At the end of 2019, a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started as an emerging pathogen for humans, first appeared in Wuhan, China, in December 2019. This novel virus causes coronavirus disease 2019 (COVID-19), named by the WHO on 11 February 2020, and it has been characterized as a pandemic on 11 March 2020. COVID-19 has become the leading cause of death globally, resulting in huge economic and social disruption internationally (Hodgson et al., 2021). As of 10 September 2021 as declared by the WHO, over 223 million confirmed cases of SARS-CoV-2 infection have been detected globally in which ∼4.6 million deaths occurred (WHO, 2021). It is alarming that still now considerably a large number of patients are dying due to COVID-19. The existence of this pandemic virus had been confirmed in over 200 countries or territories, indicating that corona virus was exponentially spread out throughout the world.

One of the leading causes of morbidity and mortality might be the adverse drug reactions (ADRs) associated with current medications administered for the management of COVID-19 since the mortality rate was significantly higher in COVID-19 patients with multiple comorbidities and particularly in older patients (Manjaly Thomas et al., 2020; Ramírez et al., 2020; Biswas et al., 2021a; Falcão et al., 2021; Melo et al., 2021; Rezaee et al., 2021). Polypharmacy is highly predictable in multiple comorbid patients, and also, age-related degradation of organ function in older patients is placing them highly vulnerable to drug–drug interactions (DDIs) and consequently the most notorious ADRs or toxicities of the COVID-19 therapeutics. A recent pharmacovigilance study conducted in Spain reported the 4.75-fold higher incidence of severe ADRs in the COVID-19 patients compared to non-COVID-19 patients, in which the prevalence of severe ADRs was the highest with tocilizumab (59.8%) followed by dexketoprofen (13.9%), azithromycin (8.4%), dexamethasone (7.6%), lopinavir–ritonavir (7.4%), and chloroquine (CQ)/hydroxychloroquine (HCQ) (6.9%) (Ramírez et al., 2020). Another pharmacovigilance study conducted in Brazil with 402 COVID-19 patients indicated that chloroquine (CQ) (OR = 5.4; 95% CI: 1.9–15.6) and HCQ (OR = 2.1; 95% CI: 1.2–3.6) were the only culprit drugs associated with severe ADRs (Melo et al., 2021). A prospective observational study identified a total of 102 ADRs in 149 COVID-19 patients where the incidence of ADRs was significantly higher in patients who have taken HCQ than in the patients who have taken remdesivir (RDV) (47.5 vs. 12.5%; p < 0.001), as evidenced recently (Falcão et al., 2021). This is consistent with a predictive study showing that at least 329 DDIs are feasible in patients taking HCQ, and at the very least, 29 severe DDIs were identified from different reputed international interaction resources, predicted to cause severe toxicity of HCQ (Biswas and Roy, 2021). A hospital-based pharmacovigilance study conducted in China identified ∼38% ADRs in COVID-19 patients, where drug-induced gastrointestinal disorders were 23% and liver system disorders were ∼14%. These ADRs were mainly associated with the use of lopinavir/ritonavir (∼64%) and umifenovir (∼18%). Multivariate logistic analysis indicated that the number of drugs used while COVID-19 patients were staying in the hospital was one of the strongest independent risk factors for these ADRs (OR: 3.17; 95% CI 1.60–6.27; p = 0.001), as reported in this observational study (Sun et al., 2020).

Although there are no specific therapeutic recommendations for treating COVID-19, however, many off-label drugs are being currently administered for the management of COVID-19 and severe ADRs; for example, QT prolongation, cardiac arrhythmias, thrombosis, retinopathy, hepatotoxicity, and increased risk of infection due to DDIs are feasible in these patients as evidenced and suggested elsewhere (Biswas et al., 2020a; Lemaitre et al., 2020; Manjaly Thomas et al., 2020; Ramírez et al., 2020; Sun et al., 2020; Biswas and Roy, 2021; Falcão et al., 2021; Melo et al., 2021; Rezaee et al., 2021).

While it is increasingly true of DDIs for COVID-19 therapeutics, it is likely that the cytochrome P450 (CYP) enzymes or transporter proteins affecting the pharmacokinetics (PK) or pharmacodynamic (PD) properties were mostly involved in the reported and predicted DDIs of drugs used in the treatment of COVID-19. However, the genetic variants modulating the PK/PD profiles of COVID-19 drugs regulating the safety or effectiveness are not clinically studied yet, posing serious scarcity of pharmacogenomic data in the literature.

