Intramuscular Versus Intravenous SARS-CoV-2 Neutralizing Antibody Sotrovimab for Treatment of COVID-19 (COMET-TAIL): A Randomized Non-inferiority Clinical Trial DOI Open Access
Adrienne E. Shapiro, Elias Sarkis,

Jude Acloque

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: March 24, 2023

Abstract Background Convenient administration of coronavirus disease 2019 (COVID-19) treatment in community settings is desirable. Sotrovimab a pan-sarbecovirus dual-action monoclonal antibody formulated for intravenous (IV) or intramuscular (IM) early mild/moderate COVID-19. Methods This phase 3, randomized, multicenter, open-label study tested non-inferiority IM to IV using 3.5% absolute margin. From June August 2021, patients aged ≥12 years with COVID-19, not hospitalized receiving supplemental oxygen, and at high risk progression were randomized 1:1:1 single 500-mg sotrovimab infusion 250-mg injection. The primary composite endpoint was all-cause hospitalization >24 hours acute management illness death through day 29. Results 500 mg non-inferior IV: 10/376 (2.7%) participants the group versus 5/378 (1.3%) met (absolute adjusted difference: 1.06% [95% confidence interval [CI]: −1.15%, 3.26%]). CI upper limit lower than prespecified margin 3.5%. enrollment discontinued because greater proportion hospitalizations seen that groups. Serious adverse events occurred <1% 2% across Four experienced serious related died (500 IM: 2/393 [<1%]; 250 2/195 [1%]). Conclusions injection well tolerated administration. could expand outpatient access Registration ClinicalTrials.gov Identifier: NCT04913675 Key Points COVID-19 high-risk patients, measured by >24h 29, well-tolerated. should provide easier treatment.

Language: Английский

Intramuscular vs Intravenous SARS-CoV-2 Neutralizing Antibody Sotrovimab for Treatment of COVID-19 (COMET-TAIL): A Randomized Noninferiority Clinical Trial DOI Creative Commons
Adrienne E. Shapiro, Elias Sarkis,

Jude Acloque

et al.

Open Forum Infectious Diseases, Journal Year: 2023, Volume and Issue: 10(8)

Published: July 12, 2023

Convenient administration of coronavirus disease 2019 (COVID-19) treatment in community settings is desirable. Sotrovimab a pan-sarbecovirus dual-action monoclonal antibody formulated for intravenous (IV) or intramuscular (IM) early mild/moderate COVID-19.

Language: Английский

Citations

12
Prediction of human pharmacokinetics of Fc-engineered therapeutic monoclonal antibodies using human FcRn transgenic mice DOI Creative Commons
Kenta Haraya,

Takuya Ichikawa,

Naoaki Murao

et al.

mAbs, Journal Year: 2025, Volume and Issue: 17(1)

Published: March 25, 2025

Human FcRn transgenic mice (Tg32) have been widely used to evaluate the pharmacokinetics of mAbs and predict human pharmacokinetics. This study aims establish an approach for predicting Fc-engineered with enhanced binding mutations using Tg32 mice. MAbs were intravenously administered at 10 mg/kg in absence or presence IVIG (1000 mg/kg) Pharmacokinetic parameters (CL, Q, Vc, Vp) estimated compared clinical data. Optimal allometric scaling exponents determined improve accuracy pharmacokinetic predictions mAbs. Moreover, we predicted plasma concentration-time profile after IV injection humans based on optimized exponent. While normal exhibited a higher CL its absence, showed comparable both conditions. The larger difference between observed closely matched results. A significant positive correlation was IVIG. optimal CL, Vp 0.73, 0.60, 0.95, 0.87, respectively. Using these exponents, mAb accurately predicted. establishes robust methodology mice, achieving prediction that cynomolgus monkeys. approach, as viable alternative monkeys, can accelerate preclinical development promising binding.

Language: Английский

Citations

0
Population pharmacokinetics and exposure‐response analysis of a single dose of sotrovimab in the early treatment of patients with mild to moderate COVID‐19 DOI Creative Commons

Jennifer E. Sager,

Asma El‐Zailik,

Julie Passarell

et al.

CPT Pharmacometrics & Systems Pharmacology, Journal Year: 2023, Volume and Issue: 12(6), P. 853 - 864

Published: March 16, 2023

Sotrovimab is a recombinant human monoclonal antibody that has been shown to prevent progression hospitalization or death in non-hospitalized high-risk patients with mild moderate coronavirus disease 2019 following either intravenous (i.v.) intramuscular (i.m.) administration. Population pharmacokinetic (PopPK) and exposure-response (ER) analyses were performed characterize single dose sotrovimab pharmacokinetics (PK) the relationship between exposure response (probability of progression), as well covariates may contribute between-participant variability PK efficacy i.v. i.m. was described by two-compartment model linear elimination; absorption characterized sigmoid model. PopPK covariate analysis led addition effect body weight on systemic clearance peripheral volume distribution, sex bioavailability first-order rate (KA), mass index KA. However, magnitude not pronounced therefore expected be clinically relevant based available data date. For ER analysis, measures predicted using final An developed measure concentration at 168 h probability within dataset for COMET-TAIL. The number risk factors (≤1 vs. >1) incorporated an additive shift model-estimated placebo but had no impact overall drug response. Limitations generalization these results describe exposure-progression across severe acute respiratory syndrome-coronavirus 2 variants.

Language: Английский

Citations

7
The Effect of Gastrointestinal Graft-Versus-Host Disease and Diarrhea on the Pharmacokinetic Profile of Sotrovimab in Hematopoietic Stem Cell Transplant Recipients DOI Creative Commons
Jim Boonyaratanakornkit, Qianwen Wang, Ahmed Nader

et al.

