Model-based assessment of VRC07-523LS dosing in infants through population pharmacokinetic -pharmacodynamic modelling in adults and infants
Year: 2025
Type: article
Abstract: OBJECTIVES: To develop a population pharmacokinetic (popPK) model to understand factors affecting the broadly neutralizing HIV antibody (bNAb) VR07-523LS disposition and infant predicted serum neutralization 80% inhibitory dilution titre ratio (PT80) and its potential relationship to antiviral effects. METHODS: PK data from two studies were used: infants exposed to HIV initiating therapy ≤5 days of age (IMPAACT P1112, n = 21) and healthy adults (VRC605, n = 25). The infant study implemented fixed subcutaneous (s.c.) dosing whereas the adult study implemented weight-based dosing, via both intravenous (i.v.) and s.c. routes. Monte Carlo simulation assessed two doses (80 mg followed by 100 mg at 12 weeks) to determine the maintenance of levels >10 µg/mL in virtual infants. The broadly neutralizing antibodies (bNAbs) concentration/IC80 ratio (PT80) was calculated on the basis of simulated concentrations from the popPK model and VRC07-523LS HIV-1 sensitivity (IC80) distribution. RESULTS: This model predicts typical infant CL/F and t1/2 of 159 mL/day/70 kg and 39 days. Comparatively, predicted adult typical CL/F and t1/2 were 269 mL/day/70 kg and 31 days. Concentrations were >10 µg/mL in >87% of virtual infants at 12 weeks following one dose and >98% at 24 weeks following two doses. Median (90% predictive interval) PT80 was 163 (71-383), 116 (51-274) and 61 (26-144) at 6, 8 and 12 weeks, respectively. Significant model covariates included age (infant versus adult) and multiple dosing. CONCLUSIONS: Age and repeat dosing influence VRC07-523LS PK. An 80-mg dose followed by 100 mg at 12 weeks rapidly achieves and maintains concentrations >10 µg/mL for >24 weeks. This dosing strategy is expected to result in antiviral effects in patients with sensitive viruses and supports further evaluation of VRC07-523LS.
DOI: 10.1093/jac/dkaf449
Institutions: University of California San Diego, Children's Hospital of Orange County, University of California, Irvine, University of Colorado Anschutz, University of Colorado Denver, Frontier Science & Technology Research Foundation, Inc., Family Health International 360, National Institute of Allergy and Infectious Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Vaccine Research Center
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,784
OpenAlex ID: W7124745640