The PK and PD properties of the COVID-19 drugs are very potential factors to explore the pharmacogenetics association study; however, it appears that drug-developing authorities and scientists did not consider the pharmacogenetics interference in drug response variability, which could affect either the safety/effectiveness of COVID-19 drugs or the severity of COVID-19 progression. In this review, we will discuss in detail the pharmacogenetics of COVID-19 therapeutics with a particular focus on drugs targeting SARS-CoV-2 life cycle, drug–drug interactions (DDIs), and drug–herb interactions (DHIs) potentially affecting the pharmacogenetic interventions. We will also discuss some of the genetic variants potentially affecting the severity of COVID-19 progression.

SARS-CoV-2 is a positive-sense, single-stranded RNA-enveloped virus in the Betacoronavirus genus (Attaway et al., 2021). Bats and pangolins may be the animal hosts of SARS-CoV-2 as there is a >90% gene homology to SARS-CoV-2 found to infect humans (Hu et al., 2021a). Currently, it remains unclear if SARS-CoV-2 was directly transferred from bat/pangolins to humans or an intermediate host was required for transmission. In light of the current pandemic, researchers first compared SARS-CoV-2 with the previous endemic SARS-CoV (2002–2003) and MERS-CoV (2012) (da Costa et al., 2020). SARS-CoV-2 propagates and migrates down the respiratory tract along the conducting airways. The entry process of SARS-CoV-2 into host cells is via the binding of the S protein to the ACE2 receptor (Figure 1).

The virion releases its RNA. Some RNA is translated into proteins by the host cell’s machinery. Proteins and RNA are assembled into a new virion in the Golgi and released. ACE2 receptors are highly expressed in the upper respiratory tract of humans (Lan et al., 2020). Proteolytic cleavage of the S protein by serine proteases including transmembrane protease serine 2 (TMPRSS2), cathepsin L, and furin is required for binding to the ACE2 receptor (Wang et al., 2020b). In the lower respiratory tract, type II pneumocytes and alveolar macrophages also express ACE2 receptors and can be infected, and release several chemokines/cytokines. Once the virus attaches to the host cell receptors, it undergoes endocytosis, viral maturation, replication, and release of more virus within the cytoplasm of the host cell. SARS-CoV-2 infection begins with viral replication and partially avoids host recognition during the initial infection and before the host innate response is enabled (Bergmann and Silverman, 2020).

Angiotensin-converting enzyme 2 (ACE2) functions as a master regulator of the renin-angiotensin system (RAS) mainly by converting Ang (angiotensin) I and Ang II into Ang 1–9 and Ang 1–7, respectively. The ACE2 system is a critical protective pathway against heart failure, myocardial infarction, and hypertension, and against lung disease and diabetes mellitus. ACE2 is widely expressed, including in the lungs, cardiovascular system, gut, kidneys, central nervous system, and adipose tissue. ACE2 has recently been identified as the SARS-CoV-2 receptor (Kuhn et al., 2004). The loss of ACE2 function following binding by SARS-CoV-2 is driven by endocytosis and activation of proteolytic cleavage. Ang II levels elevate with increased activity of angiotensin 1 receptors (AT1R) at the cost of ACE2/Ang 1–7-driven pathways, leading to adverse fibrosis, hypertrophy, increased reactive oxygen species (ROS), vasoconstriction, and gut dysbiosis. ADAM17 (a disintegrin and metalloproteinase 17)-mediated proteolytic cleavage of ACE2 is upregulated by endocytosed SARS-CoV-2 spike proteins. The activation of the AT1R by elevated Ang II levels also further increases ADAM17 activity. ADAM17 correspondingly also cleaves its primary substrate releasing soluble TNF-α (tumor necrosis factor-α) into the extracellular region where it has auto- and paracrine functionality. TNF-α activation of its tumor necrosis factor receptor (TNFR) represents a third pathway elevating ADAM17 activity (Gheblawi et al., 2020). TNF-α along with systemic cytokines released due to SARS-CoV-2 infection can lead to a cytokine storm.

The cells of the airway epithelium are the first line of defense (innate immune system), providing a mechanical barrier (mucociliary escalator) that expels particles and pathogens via cilia, mucus, and induced coughing. This barrier includes cells of the pulmonary epithelium, alveolar macrophages (AMs), and dendritic cells (DCs). The AMs and DCs express pattern recognition receptors (PRRs), including Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs), that can detect molecules from pathogens (pathogen-associated molecular patterns—PAMPs) or molecules released from damaged cells (damage or danger-associated molecular patterns—DAMPs) (Figure 2–I).

