Fixed dosing versus weight-based dosing of HIV-1 prophylactic monoclonal antibodies in adults: a post-hoc, cross-protocol pharmacokinetics modelling study

Area of Science:

• Pharmacokinetics and Pharmacodynamics
• Immunology
• Drug Development

Background:

• Pharmacokinetic (PK) modeling and simulations are crucial for optimizing therapeutic monoclonal antibody (mAb) dosing strategies.
• Early-phase clinical trial data from adults without HIV-1 were used to compare dosing strategies for three HIV-1 broadly neutralizing mAbs.

Purpose of the Study:

• To compare fixed versus weight-based dosing strategies for three HIV-1 broadly neutralizing monoclonal antibodies (mAbs).
• To evaluate the impact of body weight on mAb pharmacokinetics and predicted neutralization efficacy.

Main Methods:

• A two-compartment population PK model was employed to analyze serum concentrations from individuals receiving PGDM1400LS, PGT121.414.LS, or VRC07-523LS.
• Simulations compared fixed and weight-based dosing, assessing concentrations, AUC, and predicted neutralization titres against HIV-1 strains.

Main Results:

• Body weight had a modest effect on mAb clearance and distribution.
• Fixed and weight-based dosing strategies yielded comparable population-level concentrations, AUC, and predicted neutralization titres.
• Fixed dosing showed potential to correct underdosing in lower-weight individuals and offered comparable exposure in higher-weight individuals.

Conclusions:

• A fixed-dose approach, potentially with weight banding, is advantageous for HIV-1 prophylactic mAbs.
• Fixed dosing enhances operational efficiency and maintains pharmacokinetic comparability and inter-individual consistency.
• This strategy simplifies administration while ensuring effective neutralization capacity.