# Will the Use of Pharmacogenetics Improve Treatment Efficiency in COVID-19?
## 3 Lopinavir/Ritonavir  
Lopinavir is a human immunodeficiency virus (HIV) protease inhibitor, which, in combination with ritonavir, can suppress viral replication [2]. It was demonstrated to block a post-entry step in the MERS-CoV replication cycle, thus it appears a potential agent for COVID-19 treatment [37]. A computational approach used to screen for available commercial medicines that may function as inhibitors for the protease M\({}^{\text{pro}}\) of 2019-nCoV (key enzyme for coronavirus replication) has revealed that lopinavir and ritonavir are potential candidates [38]. The results of studies indicate that M\({}^{\text{pro}}\) of different coronaviruses is highly conserved in terms of sequence and 3D structures and it is of high functional importance [39]. Therefore the M\({}^{\text{pro}}\) is considered an attractive target for the design of anticoronaviral drugs [38]. Moreover, it has been found that lopinavir and ritonavir could act as inhibitors of SARS-CoV-2 3 CLpro protein which cleaves polyproteins into an RNA-dependent RNA polymerase and a helicase 1 during the replication process. However, treatment with lopinavir and ritonavir is not currently recommended in the therapy of COVID-19 due to a lack of efficacy in a small randomized controlled trial [40]. Lopinavir undergoes rapid metabolism by the CYP3A4 enzyme and therefore the co-administration of a low dose of a powerful inhibitor of CYP3A4 (ritonavir) is necessary to achieve optimal plasma concentrations of lopinavir for its antiretroviral activity [41; 42]. Moreover, ritonavir inhibits the P-gp in the gut wall thus ameliorating lopinavir absorption [43]. Standard regimen treatment with lopinavir/ritonavir includes the use of the following doses: 400 mg/100 mg bid for adults for 10-21 days [44]. Variants in _CYP3A5_, _ABCC2_, and _SLC01B1_ genes have been suggested to potentially affect plasma concentrations of lopinavir. However, conflicting results were obtained from various pharmacogenetic studies. Variants within _CYP3A4_ and _ABCB1_ genes can modulate the pharmacokinetics and pharmacodynamics of both lopinavir and ritonavir. Ritonavir is also metabolized by CYP2J2, CYP3A5, and CYP2D6 [3]. The fact that this drug increases concentrations of other medications metabolized by CYP3A4 should be taken into consideration if it is used as a polytherapy. Lopinavir and ritonavir are contraindicated with drugs that are highly metabolized by CYP3A enzymes or are potent CYP3A inducers [25]. Moreover, ritonavir may also affect the biotransformation of some medicines metabolized via UGT-catalysed glucuronidation [3]. The carriers of _CYP3A4_*22/*22, alone or in combination with _SLC01B1_ rs4149056 have been found to require a reduced dosage of lopinavir/ritonavir due to higher lopinavir trough concentration. In turn, the polymorphism rs28371759 _CYP*18B_ within CYP3A4 (occurring more frequently in East Asians) is associated with enhanced CYP3A4 activity and thus faster metabolism of drugs like lopinavir [45]. Another variation that could affect the treatment with lopinavir and ritonavir is _CYP3A5_*3. The results of studies indicated that carriers of _CYP3A5_*3/*3 genotypes were lacking CYP3A5 expression as a result of altered mRNA splicing [46]. Therefore, it has been suggested that such patients may require lower doses of lopinavir and ritonavir. Lopinavir and ritonavir are substrates of efflux transporter protein encoded by the ABCB1 gene. Approximately 66 coding SNPs have been identified within the ABCB1 gene [47]. The following polymorphisms: rs2032582 alleles T and A, rs9282564, and rs2229109 have been suggested to raise the drug concentration via diminishing the efflux of ABCB1. These SNPs occur in various populations with different frequencies. rs2032582 A allele is most prevalent in Africans (in 90% of the population), rs2032582 T allele in East Asians, and rs9282564 in Europeans. These patients may show a more pronounced response to the drugs transported by the ABCB1 [3].