P-1666. Ensitrelvir (ESV) Population Pharmacokinetics (PK) in Nonhospitalized Adults with COVID-19

TL;DR

This study analyzed how a new drug called Ensitrelvir behaves in the bodies of nonhospitalized adults with COVID-19.

Contribution

The study provides population pharmacokinetics data for Ensitrelvir in nonhospitalized adults with or without risk factors for severe disease.

Findings

Ensitrelvir's population PK parameters were similar to those in individuals without COVID-19.

Sex and weight were identified as significant covariates affecting drug clearance and volume of distribution.

About 16% of participants had all PK samples below the limit of quantitation, indicating non-adherence.

Abstract

ESV is an investigational oral protease inhibitor for severe acute respiratory syndrome coronavirus-2 infection. SCORPIO-HR was a Phase 3 global trial in nonhospitalized adults with COVID-19 with or without risk factors for progression to severe disease. A population PK study was conducted in a subset of participants.

Participants were randomized (1:1) to receive once-daily ESV (375 mg: Day 1, 125 mg: Days 2–5) or matching placebo. PK samples were collected on Days 1, 4, and 8 from n=400 participants. Population PK analysis used nonparametric methods (Pmetrics); covariates (age, sex, race, weight) were investigated.

PK samples were quantified from 222 participants randomized to ESV. Among them, 35 (16%) were excluded as all samples were < limit of quantitation (BLQ). An additional 21 (9.5%) were excluded for sporadic non-adherence (≥ 2 samples BLQ; n=8), as not evaluable, or inconsistent/not reported dose-sample collection times. The final data set was 166 participants with 579 detectable ESV levels. These 166 participants [n or mean (SD)] were: male, 106 (64%); age, 39.5 ± 13.8 yrs; weight, 68.4 ± 12.8 kg; Asian, 125 (75%); Black, 14 (8%); White, 25 (15%); unknown, 2. The final base model was an oral absorption (with lag), 2-compartmental model. Covariate analysis identified no race effect. In the final covariate model (Figure 1), there was an ≈13% effect on apparent clearance (CL/F) by sex, where CL/F in males was > females. Additionally, an effect on median central volume (Vc)/F by weight (centered to a 70kg person, 6.8L vs 7.3L) was found where Vc decreased as weight decreased and concentrations could increase. Covariate-adjusted final model PK estimates (median) were: CL/F, 0.313L/h; Vd/F, 18.66L; and terminal half-life 41h. Day 4 predose and 1.5h postdose mean (SD) concentrations were 17.5 (±5.8) and 20.5 (±6.7) µg/mL, respectively.

ESV population PK parameters with covariate adjustment compared well with literature values from participants without COVID-19, indicating ESV PK disposition was not affected by COVID-19 in nonhospitalized symptomatic adults. The 16% of participants with all PK samples BLQ indicated no doses were taken and highlights the importance of objective adherence assessment in future COVID-19 studies.

Nathaniel J. Rhodes, PharmD MS, Apothecademy, LLC: Advisor/Consultant Kara W. Chew, M.D., M.S., Pfizer: Medical writing support (no direct compensation) David A. Wohl, M.D., EMD Serono: Advisor/Consultant|EMD Serono: Honoraria|Gilead Sciences: Advisor/Consultant|Gilead Sciences: Honoraria|Merck: Advisor/Consultant|Merck: Honoraria|Regeneron: Advisor/Consultant|Regeneron: Honoraria|Theratechnologies: Advisor/Consultant|Theratechnologies: Honoraria|ViiV: Advisor/Consultant|ViiV: Honoraria Joseph Eron, MD, Gilead Sciences: Advisor/Consultant|Invivyd: DSMB|Merck: Advisor/Consultant Simon Portsmouth, MD, Shionogi Inc.: Employee Takeki Uehara, Ph.D., Shionogi, Inc.: Employee David Smith, MD, MAS, Bayer: Advisor/Consultant|Biosciences: Advisor/Consultant|Fluxergy: Stocks/Bonds (Private Company)|Gilead: Advisor/Consultant|Hyundai: Advisor/Consultant|IAS USA: Honoraria|Linear Therapies: Stocks/Bonds (Private Company)|Model Medicines: Advisor/Consultant|Model Medicines: Stocks/Bonds (Private Company)|NIH: Grant/Research Support|Pharma Holdings: Advisor/Consultant|Red Queen Therapeutics: Advisor/Consultant Judith S. Currier, MD, MSc, Merck and Co.: Honoraria Annie Luetkemeyer, MD, Cepheid: Grant/Research Support|Gilead: Grant/Research Support|GSK: Grant/Research Support|Merck: Grant/Research Support|ViiV: Grant/Research Support

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