Top

Published in:

Open Access 13-11-2023 | Pharmacokinetics | Original Research Article

Pharmacokinetics, Safety, and Tolerability of Anti-SARS-CoV-2 Monoclonal Antibody, Sotrovimab, Delivered Intravenously or Intramuscularly in Japanese and Caucasian Healthy Volunteers

Authors: Ahmed Nader, Elizabeth Alexander, Dimitra Brintziki, Amina Z. Haggag, Stephen A. Harrison, Ian A. Hawes, Marjan Hezareh, Andrew M. Lippa, Arisa Okamasa, Malek Okour, Nobuhiko Okuda, Jennifer E. Sager, Scott Segal, Yuri Shida, Andrew Skingsley, Robert Williams, Esther Y. Yoon, Daren Austin

Published in: Clinical Pharmacokinetics | Issue 1/2024

Abstract

Background and Objective

Sotrovimab 500 mg administered by a single intravenous (IV) infusion has been granted special approval for emergency use in Japan for treatment of SARS-CoV-2 infection in adults and children aged ≥ 12 years weighing ≥ 40 kg. This Phase 1, single-dose study investigated the pharmacokinetics, safety, and tolerability of IV or intramuscular (IM) sotrovimab 500 mg doses versus placebo in healthy Japanese and Caucasian volunteers.

Methods

This was a two-part, Phase 1, randomized, placebo-controlled, single-blind study. In Part 1, participants received a single sotrovimab 500 mg IV infusion or matching placebo on Day 1. In Part 2, participants received a single sotrovimab 500 mg IM dose or matching placebo on Day 1, administered as two 4 mL injections.

Results

There was no effect of ethnicity on the peak or total serum exposure of IV sotrovimab through Week 18; after adjusting for body weight, the point estimate and 90 % confidence interval for the ratio of total exposure between Japanese and Caucasian participants fell within conventional bioavailability bounds (80–125%). Geometric mean C_max and AUC_last following a single IM administration of sotrovimab were higher in Japanese participants compared with Caucasian participants, even after adjustment for body weight. Overall, a single IV or IM dose of sotrovimab was well tolerated by both Japanese and Caucasian participants.

Conclusions

After adjusting for body weight, exposures following a single IV dose of sotrovimab 500 mg were similar between Japanese and Caucasian participants, and higher in Japanese participants following IM administration. Higher exposures were not associated with any safety signals.

Trial Registration

ClinicalTrials.Gov: NCT04988152.

Gebru AA, Birhanu T, Wendimu E, et al. Global burden of COVID-19: situational analysis and review. Hum Antibodies. 2021;29(2):139–48. https://doi.org/10.3233/HAB-200420.CrossRefPubMed

Monteiro Pires S, Wyper GMA, Wengler A, et al. Burden of disease of COVID-19: strengthening the collaboration for national studies. Front Public Health. 2022;10:907012. https://doi.org/10.3389/fpubh.2022.907012.CrossRef

European Centre for Disease Prevention and Control. Risk factors and risk groups. 2022. https://www.ecdc.europa.eu/en/covid-19/latest-evidence/risk-factors-risk-groups. Accessed 11 May 2023.

World Health Organization. WHO Coronavirus (COVID-19) dashboard: global vaccination data. 2022. https://covid19.who.int. Accessed 11 May 2023.

World Health Organization. WHO Coronavirus (COVID-19) dashboard: Japan vaccination data. 2022. https://covid19.who.int/region/wpro/country/jp. Accessed 11 May 2023.

Hwang Y-C, Lu R-M, Su S-C, et al. Monoclonal antibodies for COVID-19 therapy and SARS-CoV-2 detection. J Biomed Sci. 2022;29(1):1. https://doi.org/10.1186/s12929-021-00784-w.CrossRefPubMedPubMedCentral

Gupta A, Gonzalez-Rojas Y, Juarez E, et al. Effect of sotrovimab on hospitalization or death among high-risk patients with mild to moderate COVID-19: a randomized clinical trial. JAMA. 2022;327(13):1236–46. https://doi.org/10.1001/jama.2022.2832.CrossRefPubMedPubMedCentral

Hirsch C, Park YS, Piechotta V, et al. SARS-CoV-2-neutralising monoclonal antibodies to prevent COVID-19. Cochrane Database Syst Rev. 2022;6(6):CD014945. https://doi.org/10.1002/14651858.CD014945.pub2.

Pinto D, Park Y-J, Beltramello M, et al. Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody. Nature. 2020;583(7815):290–5. https://doi.org/10.1038/s41586-020-2349-y.CrossRefPubMed

10.

Cathcart AL, Havenar-Daughton C, Lempp FA, et al. The dual function monoclonal antibodies VIR-7831 and VIR-7832 demonstrate potent in vitro and in vivo activity against SARS-CoV-2. bioRxiv. Preprint posted online April 1, 2022. https://doi.org/10.1101/2021.03.09.434607.

11.

Ko S-Y, Pegu A, Rudicell RS, et al. Enhanced neonatal Fc receptor function improves protection against primate SHIV infection. Nature. 2014;514(7524):642–5. https://doi.org/10.1038/nature13612.CrossRefPubMedPubMedCentral

12.

Zalevsky J, Chamberlain AK, Horton HM, et al. Enhanced antibody half-life improves in vivo activity. Nat Biotechnol. 2010;28(2):157–9. https://doi.org/10.1038/nbt.1601.CrossRefPubMedPubMedCentral

13.