Upon recognition, these sensors recruit the adaptor proteins, MyD88 and MAVS, respectively, and induce downstream signaling. Ultimately, this leads to the activation of the transcription factors, IRF3/7 and NF-κB, and the subsequent production of type I interferons (IFN-α and IFN-β) and pro-inflammatory cytokines (e.g., IL-6 and TNF-α), respectively. Additionally, the virus is thought to activate the inflammasome sensor, NLRP3, resulting in the secretion of the highly inflammatory cytokine IL-1β and the induction of pyroptosis, an inflammatory form of cell death (Lim et al., 2016).

T cells and B cells are activated (adaptive immune system) by antigen presentation and cytokines from DCs and AMs, and activation of the complement system. IL-6 promotes the differentiation to cytotoxic T cells, helper T cells (Th), and plasma cells. IL-1β promotes the differentiation of Th17, which functions by stimulating neutrophil recruitment and inflammation (Figure 2–II). Cytotoxic T cells play a crucial role in SARS-CoV-2 clearance due to their ability to selectively eliminate virus-infected cells by inducing apoptosis via ligands such as Fas ligand (FasL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and perforin/granzyme-mediated pathway (Ranasinghe et al., 2016; Huang et al., 2019). Th1 helps in the activation of cytotoxic T cells. Th2 activates B cells to produce antibodies and become plasma cells. These antibodies contribute to SARS-CoV-2 clearance. There are memory T and B cells that can help against the recurrent infection (Figure 1).

Neutrophils are attracted by chemokines/cytokines swarm to the site of infection. Subsequently, activated neutrophils undergo degranulation and (neutrophil extracellular traps) NET formation, releasing intracellular DAMPs, DNA, histones, and neutrophil elastase that activates the PRRs of surrounding immune and non-immune cells to induce cytokine secretion (Figure 2–III). Neutrophils and NETs drive necro-inflammation in COVID-19 (Barnes et al., 2020). The extracellular DNA released by NETs activates platelets, and aggregated NETs provide a scaffold for binding of erythrocytes and activated platelets that promote thrombus formation (Mozzini and Girelli, 2020).

In a later phase of SARS-CoV-2 infection, the complement system will be triggered via antibodies bound to the virus (Noris et al., 2020). C3 can be converted into C3a and C3b. C3b mediates pathogen opsonization and activates the conversion of C5 into C5a and C5b. C5b mediates the formation of the membrane attack complex (MAC), which leads to cell lysis. C3a and C5a promote immune cell recruitment to the site of infection (Figure 2–IV).

Excessive cytokines produced by macrophages and DCs, that is, IL-1β, IFN-I, CXCL10, CXCL11, IL-6, IP-10, and TNF-α, are called cytokine storm (Ahmed-Hassan et al., 2020) (Figure 2–V). Cytokine storm and C5a lead to the influx of immune cells (e.g., granulocytes, monocytes, T cells, B cells, and NK cells) into the infected site (Wang et al., 2015) (Figure 2–VI). The overwhelming infiltrate of immune cells causes excessive pulmonary inflammation (severe pneumonia) with destructive effects on human tissue, resulting in destabilization of endothelial cell to cell interactions, damage of vascular barrier, capillary damage, diffuse alveolar damage (DAD), pulmonary fibrosis, systemic inflammation, hyperferritinemia, hemodynamic instability, and multi-organ failure, and if left untreated, it leads to death (Ackermann et al., 2021; Chen and Pan, 2021) (Figure 2–VII). Acute respiratory distress syndrome (ARDS), as a result of DAD, leads to low oxygen saturation levels and is a major cause of mortality in COVID-19. SARS-CoV-2 also can infect the endothelial cells, causing endothelial injury, endotheliitis, and microthrombus formation in several organs, especially in alveolar capillary (Varga et al., 2020). The electron microscopy shows new vessel growth through a mechanism of intussusceptive angiogenesis, especially in patients with a long duration of hospitalization (Ackermann et al., 2020). These microangiopathies could be the factors, which are worsening the ARDS. Although the exact mechanism of ARDS in COVID-19 patients is not fully understood, the excessive production of pro-inflammatory cytokines is considered to be one of the major contributing factors (Chen et al., 2020).

