Model Informed Development of VRC01 in Newborn Infants Using a Population Pharmacokinetics Approach.

VRC01 is a first-in-class, potent, broadly neutralizing antibody that targets the CD4 binding site of gp120 on HIV-1 viruses, and is under development as a novel HIV therapeutic. This study utilized population pharmacokinetic modeling to characterize VRC01 pharmacokinetics to guide dosing selection for ongoing phase 2 clinical trials in pediatric patients. Combining VRC01 pharmacokinetic data from 3 adult and 1 infant clinical trials, a total of 1475 VRC01 serum concentrations from 100 participants were used in the analysis (40 infants, 60 adults). VRC01 was administered either intravenously (IV) or subcutaneously (SC) (1 - 40 mg/kg). All infants received SC doses as compared to 13% SC and 87% IV in adults. The data were well described by a two-compartment model. Clearance was 37% higher in adults with HIV infection and 83% lower in infants than adults. Subcutaneous bioavailability was 55% in adults. Rapid absorption was seen in infants indicating therapeutic levels could be achieved quickly. Monte Carlo simulations were used to determine optimal dosing and demonstrated 40 mg/kg SC at weeks 0, 2, 6, and 10 would maintain VRC01 levels at the suppressive target concentration of 50 μg/mL for the first 14 weeks of life in infants. The current analysis provides new insight into differences in monoclonal antibody pharmacokinetics between infants and adults and demonstrates the utility of a population pharmacokinetic approach in informing drug development for infant populations.