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Population pharmacokinetics analysis of VRC01, an HIV-1 broadly neutralizing monoclonal antibody, in healthy adults.

ABSTRACT: The monoclonal antibody VRC01 targets the CD4 binding site of the human immunodeficiency virus (HIV)-1 envelope. In the clinical study HVTN 104 (NCT02165267), 84 HIV-uninfected adults received multiple-dose intravenous (IV) VRC01 (10, 20, 30 or 40 mg/kg) every 4 or 8 weeks or subcutaneous (SC) VRC01 (5 mg/kg) every 2 weeks, and were followed for 32 weeks. We conducted a population pharmacokinetics (popPK) analysis based on 1117 VRC01 serum concentrations using a 2-compartment PK model with first-order elimination; for SC VRC01 a depot compartment with a first-order absorption rate constant was also included. All PK parameters were estimated with acceptable precision. Estimated bioavailability of SC VRC01 was 74%, with peak concentrations occurring 2-3 d after administration. For both IV and SC VRC01, population mean estimates for clearance (CL), central volume of distribution (Vc), inter-compartmental distribution clearance (Q) and peripheral volume of distribution (Vp) were 0.40 L/day, 1.94 L, 0.84 L/day and 4.90 L, respectively; the estimated terminal half-life was 15 d and these were independent of VRC01 dose. Body weight significantly influenced CL (1.2% fold/kg), Vc (1.0% fold/kg), Q (0.69 log(L/day)/kg) and Vp (0.82 log(L)/kg). The developed popPK model, supporting weight-dependent dosing regimens, projected positive trough levels, 5.54 (95% prediction interval: 1.69, 14.5) mcg/mL and 15.9 (5.29, 46.63) mcg/mL, respectively, for the 10 mg/kg and 30 mg/kg 8-weekly regimens being evaluated in ongoing HIV prevention efficacy studies of IV VRC01. These results are critical for future dose-regimen selection and modeling research to identify VRC01 serum concentration levels sufficient for protection against HIV infection.

SUBMITTER: Huang Y

PROVIDER: S-EPMC5524155 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Population pharmacokinetics analysis of VRC01, an HIV-1 broadly neutralizing monoclonal antibody, in healthy adults.

Huang Yunda Y Zhang Lily L Ledgerwood Julie J Grunenberg Nicole N Bailer Robert R Isaacs Abby A Seaton Kelly K Mayer Kenneth H KH Capparelli Edmund E Corey Larry L Gilbert Peter B PB

mAbs 20170403 5

The monoclonal antibody VRC01 targets the CD4 binding site of the human immunodeficiency virus (HIV)-1 envelope. In the clinical study HVTN 104 (NCT02165267), 84 HIV-uninfected adults received multiple-dose intravenous (IV) VRC01 (10, 20, 30 or 40 mg/kg) every 4 or 8 weeks or subcutaneous (SC) VRC01 (5 mg/kg) every 2 weeks, and were followed for 32 weeks. We conducted a population pharmacokinetics (popPK) analysis based on 1117 VRC01 serum concentrations using a 2-compartment PK model with first ...[more]

PMID: 28368743

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Project description:IntroductionThe last 12 years have seen remarkable progress in the isolation and characterization of at least five different epitope classes of HIV-specific broadly neutralizing antibodies (bnAbs). Detailed analyses of these bnAb lineages, maturation pathways and epitopes have created new opportunities for vaccine development. In addition, interest exists in passive administration of monoclonal antibodies as a viable option for HIV prevention.DiscussionRecently, two antibody-mediated prevention (AMP) trials of a passively administered monoclonal antibody targeting the HIV envelope CD4 binding site, called VRC01, provided proof-of-concept that monoclonal antibody infusion could offer protection against HIV acquisition. While the trials failed to show overall protection against HIV acquisition, sub-analyses revealed that VRC01 infusion provided a 75% prevention efficacy against HIV strains that were susceptible to the antibody. The study also demonstrated that in vitro neutralizing activity, measured by the TZM-bl/pseudovirus assay, was able to predict HIV prevention efficacy in humans. In addition, the AMP trials defined a threshold protective concentration, or neutralization titer, for the VRC01 class of bnAbs, explaining the observed low overall efficacy and serving as a benchmark for the clinical testing of new bnAbs, bnAb cocktails and neutralizing antibody-inducing vaccines. Newer bnAbs that exhibit greater potency and breadth of neutralization in vitro than VRC01 are available for clinical testing. Combinations of best-in-class bnAbs with complementary magnitude, breadth and extent of complete neutralization are predicted to far exceed the prevention efficacy of VRC01. Some engineered bi- and trispecific mAbs exhibit similar desirable neutralizing activity and afford advantages for manufacturing and delivery. Modifications that prolong the serum half-life and improve genital tissue persistence offer additional advantages.ConclusionsIterative phase 1 trials are acquiring safety and pharmacokinetic data on dual and triple bnAbs and bi- and trispecific antibodies in preparation for future AMP studies that seek to translate findings from the VRC01 efficacy trials and achieve acceptable levels of overall prevention efficacy.

Dataset Information

Population pharmacokinetics analysis of VRC01, an HIV-1 broadly neutralizing monoclonal antibody, in healthy adults.

Publications

Population pharmacokinetics analysis of VRC01, an HIV-1 broadly neutralizing monoclonal antibody, in healthy adults.

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