title: 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.
authors.affiliation: a Vaccine and Infectious Disease Division, Public Health Division , Fred Hutchinson Cancer Research Center , Seattle , WA , USA.|b Department of Global Health , University of Washington , Seattle , WA , USA.
authors.forename: Yunda
authors.initials: Y
authors.lastname: Huang
authors.affiliation: c Vaccine And Infectious Disease Division , Fred Hutchinson Cancer Research Center , Seattle , WA , USA.
authors.forename: Lily
authors.initials: L
authors.lastname: Zhang
authors.affiliation: d Vaccine Research Center, National Institute of Allergy and Infectious Diseases , Bethesda , MD , USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Ledgerwood
authors.affiliation: c Vaccine And Infectious Disease Division , Fred Hutchinson Cancer Research Center , Seattle , WA , USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Grunenberg
authors.affiliation: e Vaccine Research Center, National Institute of Allergy and Infectious Diseases , Bethesda , MD , USA.
authors.forename: Robert
authors.identifier: 0000-0002-4171-9869
authors.initials: R
authors.lastname: Bailer
authors.affiliation: c Vaccine And Infectious Disease Division , Fred Hutchinson Cancer Research Center , Seattle , WA , USA.
authors.forename: Abby
authors.initials: A
authors.lastname: Isaacs
authors.affiliation: f Duke Human Vaccine Institute, Duke University Medical Center , Durham , NC , USA.
authors.forename: Kelly
authors.identifier: 0000-0002-2009-3270
authors.initials: K
authors.lastname: Seaton
authors.affiliation: g The Fenway Institute , Boston , MA , USA.
authors.forename: Kenneth H
authors.identifier: 0000-0001-7460-733X
authors.initials: KH
authors.lastname: Mayer
authors.affiliation: h University of California , San Diego , CA , USA.
authors.forename: Edmund
authors.initials: E
authors.lastname: Capparelli
authors.affiliation: c Vaccine And Infectious Disease Division , Fred Hutchinson Cancer Research Center , Seattle , WA , USA.
authors.forename: Larry
authors.initials: L
authors.lastname: Corey
authors.affiliation: a Vaccine and Infectious Disease Division, Public Health Division , Fred Hutchinson Cancer Research Center , Seattle , WA , USA.|i Department of Biostatistics , University of Washington , Seattle , WA , USA.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Gilbert
mesh_terms: D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D057134:Antibodies, Neutralizing / Q000008:administration & dosage*; D000080908:Broadly Neutralizing Antibodies; D004305:Dose-Response Relationship, Drug; D005260:Female; D015483:HIV Antibodies / Q000008:administration & dosage*; D015497:HIV-1; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000080908:Broadly Neutralizing Antibodies; D015483:HIV Antibodies; C578595:VRC01 monoclonal antibody
keywords: Body weight; VRC01 serum concentration; multiple-dose; time-concentration curve; two-compartment