Abstract Body

VRC01LS, a long-acting variant of VRC01, is a broadly neutralizing monoclonal antibody (bNAb) with activity against many HIV-1 strains. The increased half-life from the 2 amino acid modifications in the native Fc region of the VRC01 antibody makes VRC01LS a desirable candidate for use as infant prophylaxis and treatment. The current study aimed to develop a composite VRC01LS population pharmacokinetic (PopPK) model in infants and adults to help optimize infant VRC01LS dosing.

VRC01LS PK data were pooled from two separate studies: HIV-exposed infants (IMPAACT P1112, N= 21) and healthy adults (VRC606, N= 49). All infants received a dose of VRC01LS subcutaneously (SC) using weight-band dosing (<4.5kg: 80 mg; ?4.5kg: 100 mg) within the first 4 days of life. Breast-fed infants also received a 2nd dose at week 12. Adults received 1 or 3 doses of VRC01LS at 5-40mg/kg IV or 5 mg/kg SC. A total of 907 VRC01LS concentrations were analyzed using NONMEM version 7.3, FOCEI method. Allometric scaling was incorporated into the PopPK model before evaluation of other potential covariates. Age group (infants vs. adults), gender, dose (mg/kg), dose number (1st vs 2nd/3rd Dose), creatinine and hematocrit were evaluated as potential covariates. A Monte Carlo simulation (n=1000) was performed using the final model to predict (median, 95% CI) infant VRC01LS concentrations following SC administration.

A two-compartment model best describes the data. The key PopPK parameters are: Clearance (CL, L/h/70kg) = 0.00148*(WT/70)0.85 Volume at Steady State (Vss, L/70kg) = 3.53*(WT/70) *0.829 (If 2nd/3rd Dose ) Rate of Absorption (KA, 1/h) = 0.0129*2.78 (if infant) Bioavailability (F, %) = 63.8*0.714 (if infant) Between-subject variabilities are 27% for CL and 24% for Vss. Infants have lower bioavailability and more rapid absorption than adults. VRC01LS CL/F in infants is confounded by the ‘dilutional’ effect of infant growth; mean weight increased from 3.0kg at birth to 5.7kg at week 12. Infant VRC01LS CL/F is lower than previously reported for VRC01 (Li CPT 2020). Monte Carlo simulations of 80mg in infants shortly after birth predicts a median week 12 concentration of 34.5mcg/mL with 9.8% of VRC01LS concentrations ? 50mcg/mL and 96.3% of VRC01LS concentrations ? 20mcg/mL.

The PopPK of VRC01LS demonstrates slow elimination in infants and adults allowing every 12 week dosing. VRC01LS has promise in infant HIV prophylaxis and treatment.