006: Infant & Adult VRC07-523LS Population Pharmacokinetic Modeling to Predict HIV Prevention in Breastfed Infants

Statement of Purpose: VRC07-532LS is a second-generation, potent, broadly neutralizing, monoclonal antibody (bNAb) targeting the HIV-1 CD4 binding site under study for HIV-1 prophylaxis and intensive early treatment regimens for children and adults. This study developed a population pharmacokinetic (popPK) model from infants and adults to understand factors affecting VRC07-523LS disposition and predict infants’ exposures associated with potential use during breastfeeding.

Description of Methods & Materials: VRC07-523LS pharmacokinetic (PK) data from 2 separate studies were utilized for the analysis: healthy adults (VRC605, n=25), and HIV-exposed infants initiating therapy ≤5 days of age (IMPAACT P1112, n=21). In adults, 4 groups were administered either one dose of 1, 5, 20 or 40 mg/kg intravenous (IV) or 5 mg/kg subcutaneous (SC). Two groups received three doses of either 20 mg/kg IV or 5 mg/kg SC. The infant study had two dosing cohorts: Cohort 1 received a single 80-mg SC dose whereas Cohort 2 received the same initial dose and a second dose of 100 mg at Week 12, if the infant was breastfed. A total of 638 VRC07-523LS concentrations (ELISA assay) collected up to 84 weeks were utilized in a two-compartment popPK model (NONMEM v7.5). Allometric scaling was utilized in the model: Apparent clearance (CL/F): (WTKG/70)0.85; apparent steady state volume of distribution (Vss/F): (WTKG/70)1.0 [Deng et al. 2010]. Covariates were evaluated using univariable then multivariable assessment. Monte Carlo simulations of the final model assessed two doses (80 mg followed by 100 mg at 12 weeks; 2,100 virtual subjects) to determine the maintenance of VRC07-523LS levels >10 µg/mL. The bNAb concentration/IC80 ratio (PT80) was calculated at 8 and 12 weeks based on PK simulations from the final popPK model and the distribution of IC80 from 208 isolates. Calculated PT80 values were used to estimate the VRC07-523LS HIV-1 prevention efficacy based on a bNAb pharmacodynamic (PD) model from the AMP PrEP study efficacy [Gilbert et al. 2022].

Data & Results: VRC07-523LS concentration data were well described by the model. The final popPK model is: Vss/F (L) = 13.54 x (WTKG/70)1.0 x 1.44 (if repeat dose) CL/F (L/hr) = 0.007 x (WTKG/70)0.85 x 1.74 (if adult) Between subject variability for Vss/F and CL/F were 37% and 32%, respectively. Early concentrations were lower in infants following SC administration than adults IV due to a larger Vss after the first dose and low F (24%). This model predicts a typical CL/F of 4.02 and 4.32 mL/kg/day in infants and healthy adults, respectively. VRC07-523LS concentrations exceeded 10 µg/mL in >80% of virtual infants at 12 weeks and >96% at 24 weeks (Figure 1). Median PT80 were 110 and 57 at 8 and 12 weeks, which estimates HIV-1 prevention efficacies of 78% and 58%, respectively.

Interpretation, Conclusion or Significance: Age and dose number are key factors in VRC07-523LS PK. An 80-mg SC dose of VRC07-523LS followed by 100 mg at 12 weeks rapidly achieves and maintains concentrations >10 µg/mL for more than 24 weeks. This is expected to result in >50% prevention efficacy in infants and supports further evaluation of VRC07-523LS during breastfeeding.

Disclosures: