ABSTRACT
Background. Ensitrelvir is a novel oral SARS-CoV-2 3C-like protease inhibitor, and under late clinical development stage for COVID-19 diseases. Ensitrelvir exhibited an inhibition potency for organic cation transporter 1 (OCT1) and multidrug and toxin extrusion protein 1 (MATE1) in in vitro study and clinical drug-drug interaction (DDI) study is required judging fromDDI guidance.Metformin is widely used for treatment of diabetes, and is a sensitive substrate for OCT1 and MATE1. We evaluated the effect of ensitrelvir on the pharmacokinetics (PK) ofmetformin with physiologically-based pharmacokinetic (PBPK) modeling and simulation and clinical DDI study. Methods. The PBPK model of ensitrelvir was developed based on the physicochemical parameters, in vitro transporter inhibition parameters, and estimated PK parameters for human. DDI simulations between ensitrelvir and metformin were performed. Simcyp PBPK Simulator (Version 20, Certara UK Limited, UK) was used to develop PBPK model and simulate the DDIs. The in vitro 50% inhibitory concentration (IC50) values of each transporter were used as inhibition constant (Ki) for DDI simulations. Based on the PBPK analysis, the clinical DDI study planed. Results. PBPK analysis: As the result of DDI simulation, ensitrelvir increased the area under the curve (AUC) of metformin by 12%. The result suggests that in vivo DDI potency of ensitrelvir via inhibition of OCT1 or MATE1 would be low at a single dose of ensitrelvir 1000 mg. Clinical DDI study: The plasma concentration-time profile of metformin and ensitrelvir were monitored after 96 hours from a single dose of metformin with or without ensitrelvir. Ensitrelvir does not have effect on the PK of metformin (a geometric mean of AUC ratio was 1.02, Japanese healthy subjects, N=14), suggesting no MATE1 and OCT1 inhibition by ensitrelvir at a clinical dose. The PBPK analysis could well predict the clinical DDI study result. Conclusion. The results of PBPK analysis and the clinical DDI study suggest that no OCT1 and MATE1 inhibition by ensitrelvir is in the clinical dose. Therefore, ensitrelvir does not have a clinically meaningful effect on the pharmacokinetic profile of OCT1 and/or MATE1 substrates including metformin.
ABSTRACT
Background. Ensitrelvir is a new drug candidate to treat COVID-19 disease. According to the in vitro drug-drug interaction (DDI) study, time-dependent inhibition by ensitrelvir was observed on cytochrome P450 3A (CYP3A). The purpose of this study was to evaluate the effect of ensitrelvir on the pharmacokinetics (PK) of CYP3A substrates by clinial DDI studies and physiologically-based pharmacokinetic (PBPK) analyses. Methods. Clinical studies: The effect of once daily multiple-doses of ensitrelvir with the loading dose on Day 1/ maintenance dose (750/250 mg) for 6 days on the PK of midazolam (MDZ) was assessed. MDZ was administered on Days -2 and 6. The effects of once daily multiple-doses of ensitrelvir with 750/250 mg for 5 days on the PK of dexamethasone (DXS) and prednisolone (PLS) were also assessed because these corticosteroids were also CYP3A substrates. DXS and PLS were administered on Days -2, 5 (co-administration with ensitrelvir), 9 and 14 to evaluate the effects after the last dose of ensitrelvir. PBPK analyses: The effects of once daily multiple-doses of ensitrelvir with another dose regimen (the loading dose/mentenance dose [375/125 mg] for 5 days) on the PK of CYP3A substrates were predicted using Simcyp PBPK Simulator (Version 20, Certara UK Limited, UK). Results. The AUC0-inf of MDZ co-administered with ensitrelvir was increased by 8.80-fold compared to those of MDZ alone, indicating that ensitrelvir is a strong CYP3A inhibitor with 750/250 mg for 6 days. The AUC0-inf of DXS on Day 5 was increased 3.47-fold and the effect of ensitrelvir on the PK of DXS was diminished over time after the last dose of ensitrelvir. The AUC0-inf of PLS on Day 5 was increased 1.25-fold and no clinically meaningful effect of ensitrelvir on the PK of PLS was observed. The PBPK analyses predicted that the co-administration of ensitrelvir increased the AUC of MDZ by 3.83-fold and the AUC of DXS by 2.49-fold following ensitrelvir at 375/125 mg for 5 days. A clinical study with MDZ under the analyses conditions is underway to confirm the PBPK results. Conclusion. The clinical study revealed that ensitrelvir affects the PK of CYP3A substrates with 750/250 mg for 5 or 6 days. The PBPK analyses suggests that ensitrelvir is expected to a moderate inhibitor of CYP3A with 375/125 mg for 5 days.
ABSTRACT
The rapid transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-driven infection signifies an ultimate challenge to global health, and the development of effective strategies for preventing and/or mitigating its effects are of the utmost importance. In the current study, an in-depth investigation for the understanding of the SARS-CoV-2 inactivation route using graphene oxide (GO) is presented. We focus on the antiviral effect of GO nanosheets on three SARS-CoV-2 strains: Wuhan, B.1.1.7 (U.K. variant), and P.1 (Brazilian variant). Plaque assay and real-time reverse transcription-polymerase chain reaction (RT-PCR) showed that 50 and 98% of the virus in a supernatant could be cleared following incubation with GO (100 μg/mL) for 1 and 60 min, respectively. Transmission electron microscopy (TEM) analysis and protein (spike (S) and nucleocapsid (N) proteins) decomposition evaluation confirm a two-step virus inactivation mechanism that includes (i) adsorption of the positively charged spike of SARS-CoV-2 on the negatively charged GO surface and (ii) neutralization/inactivation of the SARS-CoV-2 on the surface of GO through decomposition of the viral protein. As the interaction of S protein with human angiotensin-converting enzyme 2 (ACE2) is required for SARS-CoV-2 to enter into human cells, the damage to the S protein using GO makes it a potential candidate for use in contributing to the inhibition of the worldwide spread of SARS-CoV-2. Specifically, our findings provide the potential for the construction of an effective anti-SARS-CoV-2 face mask using a GO nanosheet, which could contribute greatly to preventing the spread of the virus. In addition, as the effect of surface contamination can be severe in the spreading of SARS-CoV-2, the development of efficient anti-SARS-CoV-2 protective surfaces/coatings based on GO nanosheets could play a significant role in controlling the spread of the virus through the utilization of GO-based nonwoven cloths, filters, and so on. © 2021 American Chemical Society.