A common characteristic of SARS-CoV-2 is asymptomatic transmission, which is likely the cause of rampant spread and transmission. Given SARS-CoV-2 entry is primarily via the respiratory tract, upper and lower respiratory tract involvement is the most common manifestation. About one-third of patients hospitalized with SARS-CoV-2 infection meet the criteria for acute respiratory distress syndrome (Attaway et al., 2021). The main clinical manifestations of COVID-19 are fever (90% or more), cough (around 75%), and dyspnea (up to 50%) (Jiang et al., 2020). A small but significant subset has gastrointestinal symptoms. Preliminary estimates of case fatality, likely to fall as better early diagnostic efforts come into play, are about 2%, mostly due to ARDS, acute kidney injury, and myocardial injury (Jiang et al., 2020). The clinical manifestations are summarized in Figure 3 as described elsewhere (Huang et al., 2020; Jiang et al., 2020; Alizadehsani et al., 2021).

It is well recognized that COVID-19 has four stages of progression in which the first stage is initiated by upper respiratory tract infection. In the second stage, the symptoms of dyspnea and pneumonia appeared. In the third stage of COVID-19, cytokine storm followed by the hyperinflammatory state predominantly worsens the clinical scenario. The final stage of COVID-19 progression is either death or recovery. While as many as 800 clinical trials are ongoing and some of these have already been completed worldwide, currently, no treatment was found to be clinically effective to act selectively against the SARS-CoV-2 infection (Becker, 2020; Stasi et al., 2020). Currently, different therapeutics are being applied to treat moderate-to-severe COVID-19 patients considering the pathological features and various stages of COVID-19, of which repurposed drugs are being used predominantly (Becker, 2020; Song et al., 2020; Stasi et al., 2020; Gavriatopoulou et al., 2021).

Gilead Sciences first developed remdesivir (RDV) in 2017 for the treatment of infection caused by Ebola virus. In the United States, South Korea, and China, RDV was clinically evaluated in moderate-to-severe COVID-19 patients through several phase 3 clinical trials (Gavriatopoulou et al., 2021). Based on reviewing current evidence from randomized, double-blinded, placebo-controlled clinical trials, the FDA has been persuaded to believe the potential benefits of RDV over potential risks for the treatment of severe hospitalized COVID-19 patients (FDA, 2020). Henceforth, the FDA issued an Emergency Use Authorization (EUA) for emergency use of RDV for the treatment of hospitalized severe COVID-19 adult and children patients where severity of COVID-19 has been defined as SpO₂ ≤ 94% on room air, requiring supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (FDA, 2020). It is reported that RDV can inhibit RNA-dependent polymerase and may therefore be effective in the treatment of SARS-CoV-2 infection. It is actually a phosphoramidate prodrug having broad-spectrum activity against various viruses, for example, Paramyxoviridae, Filoviridae, Pneumoviridae, and Orthocoronavirinae, that is, SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), as described elsewhere (Sheahan et al., 2017; Martinez, 2020; Gavriatopoulou et al., 2021). Although the FDA has recommended emergency use of RDV in severe COVID-19 patients, however, the safety and efficacy of RDV in COVID-19 patients as evidenced in multiple recent meta-analyses are controversial and inconsistent (Angamo et al., 2021; Elsawah et al., 2021; Tao et al., 2021).

Chloroquine (CQ) and hydroxychloroquine (HCQ) were included on the essential lists of medications of the World Health Organization (WHO) and used for several decades for the prophylaxis of malaria. They are also used for the treatment of rheumatoid arthritis, systemic lupus erythematosus, Sjogren’s syndrome, and post-Lyme’s disease arthritis (Shippey et al., 2018; Schrezenmeier and Dörner, 2020; Gavriatopoulou et al., 2021). Although HCQ and CQ may exhibit anti-inflammatory, immunomodulating, anti-infective, antithrombotic, and metabolic effects, however, they can also inhibit SARS-CoV-2 host entry by binding to the host cell angiotensin-converting enzyme-2 (ACE2) receptor, thereby impairing SARS-CoV-2 spike protein recognition (Becker, 2020; Fantini et al., 2020). These drugs act by blocking 2019-nCoV entry into host cells by inhibiting glycosylation of host receptors, proteolytic processing, and endosomal acidification (Sanders et al., 2020). Several clinical trials had assessed the safety and efficacy of CQ/HCQ in COVID-19 patients. Based on primary results from some clinical trials, the U.S. FDA had approved emergency use of CQ/HCQ for the treatment of COVID-19 patients on 28 March 2020. Later, the U.S. FDA issued a cautioning statement against CQ/HCQ use in COVID-19 patients due to serious cardiac toxic effects, for example, arrhythmias on April 24, 2020. Finally, on 15 June 2020, the FDA revoked the EUA use of CQ/HCQ as a potential COVID-19 therapy after accumulating negative data from clinical trials (Gavriatopoulou et al., 2021).

