devastating effects in older men [2] .

Infectious and inflammatory diseases alter drug metabolism predominantly down-regulating the drug metabolizing enzymes (cytochrome P450 enzymes (CYP), phase II enzymes etc.) [3] . In animals "hyperinflammation" effects on CYP expression appear to be sex and CYP dependent [3] , while, at best of our knowledge, we still don't know if sex controls this process in humans. Changes in pharmacokinetics can lead to adverse drug reactions (ADR), drug-drug interactions and a decrease in drug efficacy. Therefore, we wonder if the drug kinetic obtained in healthy individuals or in patients without a massive inflammatory reaction is transferable to COVID-19 patients of both sexes.

The majority of approved drugs, including COVID-19 repurposed drugs, are metabolized by CYP3A4 enzyme, and women have more protein and metabolize CYP3A4 substrates more quickly than men [4] . As inflammatory response is bigger in men with COVID-19 than in women [2] , it is possible to speculate that men could have a greater inhibition of CYP450 enzymes that, together with a greater activity of CYP34A in women, could contribute to generate sexual dimorphism in the pharmacokinetics of COVID-19 treatments.

In addition, among drugs repurposed for COVID-19 there are some biologicals that alone or in combination with small synthetic drugs may interferes with the inflammatory pathways.

Consequentially, biologics therapy can change the expression and activity of the drug metabolizing enzymes depending on the pro-or-anti-inflammatory properties of the biologic drug [3] . For example, tocilizumab, repurposed drug for COVID-19, elevates metabolism of simvastatin in rheumatoid arthritis patients [3] .

Although things are slowly changing, especially in phase 3 trials, early stage trials are still heavily male-biased [4] . Consequentially, information deriving from early stage is mainly missing in women, however there are cases where information is missing in men and this lack of acknowledgement reflects on repurposed drugs.

Finally, many of drugs repurposed for COVID-19 prolong the QT interval including the remdesivir (an anti-Ebola agent), that is the only drug approved by FDA for the treatment of COVID-19 [5].

As already mentioned, many of repurposed drugs are metabolized by CYP3A4 which can be downregulated by inflammation (which is bigger in old men) and or by combination therapy with inhibitors of CYP3A4, therefore the risk of QT-prolongation and drug-induced cardiac death could be enhanced [4] . This point is crucial because Covid-19 patients often have myocardial damage that might be a trigger for enhanced arrhythmic risk [2] . In line with this, a descriptive comparison of drugs used in COVID-19 and in non-COVID-19 indications (performed using global ADR database VigiBase) evidences more ADR reports (with exception of chloroquine) in men than in women in line with a greater risk for COVID-19 in men [6] . In men, the main reported ADR is QTprolongation followed by diarrhea, nausea, hepatitis, and vomiting. In women, the most reported ADR is diarrhea followed by QT-prolongation, nausea, vomiting, and upper abdominal pain.

Notably, the literature in non COVID-19 patients sustains that to be a woman is a risk factor for QT-prolongation [4] but Zekarias and collegues's paper does not show it in COVID-19 patients [6] .

In our opinion, COVID-19 offers a remarkable opportunity to enrich the pharmacological culture, as studying the repurposed drugs in both men and women represents a real opportunity and not a double-edged sword and this could a useful to avoid the perpetuation of gender bias. Despite all the available technology, once again, only a limited space is reserved to sex and gender, even in a pathology that presents significant sexual differences in lethality, that heavily involves the immune system (essentially sexually dimorphic), and in which the pharmacokinetics of drugs can be substantially different from that obtained in healthy individuals or in subjects suffering from diseases with low inflammatory reaction.

I wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.

J o u r n a l P r e -p r o o f

Candidate drugs against SARS-CoV-2 and COVID-19

COVID-19 as an acute inflammatory disease

Regulation of drug-metabolizing enzymes in infectious and inflammatory disease: implications for biologics-small molecule drug interactions

Sex-Gender variable: Methodological recommendations for increasing scientific value of clinical studies

Sex differences in reported adverse drug reactions to COVID-19 drugs in a global database of individual case safety reports