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Levels of Long-Acting Anti-HIV bNAb High in Infants After 1 or 2 Doses--But Not High Enough
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International Workshop on Clinical Pharmacology of HIV, Hepatitis, and Other Antiviral Drugs Virtual Meeting, September 28-30, 2020
By Mark Mascolini for NATAP and Virology Education
Population pharmacokinetic modeling of the HIV-specific broadly neutralizing antibody (bNAb) VRC01LS in infants indicated that concentrations would stay above 20 mcg/mL for 6 months after doses at 0 and 12 weeks in almost all infants [1]. But the target is 50 mcg/mL. Early infant growth had a large impact on VRC01LS concentration, according to results reported by University of California, San Diego researchers and collaborators at other centers.
The monoclonal antibody VRC01LS, the first long-acting anti-HIV bNAb, has activity against up to 90% of HIV-1 strains. Because of its long half-life, VRC01LS has emerged as an HIV PrEP candidate and as possible treatment for infants, in whom treatment adherence remains a challenge. A phase 1 dose-escalation study of VRC01LS in healthy adults measured a half-life more than 4-fold higher than that of wild-type bNAb VRC01, a result suggesting the possibility of maintaining therapeutic levels with less frequent and lower doses [2]. VRC01LS is a modified version of the bNAb VRC01; both target the CD4 binding site HIV uses to enter cells.
The new study set out to describe the population pharmacokinetics of subcutaneous VRC01LS in early infancy among HIV-exposed African and US infants participating in the phase 1 IMPAACT P1112 trial [3]. The 21 healthy infants entered the trial at a median age of 2 days (range 0 to 4) and a median weight of 2.8 kg (range 2.5 to 3.8). They received a subcutaneous dose of 80 mg if weighing less than 4.5 kg and 100 mg if weighing 4.5 kg or more. While 10 nonbreastfed infants got a single dose on day 1, 11 breastfed infants received a second dose at week 12.
Researchers collected pharmacokinetic samples 24 hours and 2, 4, 8, 12, 14, 16, and 24 weeks after VRC01LS dosing in breast-fed infants, and at those times plus 36 and 48 weeks in nonbreastfed infants. Before assessing other potential covariates, the investigators incorporated allometric scaling into the population pharmacokinetic model with clearance (CL/F) scaled as (WT/70)^0.85 and volume of distribution (VD) as (WT/70)^1.0. Potential covariates included infant age, infant sex, breastfeeding, and location (US or Africa). The research team used 1000 Monte Carlo simulations to predict concentrations of VRC01LS 12 and 24 weeks after dosing.
A one-compartment model proved sufficient to describe the data. Final model parameters were CL/F 71.04 x (WT/70)^0.85 mL/day and V/F 8.46 x (WT/70) x 0.84^Day past 84 days. Weight rose from 3.3 kg at birth to 5.7 kg at week 12 and had a significant impact on pharmacokinetic values. Over that time VD rose 37% from 423 mL to 579 mL and CL/F climbed 59% from 5.30 to 8.43 mL/day.
The target serum concentration was 50 mcg/mL or more for 6 months or more. The 1000 simulations predicted that a single 80-mg dose would yield a median VRC01LS concentration of 43.7 mcg/mL at week 12, when 27.1% of trough concentrations would lie at or above 50 mcg/mL and 99.8% at or above 20 mcg/mL. With a single 100-mg dose, 66.9% of trough concentrations would lie at or above 50 mcg/mL at week 12 and 99.9% at or above 20 mcg/mL. With a first dose of 80 mg and a second dose of 100 mg at week 12, 60.6% of trough concentrations would lie at or above 50 mcg/mL at week 24 and 99.8% at or above 20 mcg/mL.
The researchers concluded that a higher dose or more frequent dosing will be needed to keep VRC01LS concentrations above 50 mcg/mL in most infants. The dilution effect from early infant growth, they stressed, contributes to the drop in VRC01LA concentrations.
References
1. Yang J, Cunningham C, McFarland E, et al. Population pharmacokinetics of HIV-specific broadly monoclonal neutralizing long-acting antibody, VRC01LS, in term infants. International Workshop on Clinical Pharmacology of HIV, Hepatitis, and Other Antiviral Drugs Virtual Meeting, September 28-30, 2020. Abstract 4.
2. Gaudinski MR, Coates EE, Houser KV, et al. Safety and pharmacokinetics of the Fc-modified HIV-1 human monoclonal antibody VRC01LS: a phase 1 open-label clinical trial in healthy adults. PLoS Med 2018;15(1):e1002493. https://doi.org/10.1371/journal.pmed.1002493
3. ClinicalTrials.gov. Evaluating the safety and pharmacokinetics of VRC01, VRC01LS, and VRC07-523LS, potent anti-HIV neutralizing monoclonal antibodies, in HIV-1-exposed infants. ClinicalTrials.gov identifier NCT02256631.
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