Lopinavir (LPV) and ritonavir (RTV) are HIV protease inhibitors and used in combination with or without other antiviral drugs for the treatment of human immunodeficiency virus (HIV-1)-infected patients older than 2 years. Due to its inhibiting nature of viral DNA-dependent RNA polymerase, either combination of LPV/RTV or alone has been recommended for the treatment of COVID-19 patients; however, the results of clinical trials are not favoring the clinical outcomes and are limited in use nowadays (Cao et al., 2020; Gavriatopoulou et al., 2021). Although LPV/RTV was suggested primarily by the National Health Commission (NHC) of China as an antiviral therapy in COVID-19 patients, however, it is not recommended by the U.S. National Institute of Health (NIH) due to lack of proven clinical effectiveness in these patients (Song et al., 2020).

Arbidol was first marketed in Russia and China as a synthetic antiviral drug for the treatment of seasonal influenza. A previous study demonstrated that arbidol was broadly effective against some other viruses including SARS-CoV and was generally well tolerated in treating these viruses (Gavriatopoulou et al., 2021). Initially, the in vitro test found arbidol to be an effective inhibitor of SARS-CoV-2 infection, and it was therefore recommended by the China’s NHC guide on COVID-19 treatment option. It appeared that arbidol was found ineffective against SARS-CoV-2 infection in ongoing clinical studies, although it had significant limitations in study design and sample size in these studies (Song et al., 2020).

Favipiravir was first approved in Japan for the treatment of influenza and was later found effective against Ebola virus infection also. Although several clinical trials were undertaken in China, Japan, Canada, and Russia evaluating the safety and efficacy of favipiravir alone or in combination with other antivirals against SARS-CoV-2 infection, however, the results were not persuading the clinicians for further considerations in treating COVID-19 patients with favipiravir (Gavriatopoulou et al., 2021).

Originally, darunavir/cobicistat was developed for the treatment of HIV-1 infection. Due to its protease inhibiting activity, the clinical trial had assessed the safety and efficacy of darunavir/cobicistat in SARS-CoV-2 infection and found that darunavir/cobicistat was not effective in the treatment of COVID-19 patients (Gavriatopoulou et al., 2021).

It is worth mentioning here that there are no supporting data from clinical trials that could favor the use of any HIV protease inhibitors to treat COVID-19 patients. Followingly, recently, the NIH panel for COVID-19 treatment guidelines did not recommend the use of any HIV protease inhibitors in the treatment of COVID-19 infection due to lack of clear clinical benefit in these patients (Amanat and Krammer, 2020; Gavriatopoulou et al., 2021).

Atazanavir (ATV) was discovered early in the 2000s as an antiretroviral drug for treating HIV instead of LPV/RTV because of lesser side effects of this drug. Evidence from in silico and in vitro studies suggests that by inhibiting viral major protease, ATV would inhibit SARS-CoV-2 replication even better than LPV/RTV (Fintelman-Rodrigues et al., 2020; Stasi et al., 2020; Alavian et al., 2021).

As part of highly active antiretroviral therapy (HAART), efavirenz (EVZ) and nevirapine are mainly used in the treatment of HIV/AIDS; however, these drugs could also be used for treating SARS-CoV-2 infection because of their ability to inhibit viral RNA-dependent RNA polymerase (RdRp) (Nastri, et al., 2020). Also, nelfinavir mesylate (NFV) being an antiretroviral drug may have potential efficacy against SARS-CoV-2 infection. Recent studies suggest that it can inhibit spike protein (S) medicated cell fusion of SARS-CoV-2 and may eventually block the transfer and cell-to-cell spread of SARS-CoV-2 (Yousefi et al., 2021).

Ribavirin is a nucleoside analog and was found effective against many RNA viruses, including SARS-CoV and MERS-CoV. It mainly inhibits RNA polymerase and synthesis of viral protein. Ribavirin was widely used with or without steroids against SARS infection, outbreak in 2003. Although intravenous ribavirin in combination with LPV/RTV or interferon was suggested by China’s NHC for the treatment of patients with COVID-19, it is not recommended by the NIH (Song et al., 2020).

