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<p>VRC07-523LS is a safe and well-tolerated monoclonal antibody (mAb) targeting the CD4 binding site on the HIV envelope (Env) trimer. Efficacy of VRC07-523LS, in combination with mAbs targeting other HIV epitopes, will be evaluated in upcoming trials to prevent HIV acquisition in adults. However, differences in the pharmacokinetics (PK) of VRC07-523LS when administered alone vs. in combination with other mAbs have not been formally assessed. We performed a cross-protocol analysis of three clinical trials and included data from a total of 146 adults without HIV who received intravenous (<i>n</i> = 95) or subcutaneous (<i>n</i> = 51) VRC07-523LS, either alone (‘single’; <i>n</i> = 100) or in combination with 1 or 2 other mAbs (‘combined’; <i>n</i> = 46). We used an open, two-compartment population PK model to describe serum concentrations of VRC07-523LS over time, accounting for inter-individual variabilities. We compared individual-level PK parameters between the combined vs. single groups using the targeted maximum likelihood estimation method to adjust for participant characteristics. No significant differences were observed in clearance rate, inter-compartmental clearance, distribution half-life, or total VRC07-523LS exposure over time. However, for the combined group, mean central volume of distribution, peripheral volume of distribution, and elimination half-life were slightly greater, corresponding to slightly lower predicted concentrations early post-administration with high levels being maintained in both groups. These results suggest potential PK interactions between VRC07-523LS and other mAbs, but with small clinical impact in the context of HIV prevention. Our findings support coadministration of VRC07-523LS with other mAbs, and the use of the developed PK models to design future trials for HIV prevention.</p>

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Pharmacokinetic interaction assessment of an HIV broadly neutralizing monoclonal antibody VRC07-523LS: a cross-protocol analysis of three phase 1 trials in people without HIV

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月19日

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  • Tariro D. Chawana,
  • Stephen R. Walsh,
  • Lynda Stranix-Chibanda,
  • Zvavahera M. Chirenje,
  • Chenchen Yu,
  • Lily Zhang,
  • Kelly E. Seaton,
  • Jack Heptinstall,
  • Lu Zhang,
  • Carmen A. Paez,
  • Theresa Gamble,
  • Shelly T. Karuna,
  • Philip Andrew,
  • Brett Hanscom,
  • Magdalena E. Sobieszczyk,
  • Srilatha Edupuganti,
  • Cynthia L. Gay,
  • Sharon B. Mannheimer,
  • Christopher B. Hurt,
  • Kathryn E. Stephenson,
  • Laura L. Polakowski,
  • Hans Spiegel,
  • Margaret Yacovone,
  • Stephanie Regenold,
  • Catherine Yen,
  • Jane AG. Baumblatt,
  • Lucio Gama,
  • Dan H. Barouch,
  • Estelle Piwowar-Manning,
  • Richard A. Koup,
  • Georgia D. Tomaras,
  • Ollivier Hyrien,
  • Alison C. Roxby,
  • Yunda Huang

摘要

VRC07-523LS is a safe and well-tolerated monoclonal antibody (mAb) targeting the CD4 binding site on the HIV envelope (Env) trimer. Efficacy of VRC07-523LS, in combination with mAbs targeting other HIV epitopes, will be evaluated in upcoming trials to prevent HIV acquisition in adults. However, differences in the pharmacokinetics (PK) of VRC07-523LS when administered alone vs. in combination with other mAbs have not been formally assessed. We performed a cross-protocol analysis of three clinical trials and included data from a total of 146 adults without HIV who received intravenous (n = 95) or subcutaneous (n = 51) VRC07-523LS, either alone (‘single’; n = 100) or in combination with 1 or 2 other mAbs (‘combined’; n = 46). We used an open, two-compartment population PK model to describe serum concentrations of VRC07-523LS over time, accounting for inter-individual variabilities. We compared individual-level PK parameters between the combined vs. single groups using the targeted maximum likelihood estimation method to adjust for participant characteristics. No significant differences were observed in clearance rate, inter-compartmental clearance, distribution half-life, or total VRC07-523LS exposure over time. However, for the combined group, mean central volume of distribution, peripheral volume of distribution, and elimination half-life were slightly greater, corresponding to slightly lower predicted concentrations early post-administration with high levels being maintained in both groups. These results suggest potential PK interactions between VRC07-523LS and other mAbs, but with small clinical impact in the context of HIV prevention. Our findings support coadministration of VRC07-523LS with other mAbs, and the use of the developed PK models to design future trials for HIV prevention.