4.5 Article

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

期刊

MABS
卷 9, 期 5, 页码 792-800

出版社

TAYLOR & FRANCIS INC
DOI: 10.1080/19420862.2017.1311435

关键词

Body weight; multiple-dose; time-concentration curve; two-compartment; VRC01 serum concentration

资金

  1. National Institute of Allergy and Infectious Diseases (NIAID) US. Public Health Service [LOC: HIV Vaccine Trials Network] [UM1 AI068614]
  2. National Institute of Allergy and Infectious Diseases (NIAID) US. Public Health Service [HVTN SDMC FHCRC] [UM1 AI068635]
  3. National Institute of Allergy and Infectious Diseases (NIAID) US. Public Health Service [HVTN Laboratory Center FHCRC] [UM1 AI068618]

向作者/读者索取更多资源

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.

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