It has well established that severe COVID-19 patients are generally associated with an increased cytokine-release syndrome, which further elevated interleukin-6 (IL-6). Tocilizumab, an IL-6 receptor antagonist, is commonly used for the treatment of rheumatoid arthritis and patients having cytokine-release syndrome (Takahashi et al., 2020). It was authorized by the Agenzia Italiana del Farmaco (AIFA), the Italian Medicines Agency, to investigate its safety and efficacy in COVID-19 patients. However, a recent clinical trial did not find significant clinical benefits, for example, reduced mortality or increased survival rate in using this drug (Stasi et al., 2020; Salama et al., 2021).

Molnupiravir, a ribonucleoside prodrug of N-hydroxycytidine (NHC), was originally developed as a potent inhibitor of respiratory syncytial virus (RSV), influenza B viruses, and influenza A viruses (IAVs) of human, avian, and swine origins (Yoon et al., 2018; Jayk Bernal et al., 2021). Later, it was found to be effective as a first oral and direct-acting anti-SARS-CoV-2 agent in both in vitro and in vivo studies (Jayk Bernal et al., 2021; Kabinger et al., 2021). When molnupiravir in the form of NHC prodrug is administered orally, it circulates systemically and is phosphorylated intracellularly to NHC triphosphate, an active form of molnupravir. This active form subsequently interferes in viral replication by inducing RNA mutagenesis through incorporation of 5′-monophosphate metabolite into viral RdRp. The active compound of molnupiravir, NHC 5′-triphosphate (NHC-TP), increases “G” to “A” and “C” to “U” transition mutations in replicating coronaviruses that lead to increased antiviral effects (Ehteshami et al., 2017; Gordon et al., 2021; Jayk Bernal et al., 2021; Kabinger et al., 2021).

Another important treatment strategy against SARS-CoV-2 infection was to develop selective targets that may neutralize monoclonal antibodies (mAbs) since previous studies reported a large number of antibodies by disturbing the receptors of either SARS-CoV or MERS coronavirus (MERS-CoV) that showed neutralization activities (Du et al., 2009; de Wit et al., 2016). Generation of virus-neutralizing antibodies or neutralizing mAbs (from the B cells of convalescent patients or humanized mice sources) are being developed from B cells of convalescent patients or humanized mice against viral infections, by targeting the receptor-binding domain (RBD) of the spike (S) protein of SARS-CoV-2 by some mechanisms—directly through triggering the phagocytosis by binding to virons or infected cells—and also by two different types of distance mechanisms in an antibody-dependent enhancement (ADE) process:

a) ADE via enhanced infection-expanded viral disease and replication by viral uptake into Fc gamma receptor IIa (FcγRIIa)-expressing phagocytic cells.

To date, seven mAb neutralizing drugs including bamlanivimab, etesevimab, casirivimab, imdevimab, sotrovimab, cilgavimab, and tixagevimab either as monotherapy or as combination therapy have been approved or received EUAs from the U.S. FDA for the treatment of COVID-19 (Agarwal et al., 2020; Shi et al., 2020a; Zhang et al., 2021c; Nathan et al., 2021). All repurposed drugs with their mechanism of actions against SARS-CoV-2 infections are shown in Table 1.

Also, the different drugs acting on different phases of SARS-CoV-2 life cycle are shown in Figure 4

Pharmacogenomic considerations of currently used COVID-19 therapeutics may help clinicians to optimize the efficacy or safety of these drugs, and may accelerate the development of precision COVID-19 medicine. To mitigate devastating catastrophe associated with COVID-19, many drugs without establishing robust evidence of efficacy or magnitude of toxicities have been used in these patients either as an off-label/compassionate use or as a clinical trial under these unprecedented health situations as an urgent attempt. Although pharmacogenomic determinants are very important considerations in optimizing the efficacy or toxicity of many repurposed antiviral drugs or supportive treatments, they are the most neglected issues in COVID-19 therapeutics since there are almost no pharmacogenomics data for these drugs (Takahashi et al., 2020). It is very unlikely that pharmacogenomic associations of COVID-19 therapeutics with the efficacy or safety have not been considered yet in any clinical studies.

To combat COVID-19, computational aided-drug design and screening have been rapidly applied to identify FDA-approved drugs and newly potent compounds from available databases. Using in silico approaches, extensive research works have been carried out to acquire an understanding of mechanisms of action and SARS-CoV-2’s activities. However, there are still many foundations to be established for developing novel therapeutics agents for the treatment of COVID-19 (Amin and Jha, 2020). Herein, the current situation in the discovery of anti-SARS-CoV-2 agents at four important targets (Table 4) from in silico studies is described and summarized as follows.

