# Will the Use of Pharmacogenetics Improve Treatment Efficiency in COVID-19?
## 2 Remdesivir (GS-441524)  
Remdesivir (GS-441524) is a monophosphoramidate nucleoside analog prodrug whose main purpose was to treat the Ebola virus disease [2]. This agent acts as an analog of adenosine triphosphate (ATP) which competes with the natural ATP substrate for the incorporation into nascent RNA chains by viral RNA-dependent RNA polymerase to hinder viral replication since its activity results in premature chain termination during replication of the viral RNA [19]. The results of studies conducted on animal models have revealed that this drug shows some efficacy in the treatment of coronavirus diseases, including SARS-CoV-2 and the Middle East Respiratory Syndrome coronavirus (MERS-CoV) [20; 21]. Additionally, the data from clinical trials provided low-certainty evidence that remdesivir may decrease time to clinical improvement, the occurrence of severe adverse events, and reduce mortality of patients with severe COVID-19 [22; 23]. A double-blind, randomized, placebo-controlled trial (NIAID ACTT-1 Study (CO-US-540-5776)) of intravenous remdesivir in hospitalized adults with mild/moderate or severe COVID-19 disease demonstrated the shortening of time to recovery in patients with severe symptoms, however, no differences were found in a group of patients with mild/moderate disease [24]. The best outcomes were reported in hospitalized individuals receiving oxygen on Day 1, however, not on ventilation. This medicine received conditional approval for the treatment of COVID-19. Remdesivir was the first drug authorized as an investigational therapeutic option for COVID-19 [25]. It is recommended as a single 200 mg dose, followed by a 100 mg daily infusion [26]. The application of pharmacogenetics has been suggested to improve the efficacy of such treatment and decrease its toxicity. Remdesivir, which is administered in the form of a prodrug, requires the conversion into active form--GS-443902 by esterases (which leads to the formation of intermediate metabolite, GS-704277) followed by phosphorylation. CYP2C8, CYP2D6, and CYP3A4 (to a lesser extent) enzymes were found to affect the metabolic conversion of remdesivir [27]. Numerous studies have demonstrated that enzymes of cytochrome P450 are very polymorphic. The Pharmacogene Variation Consortium have described over 140 identified CYP2D6 alleles differing in enzyme activity; some variants are lacking enzymatic activity (e.g., _CYP2D6*3_, \"4_, \"6), and other display diminished activity (e.g., _CYP2D6*10_, \"17_, \"29 or \"4_1) or enhanced activity due to duplication or multiplication of active alleles (e.g., _CYP2D6*1 xN_, \"2 xN_) [28]. The prevalence of some CYP2D6 polymorphisms was found to be higher in some populations. So far, more than 34 allelic variants have been identified, however, there is no detailed clinical data concerning their significance [29]. No non-functional alleles of _CYP2C8_ have been described yet [29]. Since cytokines released in the process of inflammatory responses (e.g., interleukin-6; IL-6) reduce the expression of CYP enzymes (i.e., CYP3A4), it appears that polymorphisms within the _CYP3A4_ gene may affect the response to the treatment. The underlying mechanism for CYP down-regulation involves the translational activation of C/EBPbeta-LIP which competes with and counteracts constitutive C/EBP transactivators [30]. The knowledge of the presence of specific P450 alleles combinations helps to predict the metabolic phenotype of the patient. Individuals who have two functional alleles are classified as extensive metabolizers, those with duplicated or multiplied functional alleles display the ultrarapid metabolizers phenotype. In turn, individuals carrying two null alleles are poor metabolizers, while those with one functional allele and one null allele are intermediate metabolizers [31]. All these patients may require the modification of drug dose to provide optimal efficiency and avoid serious adverse events.