Sotrovimab is a recombinant human monoclonal antibody that has been shown to prevent progression to hospitalization or death from severe disease in non-hospitalized high-risk patients with mild-to-moderate COVID-19 following either intravenous (IV) or intramuscular (IM) administration. Population pharmacokinetic (popPK) and exposure-response (ER) analyses were performed to characterize sotrovimab PK and the relationship between exposure and response (probability of progression), as well as covariates that may contribute to between-participant variability in sotrovimab PK and efficacy following IV or IM administration. Sotrovimab PK was described by a two-compartment model with linear elimination; IM absorption was characterized by a sigmoid absorption model. PopPK covariate analysis led to the addition of the effect of body weight on systemic clearance and peripheral volume of distribution, sex on IM bioavailability and first-order absorption rate (KA), and body mass index on KA. However, the magnitude of covariate effect was not pronounced and was therefore not expected to be clinically relevant based on available data to date. For ER analysis, sotrovimab exposure measures were predicted using the final popPK model. An ER model was developed using the exposure measure of sotrovimab concentration at 168 hours that described the relationship between exposure and probability of progression within the ER dataset for COMET-TAIL. The number of risk factors (≤1 vs >1) was incorporated as an additive shift on the model-estimated placebo response but had no impact on overall drug response. Limitations in the ER model may prevent generalization of these results to describe the sotrovimab exposure-progression relationship across SARS-COV-2 variants.

Jennifer E. Sager, Asma El-Zailik, Melissa Aldinger, Elizabeth L. Alexander, Wendy W. Yeh, Erik Mogalian, Chad Garner, and Maribel Reyes are employees of Vir Biotechnology and report stock ownership in Vir Biotechnology and third-party funding from GSK to Vir Biotechnology for the submitted work. Julie Passarell and Stefan Roepcke are employees of Simulations Plus, Inc. Xiaobin Li, Ahmed Nader, Andrew Skingsley, and Amanda Peppercorn are employees of GSK and report stock ownership in GSK. Adrienne E. Shapiro reports acting as a trial investigator for Vir Biotechnology and receiving nonfinancial support from Vir Biotechnology during the conduct of the study.

NCT045450060; NCT04913675; NCT04779879; NCT04634409; NCT04988152

This work was supported by Vir Biotechnology, Inc. and GSK.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics committee/IRB of Advarra, Columbia, Maryland, USA; Advarra, Aurora, Ontario, Canada; Comité de ética de la Investigación con medicamentos (CEIm), Consorci Corporació Sanitària Parc Tauli, Barcelona, Spain; Comité Nacional Transitorio de ética en Investigación para la Evaluación y Supervisión &eacutetica de los Ensayos Clínicos de la Enfermedad COVID-19, Jesús María, Lima, Peru; Health Research Authority, London - London Bridge Research Ethics Committee, London, United Kingdom; and Ethik Kommission, Medizinische Universität Wien, Vienna, Austria gave ethical approval for COMET-ICE (ClinicalTrials.gov identifier, NCT045450060). Ethics committee/IRB of Advarra, Aurora, Ontario, Canada; Chonnam National University Hospital, Gwangju, Republic of Korea; Clinical Trial Center, Institutional Review Board Center, Research Center for Biomedical Convergence, Chungnam National University Hospital, Daejeon, Republic of Korea; CEIC Hospital Clínico San Carlos, Madrid, Spain; and Advarra Institutional Review Board, Columbia, Maryland, USA gave ethical approval for COMET-PEAK (NCT04779879). Ethics committee/IRB of Advarra Institutional Review Board, Columbia, Maryland, USA; CEQ at Medical Center of Limited Liability Company Harmoniya krasy, Kyiv, Ukraine; and CPP Sud-Est II - Groupement Hospitalier Est, Bron, France gave ethical approval for COMET-TAIL (NCT04913675). Ethics committee/IRB of Western Institutional Review Board, Baylor Scott & White Research Institute, St. Vincent's Institutional Review Board, and Copernicus Group Independent Review Board gave ethical approval for BLAZE-4 (NCT04634409). Ethics committee/IRB of WCG IRB, Puyallup, Washington, USA gave ethical approval for NCT04988152.

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