Predictive association of ABCB1 C3435T genetic polymorphism with the efficacy or safety of lopinavir and ritonavir in coronavirus disease-2019 patients

24, March 2021 |

Authors:

Abstract

Until specific antiviral drugs have been developed and approved for the treatment of coron- avirus disease-2019 (COVID-19), some drugs such as favipiravir, lopinavir (LPV)/ritonavir (RTV), ribavirin, hydroxychloroquine/chloroquine and remdesivir have been recommended for the management of infection caused by SARS coronavirus-2 (SARS-CoV-2) as described elsewhere [1–3]. It has been found that a considerable pro- portion of COVID-19 patients infected with SARS-CoV-2 in likely clinical conditions were being treated with a combination therapy of LPV/RTV as first-line antiviral therapy [4]. However, there is wide variability in LPV/RTV response in COVID-19 patients as evidenced in clinical studies; randomized clinical trials of LPV/RTV have failed to prove superior efficacy compared with standard therapy [5,6]. Although many factors may trigger the clinical outcomes associated with using LPV/RTV, one of these may be genetic factor provoking drug response variability in addition to adverse clinical outcomes. Being a substrate of permeability glycoprotein (P-gp), the pharmacokinetics (PK) and pharmacodynamics (PD) of LPV/RTV may be affected by the magnitude of P-gp expression, an efflux transporter protein encoded by the ABCB1 gene [7]. P-gp may be highly expressed in some patients which may lead to poor absorption of LPV/RTV therapy as evidenced in HIV-1 infected children [8]. It is therefore predicted that similar PK effects associated with variability of P-gp expression may also occur in patients infected with SARS-CoV-2. Poor absorption of LPV/RTV may consequently lead to therapeutic failure of this antiviral therapy meaning patients are vulnerable to severe adverse clinical outcomes or even death. The effects of LPV/RTV associated with the ABCB1 genetic variability has been investigated in HIV but there was no evidence for such associations in SARS-CoV-2 due to a lack of studies assessing this effect in SARS-CoV-2 infection. However, it is reasonably assumed that such genetic effects of ABCB1 may also exist for SARS-CoV-2 infection causing COVID-19. Although metabolism of LPV/RTV may also be predominantly affected by CYP450 enzymes of CYP3A4/5 and organic anion transporter protein 1B1 (OATP1B1); however, due to avoiding genetic complexity, the present study will only consider genetic polymorphisms of ABCB1 affecting safety or efficacy of LPV/RTV.