Enhanced Clearance of HIV ‐1 Broadly Neutralizing Antibody VRC07 ‐523‐ LS During Viremia: Influences on Trial Design and Analysis

ABSTRACT Broadly neutralizing antibodies (BNAb) are capable of neutralizing multiple HIV‐1 strains through the targeting of conserved epitopes. This study's objective was to quantify the pharmacokinetic (PK) parameters describing the distribution and elimination of the BNAb VRC07‐523‐LS in people with HIV (PWH), and to identify the influence of viral load on VRC07‐523‐LS elimination. The PK of VRC07‐523‐LS was assessed in participants with and without HIV after intravenous or subcutaneous administration. A Bayesian strategy was utilized to estimate VRC07‐523‐LS PK parameters, leveraging a previously published study in adults without HIV. The effects of static viral loads on VRC07‐523‐LS exposure and time to a target trough serum concentration of 1 mg/L was then evaluated using clinical trial simulations. VRC07‐523‐LS serum concentrations were described by a two‐compartment model with first order absorption from the subcutaneous site. Typical clearance was estimated as 99.3 mL/day, which increased to a maximum of 6.46‐fold higher with viremia. Clinical trial simulations without viremia showed that a 700–2100 mg dose of VRC07‐523‐LS is expected to remain above the IC 50 of 0.055 mg/L beyond 52 weeks. With a viral load of 30,000 copies/mL, a 2100 mg dose of VRC07‐523‐LS is expected to result in 90% of participants having a concentration below 1 mg/L by 18.6 weeks, a decrease of 42 weeks compared to aviremic patients. Mechanistic modeling offers the ability to identify HIV viral load effects on BNAb PK and can improve BNAb dosing, especially with consideration of acute versus maintenance treatment.