At least 13 different vaccines have been administered until now to combat the biggest infectious challenges of the 21st century. Although majority of these vaccines are well-tolerated, they may not be responsive similarly to everyone and may also account for some vaccine-related side/toxic effects. The application of existing pharmacogenetic/pharmacogenomic science to vaccines is termed as “vaccinomics” (Hoffman et al., 1998; Poland et al., 2007, 2021; Omersel and Karas Kuželički, 2020; Soiza et al., 2021). Since the pharmacogenomic association with the safety or efficacy of many clinical important medications, for example, antiepileptics, antiplatelets, cardiovascular drugs, antidepressants, and anticancers, have been well-established and many of these considerations are now implemented in routine clinical practice in some parts of the world, we are expecting that similar approaches in terms of COVID-19 vaccines will start to appear very soon.

Some genetic insights for vaccines applied in other infectious diseases have already been recognized, for example, specific genetic polymorphisms of the TLR3 gene were associated with significantly reduced immune responses to the measles vaccine as reviewed elsewhere (Poland et al., 2018). Vaccinomics provide a promising newly evolving research area through which the safety or efficacy of vaccines may be optimized. A wide range of genotype/phenotype association data are currently being integrated into this newly emerging research field for many live viral vaccines and expecting that similar attributes will begin for COVID-19 vaccines as well. The application of vaccinomics in COVID-19 may allow us to explain the interindividual immune responses’ variability and adverse events, and may also accelerate the development of personalized vaccine (Poland et al., 2021).

Immunogenicity data of COVID-19 vaccination come from the assessment of specific T-cell responses and specific antibody responses (Zhu et al., 2020). Both activation of cytotoxic T cell and antibody production need antigen presentation via HLA class I and II, respectively. We hypothesize that variation of the HLA genotype might affect the immunogenicity of COVID-19 vaccines. Further investigation in association between HLA polymorphism and COVID-19 vaccine immunogenicity is interesting and might help to predict individual COVID-19 vaccine effectiveness.

Within a year, several vaccines have been developed and millions of doses were delivered. The ChAdOx1 nCoV-19 vaccine (AstraZeneca) has recently been reported as an increasing risk of venous thrombosis and thrombocytopenia, called vaccine-induced immune thrombotic thrombocytopenia (VITT), 7–10 days after receiving the first dose (Schultz et al., 2021). Recently, some studies showed that pathogenic antibodies to platelet factor 4 (PF4), which have a major role to develop VITT, can occur after the administration of the ChAdOx1 nCoV-19 vaccine (Scully et al., 2021). This pathogenic PF4-dependent syndrome is unrelated to the use of heparin therapy, called heparin-induced thrombocytopenia (HIT). The higher PF4 level has an association with HLA-DRB1*03:01-DQB1*02:01 haplotype (Zhang et al., 2019). Genetic variants of HLA-DRB1 and HLA-DQB1 were found ∼25% in Thai population (Puangpetch et al., 2014; Satapornpong et al., 2020), indicating that considerable proprotion of Thai population might be at risk of developing VITT associated with these genetic polymorphisms. Clinical validation of the screening of HLA-DRB1*03:01 and HLA-DQB1*02:01 to predict the occurrence of VITT should be investigated, and it might help people to avoid this life-threatening condition. Even though platelet level is very low, VITT should not be treated by platelet transfusion. Ideally, such transfusion should be avoid because it would provide a substrate for further antibody-mediated platelet activation and coagulopathy. Therefore, rapid recognition of VITT is very important.

Plenty of genes of interest that may either be involved in the severity of COVID-19 progression or may potentially modify the PK/PD profiles of COVID-19 therapeutics, and may therefore potentially affect the safety or effectiveness of these medications have been identified in this review. From reviewing the previous information, we enlisted a panel of genes as two categories: 1) mandate genetic test and 2) recommendations for the genetic test.