The Journal of Infectious Diseases, Journal Year: 2024, Volume and Issue: 230(3), P. 670 - 679

Published: May 14, 2024

Abstract Background Monoclonal antibodies (mAbs) are utilized broadly to treat cancer and infectious diseases, mAb exposure (serum concentration over time) is one predictor of overall treatment efficacy. Herein, we present findings from a clinical trial evaluating the pharmacokinetics long-acting sotrovimab targeting severe acute respiratory syndrome coronavirus 2 in hematopoietic cell transplant (HCT) recipients. Methods All participants received an intravenous infusion within 1 week prior initiating pretransplant preparative regimen. The serum was measured longitudinally for up 24 weeks posttransplant. Results Compared non-HCT participants, found that clearance 10% 26% higher autologous allogeneic HCT recipients, respectively. Overall approximately 15% lower recipients compared Exposure significantly reduced who developed diarrhea gastrointestinal graft-versus-host disease (GVHD) Conclusions These data show may be possibly related increased patients with GVHD. This phenomenon has implications dose selection duration efficacy potentially other mAbs this vulnerable patient population. Thus, regimens populations have optimized when applied populations.

Language: Английский

Citations

1
Resistance analysis in the phase III COMET-TAIL study: treatment of COVID-19 with intramuscular or intravenous sotrovimab DOI Creative Commons

Maria L. Agostini,

Gretja Schnell,

Julia di Iulio

et al.

Future Virology, Journal Year: 2024, Volume and Issue: 19(5), P. 185 - 198

Published: March 23, 2024

Aim: Sotrovimab, an engineered human monoclonal antibody, targets a conserved region of the SARS-CoV-2 spike protein. The phase III COMET-TAIL study evaluated noninferiority intravenous versus intramuscular sotrovimab for early treatment high-risk COVID-19 in 973 participants. Materials & methods: We investigated prevalence variants concern/interest (VOC/VOI) and characterized baseline, postbaseline treatment-emergent epitope amino acid substitutions. Results: Delta variant was predominant; Alpha, or Mu were detected participants meeting primary clinical endpoint progression. Of 82 with substitutions, two baseline substitutions met Conclusion: Overall, there no evidence that specific VOC/VOI, impacted

Language: Английский

Citations

0
Pharmacokinetics of the Monoclonal Antibody, Sotrovimab, in Healthy Participants Following IM Administration at Different Injection Sites DOI
Asma El‐Zailik,

Jennifer E. Sager,

Yasmin Sánchez‐Pearson

et al.

Clinical Pharmacology & Therapeutics, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 12, 2024

Sotrovimab is a recombinant human monoclonal antibody for the early treatment of mild‐to‐moderate COVID‐ 19. A phase I, open‐label, randomized, parallel‐group study was conducted to investigate pharmacokinetics, relative bioavailability, safety, and tolerability two concentrations sotrovimab administered intramuscularly at different injection sites in healthy volunteers. The consisted three parts (A, B, C) pharmacokinetic results from Part are reported herein. In A, participants were randomized 2:2:1:1 ratio 500 mg dose 62.5 mg/mL into dorsogluteal muscle, or 100 dorsogluteal, anterolateral thigh, deltoid muscles. Formulation concentration did not impact exposure following administration; point estimates (90% confidence interval [CI]) geometric mean ratios (GMRs) area under curve (AUC) inf maximum serum ( C max ) administration vs. intramuscular 0.95 (0.86–1.05) 1.14 (1.02–1.27), respectively. However, thigh resulted increased gluteal injections; CI) GMRs muscles dorsogluteally 1.63 (1.46–1.83) 1.50 (1.34–1.67) AUC , 1.82 (1.60–2.08) 1.49 (1.31–1.69) Notably, also lower variability key parameters such as AUC, apparent clearance volume distribution, earlier achievement than sotrovimab.

Language: Английский

Citations

0
Intramuscular Versus Intravenous SARS-CoV-2 Neutralizing Antibody Sotrovimab for Treatment of COVID-19 (COMET-TAIL): A Randomized Non-inferiority Clinical Trial DOI Open Access
Adrienne E. Shapiro, Elias Sarkis,

Jude Acloque

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: March 24, 2023

Abstract Background Convenient administration of coronavirus disease 2019 (COVID-19) treatment in community settings is desirable. Sotrovimab a pan-sarbecovirus dual-action monoclonal antibody formulated for intravenous (IV) or intramuscular (IM) early mild/moderate COVID-19. Methods This phase 3, randomized, multicenter, open-label study tested non-inferiority IM to IV using 3.5% absolute margin. From June August 2021, patients aged ≥12 years with COVID-19, not hospitalized receiving supplemental oxygen, and at high risk progression were randomized 1:1:1 single 500-mg sotrovimab infusion 250-mg injection. The primary composite endpoint was all-cause hospitalization >24 hours acute management illness death through day 29. Results 500 mg non-inferior IV: 10/376 (2.7%) participants the group versus 5/378 (1.3%) met (absolute adjusted difference: 1.06% [95% confidence interval [CI]: −1.15%, 3.26%]). CI upper limit lower than prespecified margin 3.5%. enrollment discontinued because greater proportion hospitalizations seen that groups. Serious adverse events occurred <1% 2% across Four experienced serious related died (500 IM: 2/393 [<1%]; 250 2/195 [1%]). Conclusions injection well tolerated administration. could expand outpatient access Registration ClinicalTrials.gov Identifier: NCT04913675 Key Points COVID-19 high-risk patients, measured by >24h 29, well-tolerated. should provide easier treatment.

Language: Английский

Citations

1