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Background and Objective <p>AZD7442 is a combination of extended half-life monoclonal antibodies (mAbs; tixagevimab and cilgavimab), developed to neutralize SARS-CoV-2. This open-label Phase 1 study compared pharmacokinetics (PK) of three AZD7442 formulations in which component mAbs were (1) co-formulated versus separately formulated and (2) derived from clonal cell line or cell pool material when separately formulated.</p> Methods <p>Healthy adults were randomized 1:1:1 to receive intramuscular (IM) AZD7442 300 mg (150 mg each of tixagevimab and cilgavimab) via one injection of co-formulated tixagevimab and cilgavimab from clonal cell line material (treatment A), or two sequential injections of tixagevimab and cilgavimab formulated separately either from clonal cell line (treatment B) or cell pool material (treatment C). Serial blood samples were collected up to 360 days post-dose to evaluate serum concentrations and anti-drug antibody responses. Standard exposure metrics (<i>C</i><sub>max</sub>, AUC<sub>last</sub> and AUC<sub>inf</sub>) were used for PK comparability assessment between treatments (A vs B, B vs C and A vs C). A post hoc analysis using partial area under the curve (pAUC) was also conducted.</p> Results <p>In total, 224 participants were randomized and dosed. Serum concentration–time profiles overlapped post dosing across treatments. Median time to reach peak concentration occurred within 2 weeks with mean terminal half-life 74–84 days. Pharmacokinetic comparability for tixagevimab, cilgavimab and AZD7442 was demonstrated between treatments, with geometric mean ratios (GMR) and 90% CI within 0.8000–1.2500 using traditional exposure metrics (<i>C</i><sub>max</sub>, AUC<sub>last</sub> and AUC<sub>inf</sub>) and partial AUCs (pAUCs; AUC<sub>0–d30</sub>, AUC<sub>0–d60</sub>, AUC<sub>0–d90</sub>, or AUC<sub>0–d180</sub>), except for comparison of treatment A versus B for tixagevimab, where the lower 90% CI bound for AUC<sub>last</sub> GMR (0.7933) was slightly below the pre-defined threshold of 0.8000. Low immunogenicity and acceptable safety profiles were observed across treatments.</p> Conclusions <p>Pharmacokinetic comparability of tixagevimab, cilgavimab and AZD7442 was demonstrated between the different treatments based on analyses using traditional bioequivalence metrics or pAUCs. Partial AUC could serve as an exposure metric when evaluating PK comparability for extended half-life mAbs.</p> Trial Registry <p>Clinical trials registration number: ClinicalTrials.gov NCT05166421.</p>

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Pharmacokinetic Comparability Assessment of Tixagevimab and Cilgavimab Developed for COVID-19 Prevention and Treatment Using Standard Exposure Metrics and Partial Area Under the Curve

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月31日

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  • Huixia Zhang,
  • Weifeng Tang,
  • Samuel Sadow,
  • Roberta Baronio,
  • Antonella Nadia Tullio,
  • Lauren Hirao,
  • Vitalina Dzutseva,
  • Cecil Chi-Keung Chen,
  • Alexandre Kiazand,
  • Lee-Jah Chang,
  • Taylor S. Cohen,
  • Michael Gibbs

摘要

Background and Objective

AZD7442 is a combination of extended half-life monoclonal antibodies (mAbs; tixagevimab and cilgavimab), developed to neutralize SARS-CoV-2. This open-label Phase 1 study compared pharmacokinetics (PK) of three AZD7442 formulations in which component mAbs were (1) co-formulated versus separately formulated and (2) derived from clonal cell line or cell pool material when separately formulated.

Methods

Healthy adults were randomized 1:1:1 to receive intramuscular (IM) AZD7442 300 mg (150 mg each of tixagevimab and cilgavimab) via one injection of co-formulated tixagevimab and cilgavimab from clonal cell line material (treatment A), or two sequential injections of tixagevimab and cilgavimab formulated separately either from clonal cell line (treatment B) or cell pool material (treatment C). Serial blood samples were collected up to 360 days post-dose to evaluate serum concentrations and anti-drug antibody responses. Standard exposure metrics (Cmax, AUClast and AUCinf) were used for PK comparability assessment between treatments (A vs B, B vs C and A vs C). A post hoc analysis using partial area under the curve (pAUC) was also conducted.

Results

In total, 224 participants were randomized and dosed. Serum concentration–time profiles overlapped post dosing across treatments. Median time to reach peak concentration occurred within 2 weeks with mean terminal half-life 74–84 days. Pharmacokinetic comparability for tixagevimab, cilgavimab and AZD7442 was demonstrated between treatments, with geometric mean ratios (GMR) and 90% CI within 0.8000–1.2500 using traditional exposure metrics (Cmax, AUClast and AUCinf) and partial AUCs (pAUCs; AUC0–d30, AUC0–d60, AUC0–d90, or AUC0–d180), except for comparison of treatment A versus B for tixagevimab, where the lower 90% CI bound for AUClast GMR (0.7933) was slightly below the pre-defined threshold of 0.8000. Low immunogenicity and acceptable safety profiles were observed across treatments.

Conclusions

Pharmacokinetic comparability of tixagevimab, cilgavimab and AZD7442 was demonstrated between the different treatments based on analyses using traditional bioequivalence metrics or pAUCs. Partial AUC could serve as an exposure metric when evaluating PK comparability for extended half-life mAbs.

Trial Registry

Clinical trials registration number: ClinicalTrials.gov NCT05166421.