Thai population might be at particular risk for either developing severe COVID-19 due to the HLA genetics or developing toxicities/therapeutic ineffectiveness by COVID-19 drugs. This is partly because Thai population has great diversity of HLA, transporters, and CYP genetic variants. It has been previously reported that ∼25% of the Thai population carried HLA-DQA1/HLA-DQB1 genetic polymorphisms (Puangpetch et al., 2014; Satapornpong et al., 2020), which might render COVID-19 severity. Minor allele frequencies of the CYP2C9*2 and CYP2C9*3 in Thai population were 0.08 and 5.3%, respectively. Minor allele frequencies of the CYP2C19*2, CYP2C19*3, and CYP2C19*17 in Thai population were 25.6, 2.5, and 1.8%, respectively. Approximately 30% of the CYP3A4 variant allele was identified in the Thai population as reported elsewhere (Sukprasong et al., 2021). Over 30% Thai population carried C3435T ABCB1 genetic polymorphisms as revealed in a previous study conducted in Thailand (Sensorn et al., 2013). Overall, it is concluded that considerable proportion of Thai population might be at risk of either severe COVID-19 manifestation or might be at risk of developing toxicities/ineffectiveness of the COVID-19 medications due to carrying these genetic variants. Moreover, the herbs especially andrographolide and the others as described in this review are commonly used in this population; this might also render the risk of toxicities/ineffectiveness of these herbs due to either DHIs or herbogenomics.

To our best knowledge, no clinical studies were identified in the literature to date that had assessed either metabolic or transporter genetic variants with the safety or effectiveness of current COVID-19 therapeutics. This is creating evidence impasse and delaying the target for finding appropriate therapeutics to combat COVID-19 successfully. From considering the PK/PD profiles of the current COVID-19 therapeutics under investigation as discussed in this review, it is emerging the needs for assessing genetic associations of the relevant metabolic or transporter genes of interest for optimizing the safety or effectiveness of COVID-19 therapeutics. Future clinical studies or trials are warranted to investigate such genetic associations for the achievement of precision medicine for COVID-19. Since it is well evidenced that the mortality is significantly higher in older people and having comorbidities (Biswas et al., 2021a), DDIs should also be considered in these assessments because of vulnerability to polypharmacy. Ideally, considerations of multifactorial drug–gene interactions (DGIs) of COVID-19 therapeutics may accelerate the development of precision medicine of COVID-19 in the real clinical settings as shown in Figure 7, as established in other therapeutic areas such as antiplatelets (Biswas et al., 2021b).

It is very important to note here that this predictive model has considered only a pharmacologically active drug involving CYP metabolism; however, in case of a prodrug, the effects will be vice versa, and this model is also applicable to other genes, for example, transporter genes affecting the safety or efficacy of COVID-19 drugs.

The global outbreak of SARS-CoV-2 has evolved into an emergent COVID-19 pandemic causing huge morbidity and mortality in the world. Many drugs without establishing clinical effectiveness or tailoring safety are being administered to tackle COVID-19 pandemic situations. A repurposing strategy might be more effective and successful if pharmacogenetic interventions of these drugs are being considered in future clinical studies/trials. Safety and effectiveness of several repurposed drugs currently being used for the management of COVID-19 may be affected by the CYP/transporter genetic variants. From reviewing the current evidence of pharmacogenetic of these drugs in either COVID-19 or other diseases, we strongly mandate to undertake pharmacogenetic assessment for at least these drug–gene pairs (atazanavir–UGT1A1, ABCB1, SLCO1B1, and APOA5; efavirenz–CYP2B6; nevirapine–HLA, CYP2B6, and ABCB1; lopinavir–SLCO1B3 and ABCC2; ribavirin–SLC28A2; tocilizumab–FCGR3A; ivermectin–ABCB1; oseltamivir–CES1 and ABCB1; clopidogrel–CYP2C19 and ABCB1, warfarin–CYP2C9 and VKORC1; NSAIDs–CYP2C9) in patients with COVID-19 for advancing precision COVID-19 therapeutics by optimizing the safety or effectiveness of these drugs.

Although it is very unlikely that there are almost no pharmacogenetic data for COVID-19 drugs, from inferring the PK/PD properties and some pharmacogenetic evidence of these drugs in other diseases/clinical conditions, it is highly likely that pharmacogenetic associations are also feasible in at least some COVID-19 drugs currently being administered as shown in this review and should be considered in future clinical studies/trials. Molecular docking and computational studies are promising to achieve new COVID-19 therapies as shown in this review. Current situation in the discovery of anti-SARS-CoV-2 agents at four important targets from in silico studies has been described and summarized in this review. Although naturally occurring compounds from different herbs against SARS-CoV-2 infection are favorable, accurate experimental investigation of these compounds is warranted to provide insightsful information. Moreover, clinical considerations of DDIs and DHIs of the existing repurposed drugs along with pharmacogenetic (e.g., efavirenz and CYP2B6) and herbogenetic (e.g., andrographolide and CYP2C9) interventions, collectively called multifactorial drug-gene interactions (DGIs), may further accelerate the development of precision COVID-19 therapies in the real-world clinical settings.