Gaudinski MR, Coates EE, Houser KV, et al. Safety and pharmacokinetics of the Fc-modified HIV-1 human monoclonal antibody VRC01LS: a phase 1 open-label clinical trial in healthy adults. PLoS Med. 2018;15(1):e1002493. https://doi.org/10.1371/journal.pmed.1002493.CrossRefPubMedPubMedCentral

14.

Shapiro AE, Sarkis E, Acloque J, et al. Intramuscular versus intravenous SARS-CoV-2 neutralizing antibody sotrovimab for treatment of COVID-19 (COMET-TAIL): a randomized non-inferiority clinical trial. Open Forum Infect Dis. 2023;10(8):ofad354. https://doi.org/10.1093/ofid/ofad354.

15.

Okamasa A, Okour M, Austin D, et al. Safety and pharmacokinetic evaluation of anti-SARS-CoV-2 monoclonal antibody sotrovimab in Japanese/Caucasian healthy adults during intravenous infusion. Kansenshogaku zasshi. 2022;96(2):39–45. https://doi.org/10.11150/kansenshogakuzasshi.96.39(article in Japanese).

16.

Chiba K, Yoshitsugu H, Kyosaka Y, et al. A comprehensive review of the pharmacokinetics of approved therapeutic monoclonal antibodies in Japan: are Japanese phase I studies still needed? J Clin Pharmacol. 2014;54(5):483–94. https://doi.org/10.1002/jcph.231.CrossRefPubMed

17.

Bender Ignacio RA, Wohl DA, Arends W, et al. Comparative pharmacokinetics of tixagevimab/cilgavimab (AZD7442) administered intravenously versus intramuscularly in symptomatic SARS-CoV-2 infection. Clin Pharmacol Ther. 2022;112(6):1207–13. https://doi.org/10.1002/cpt.2706.CrossRefPubMed

18.

Zuidema J, Pieters FAJM, Duchateau GSMJE. Release and absorption rate aspects of intramuscularly injected pharmaceuticals. Int J Pharm. 1988;47(1–3):1–12. https://doi.org/10.1016/0378-5173(88)90209-8.

19.

Larkin TA, Ashcroft E, Hickey BA, Elgellaie A. Influence of gender, BMI and body shape on theoretical injection outcome at the ventrogluteal and dorsogluteal sites. J Clin Nurs. 2018;27(1–2):e242–50. https://doi.org/10.1111/jocn.13923.CrossRefPubMed

20.

Gupta AK, Perez-Rodríguez MT, Gonzalez-Rojas Y, et al. Safety, tolerability, and viral pharmacodynamics of the IgG monoclonal antibody sotrovimab administered via intramuscular injection for the treatment of early mild-to-moderate COVID-19. Open Forum Infect Dis. 2022;9(Suppl 2):ofac492.992. https://doi.org/10.1093/ofid/ofac492.992.

Title: Pharmacokinetics, Safety, and Tolerability of Anti-SARS-CoV-2 Monoclonal Antibody, Sotrovimab, Delivered Intravenously or Intramuscularly in Japanese and Caucasian Healthy Volunteers
Authors: Ahmed Nader
Elizabeth Alexander
Dimitra Brintziki
Amina Z. Haggag
Stephen A. Harrison
Ian A. Hawes
Marjan Hezareh
Andrew M. Lippa
Arisa Okamasa
Malek Okour
Nobuhiko Okuda
Jennifer E. Sager
Scott Segal
Yuri Shida
Andrew Skingsley
Robert Williams
Esther Y. Yoon
Daren Austin
Publication date: 13-11-2023
Publisher: Springer International Publishing
Keywords: Pharmacokinetics
SARS-CoV-2
Published in: Clinical Pharmacokinetics / Issue 1/2024
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI: https://doi.org/10.1007/s40262-023-01319-2

At a glance: The STEP trials

Springer Medicine

Pharmacokinetics, Safety, and Tolerability of Anti-SARS-CoV-2 Monoclonal Antibody, Sotrovimab, Delivered Intravenously or Intramuscularly in Japanese and Caucasian Healthy Volunteers

Abstract

Background and Objective

Methods

Results

Conclusions

Trial Registration

At a glance: The STEP trials

Springer Medicine

Abstract

Background and Objective

Methods

Results

Conclusions

Trial Registration

Please log in to get access to this content

Other articles of this Issue 1/2024

Digoxin Pharmacokinetics in Patients with Obesity Before and After a Gastric Bypass or a Strict Diet Compared with Normal Weight Individuals

Impact of Key Components of Intensified Ceftaroline Dosing on Pharmacokinetic/Pharmacodynamic Target Attainment

Development of a Generic Fetal Physiologically Based Pharmacokinetic Model and Prediction of Human Maternal and Fetal Organ Concentrations of Cefuroxime

Interplay of UDP-Glucuronosyltransferase and CYP2C8 for CYP2C8 Mediated Drug Oxidation and Its Impact on Drug–Drug Interaction Produced by Standardized CYP2C8 Inhibitors, Clopidogrel and Gemfibrozil

How to Dose Vancomycin in Overweight and Obese Patients with Varying Renal (Dys)function in the Novel Era of AUC 400–600 mg·h/L-Targeted Dosing

A Comprehensive Review of the Clinical Pharmacokinetics, Pharmacodynamics, and Drug Interactions of Nirmatrelvir/Ritonavir