<p>Repurposing Drugs for COVID-19: Pharmacokinetics and Pharmacogenomics of Chloroquine and Hydroxychloroquine</p>

Abstract

Background A new coronavirus SARS-CoV-2 has been identified as the etiological agent of the severe acute respiratory syndrome, COVID-19, the source and cause of the 2019–20 coronavirus pandemic. Hydroxychloroquine and chloroquine have gathered extraordinary attention as therapeutic candidates against SARS-CoV-2 infections. While there is growing scientific data on the therapeutic effect, there is also concern for toxicity of the medications. The therapy of COVID-19 by hydroxychloroquine and chloroquine is off-label. Studies to analyze the personalized effect and safety are lacking. Methods A review of the literature was performed using Medline/PubMed/Embase database. A variety of keywords were employed in keyword/title/abstract searches. The electronic search was followed by extensive hand searching using reference lists from the identified articles. Results A total of 126 results were obtained after screening all sources. Mechanisms underlying variability in drug concentrations and therapeutic response with chloroquine and hydroxychloroquine in mediating beneficial and adverse effects of chloroquine and hydroxychloroquine were reviewed and analyzed. Pharmacogenomic studies from various disease states were evaluated to elucidate the role of genetic variation in drug response and toxicity. Conclusion Knowledge of the pharmacokinetics and pharmacogenomics of chloroquine and hydroxychloroquine is necessary for effective and safe dosing and to avoid treatment failure and severe complications.

Chloroquine and Hydroxychloroquine Interact Differently with ACE2 Domains Reported to Bind with the Coronavirus Spike Protein: Mediation by ACE2 Polymorphism

“…Taken together, the pharmacokinetic and ADME properties of CQ and HCQ complications such as heart failure and several non-reversible disorders have been previously, reported [ 45 ]. Our ADME and pharmacokinetic results confirmed previous data about pharmacokinetics and pharmacogenomics of CQ and HCQ [ 46 ]. The importance of the pharmacokinetic, ADME, and QSAR (for quantitative structure–activity relationship) assays was previously largely reported in the design and the assessment of several drugs [ 41 , 47 , 48 ].…”

Pharmacogenetics Approach for the Improvement of COVID-19 Treatment

“…Several pharmacogenetic biomarkers related to the metabolic pathway of drugs used for COVID-19 treatment have been described in the present review. In agreement with previous reports [ 7 , 8 , 9 ], there are variants in CYP2C8 , CYP2D6 , CYP3A4 , CYP3A5 , SLCO2B1 , ABCB1 , ABCC2 , CES1 , and G6PD that could help to improve the clinical outcome of the COVID-19. The scientific evidence supports the study of variants in CYP2D6, CYP3A4 , SLCO2B1 , ABCB1, and ABCC2 with the response to specific drugs ( Figure 2 ).…”

“…Both drugs are widely metabolized in the liver by CYP2C8, CYP3A4, CYP3A5, and, to a lesser extent, by CYP2D6 [ 59 ]. Genetic variants of these enzymes have been previously described ( Table 1 ), and a study have suggested that CYP2C8 , CYP2C9, and CYP3A5 genetic variants influence chloroquine malaria treatment; however, there is not enough evidence of their impact on the chloroquine pharmacokinetics or response [ 8 , 60 ]. Transporters’ variants could be critical in the pharmacogenetics of chloroquine [ 61 ].…”

“…In this sense, pharmacogenetics could explain the inter-individual variability on drug response based on the genetic of COVID-19 patients [ 6 ]. Variants in genes encoding drug-metabolizing enzymes, transporters, or receptors have been reported, and they could provide the insight to achieve a personalized therapy leading to a better outcome of this emerged disease ( Figure 1 ) [ 7 , 8 , 9 ]; nevertheless, several disease-related issues must be carefully reviewed in the pharmacogenetic study of COVID-19 treatment. Therefore, we aimed to describe the pharmacogenetic variants reported for drugs used for COVID-19 treatment.…”

SAveRUNNER: A network-based algorithm for drug repurposing and its application to COVID-19

“…However, the effectiveness of chloroquine and hydroxychloroquine remains controversial, with clinical evidence showing contrasting results. Some clinical trials reported therapeutic benefits of the drugs, while others trials showed the opposite, and others ones are still ongoing [ 60 ]. While there is growing studies to test therapeutic effect, there is also concern for toxicity and adverse effects of these medications, and thus FDA revoked the emergency-use authorization that allowed for chloroquine phosphate and hydroxychloroquine to be used to treat certain hospitalized patients with COVID-19 when a clinical trial was unavailable [ 61 ].…”