Effect of Renal Impairment on Pharmacokinetics and Safety of Ensitrelvir, a SARS-CoV-2 3CL Protease Inhibitor.

Advanced Search

Takayuki Katsube, Safwan Kezbor, Ryosuke Shimizu, Ryuji Kubota

Author Information

Takayuki Katsube: Clinical Pharmacology and Pharmacokinetics, Shionogi & Co., Ltd., 3-13, Imabashi 3-Chome, Chuo-Ku, Osaka, 541-0042, Japan. takayuki.katsube@shionogi.co.jp. ORCID
Safwan Kezbor: Shionogi Inc., 400 Campus Drive, 4th Fl., Florham Park, NJ, 07932, USA.
Ryosuke Shimizu: Clinical Pharmacology and Pharmacokinetics, Shionogi & Co., Ltd., 3-13, Imabashi 3-Chome, Chuo-Ku, Osaka, 541-0042, Japan.
Ryuji Kubota: Clinical Pharmacology and Pharmacokinetics, Shionogi & Co., Ltd., 3-13, Imabashi 3-Chome, Chuo-Ku, Osaka, 541-0042, Japan.

PMID: 38460082 DOI: 10.1007/s40121-024-00946-x

INTRODUCTION: Ensitrelvir, a novel oral inhibitor of 3C-like protease of SARS-CoV-2, shows efficacy and safety in participants with mild to moderate COVID-19. Since urinary recovery of ensitrelvir ranged from 12.9% to 21.8% across dose groups given 20-1000 mg in a single-ascending dose study, renal excretion contributes to the elimination of ensitrelvir. Therefore, the effect of renal impairment on the pharmacokinetics and safety of ensitrelvir needed to be evaluated.
METHODS: This study (NCT05363215) was a phase 1, open-label, nonrandomized, parallel-group study. The effect of renal function on the pharmacokinetics of ensitrelvir was investigated. Ensitrelvir was administered as a single dose of 375 mg to participants with normal renal function and those with mild, moderate, and severe renal impairment. The participants with normal renal function were matched to each participant with moderate renal impairment with respect to sex, age, and body mass index. The unbound fractions in plasma after administration of ensitrelvir were also evaluated. For the safety assessment, the nature, frequency, and severity of treatment-emergent adverse events were evaluated and recorded.
RESULTS: The plasma concentrations of participants with renal impairment were higher than those of participants with normal renal function. The ratios (90% confidence intervals) of the area under the plasma concentration-time curve from 0 to infinity (AUC) in participants with mild, moderate, and severe renal impairment compared to normal renal function were 1.4374 (1.1716-1.7636), 1.4885 (1.1883-1.8646), and 1.6021 (1.2782-2.0080), respectively. The plasma protein-unbound fraction was similar regardless of the plasma ensitrelvir concentration or renal function. Ensitrelvir was well tolerated in participants with mild to severe renal impairment and normal renal function.
CONCLUSION: Ensitrelvir was well tolerated by participants with renal impairment. There was no clinically meaningful increase on exposure to ensitrelvir in participants with renal impairment, indicating that no dose adjustment would be required due to renal function.

COVID-19 Ensitrelvir Renal impairment study

Unoh Y, Uehara S, Nakahara K, et al. Discovery of S-217622, a noncovalent oral SARS-CoV-2 3CL protease inhibitor clinical candidate for treating COVID-19. J Med Chem. 2022;65(9):6499��512. [DOI: 10.1021/acs.jmedchem.2c00117]
Mukae H, Yotsuyanagi H, Ohmagari N, et al. Efficacy and safety of ensitrelvir in patients With mild-to-moderate coronavirus disease 2019: the phase 2b part of a randomized, placebo-controlled, phase 2/3 study. Clin Infect Dis. 2023;76(8):1403��11. https://doi.org/10.1093/cid/ciac933 . [DOI: 10.1093/cid/ciac933]
Yotsuyanagi H, Ohmagari N, Doi Y, et al. A phase 2/3 study of S-217622 in participants with SARS-CoV-2 infection (phase 3 part). Medicine (Baltimore). 2023;102(8): e33024. https://doi.org/10.1097/MD.0000000000033024 . [DOI: 10.1097/MD.0000000000033024]
Xocova�� (Ensitrelvir Fumaric Acid) tablets 125 mg approved in Japan for the treatment of SARS-CoV-2 infection, under the emergency regulatory approval system [press release, 22 Nov 2022. https://www.shionogi.com/global/en/news/2022/11/e20221122.html . Accessed 17 Dec 2022.
Shimizu R, Sonoyama T, Fukuhara T, Kuwata A, Matsuo Y, Kubota R. Safety, tolerability, and pharmacokinetics of the novel antiviral agent ensitrelvir fumaric acid, a SARS-CoV-2 3CL protease inhibitor, in healthy adults. Antimicrob Agents Chemother. 2022;66(10):e00632-e722. https://doi.org/10.1128/aac.00632-22 . [DOI: 10.1128/aac.00632-22]
Shimizu R, Matsuzaki T, Oka R, et al. Evaluation of drug-drug interactions of ensitrelvir, a SARS-CoV-2 3CL protease inhibitor, with transporter substrates based on in vitro and clinical studies. J Clin Pharmacol. 2023;63(8):918��27. https://doi.org/10.1002/jcph.2247 . (Epub 2023 May 10). [DOI: 10.1002/jcph.2247]
Highlights of prescribing information for Paxlovid. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217188s000lbl.pdf . Accessed 10 Nov 2023.
Highlights of prescribing information for Fetroja. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209445s002lbl.pdf . Accessed 10 Nov 2023.
Highlights of prescribing information for Tricor. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021656s029lbl.pdf . Accessed 10 Nov 2023.
FDA Guidance for Industry. Pharmacokinetics in patients with impaired renal function: study design, data analysis, and impact on dosing and labeling. September 2020. https://www.fda.gov/media/78573/download
Levey SA, Coresh J, Greene T, et al. Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med. 2006;145(4):247��54. https://doi.org/10.7326/0003-4819-145-4-200608150-00004 . [DOI: 10.7326/0003-4819-145-4-200608150-00004]
WMA Declaration of Helsinki��ethical principles for medical research involving human subjects. https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/ . Accessed 23 Sep 2022.
Council for International Organizations of Medical Sciences. International Ethical Guidelines for Health-related Research Involving Humans. https://cioms.ch/wp-content/uploads/2017/01/WEB-CIOMS-EthicalGuidelines.pdf . Accessed 23 Sep 2022.
ICH International Council for Harmonisation. Efficacy guidelines. https://www.ich.org/page/efficacy-guidelines . Accessed 23 Sep 2022.
Kuroda T, Nobori H, Fukao K, et al. Efficacy comparison of 3CL protease inhibitors ensitrelvir and nirmatrelvir against SARS-CoV-2 in vitro and in vivo. J Antimicrob Chemother. 2023;78(4):946��52. [DOI: 10.1093/jac/dkad027]

Journal Article

OpenLB
Open Library of Bioscience