
Preprints with The Lancet is a collaboration between The Lancet Group of journals and SSRN to facilitate the open sharing of preprints for early engagement, community comment, and collaboration. Preprints available here are not Lancet publications or necessarily under review with a Lancet journal. These preprints are early-stage research papers that have not been peer-reviewed. The usual SSRN checks and a Lancet-specific check for appropriateness and transparency have been applied. The findings should not be used for clinical or public health decision-making or presented without highlighting these facts. For more information, please see the FAQs.
Fixed Dosing Versus Weight-Based Dosing of HIV-1 Prophylactic Monoclonal Antibodies in Adults: A Pharmacokinetics Modeling Study
23 Pages Posted: 14 Jan 2025
More...Abstract
Background: Pharmacokinetic (PK) modeling and simulations have been used to support label changes of dosing levels or strategies for multiple marketed therapeutic monoclonal antibodies (mAbs). Using data from early-phase clinical trials in people without HIV-1, we compared fixed and weight-based dosing strategies for three HIV-1 mAbs planned for prevention efficacy testing: PGDM1400LS, PGT121.414.LS, and VRC07-523LS.
Methods: We used a two-compartment population PK model to describe overall trends and inter-individual variability in post-administration serum concentrations over time from individuals administered PGDM1400LS (n=95), PGT121.414.LS (n=113), or VRC07-523LS (n=251). We evaluated the effect of body weight on various PK parameters, including clearance rate, and simulated mAb concentrations after fixed and weight-based dosing administrations using sex-assigned-at-birth-specific weights observed in participants from two recent HIV-1 mAb efficacy trials. We compared magnitudes and inter-individual variabilities of concentrations at specific post-administration timepoints and areas under the time-concentration curves (AUC).
Findings: For all three mAbs, we observed a modest effect of body weight: each PK parameter increased approximately 5% per 10% increase in body weight. The overall magnitude and variability in time-specific concentrations, AUC, and neutralization titers were comparable between the two dosing strategies for both sex-assigned-at-birth groups. The relationship between body weight and concentrations differed between the two dosing strategies with a positive correlation for weight-based dosing and a negative correlation for fixed dosing. For individuals with body weight below the 15th or above the 85th percentiles, fixed dosing resulted in <3% difference in median AUC compared to the overall population. Fixed dosing improved AUC in lighter weight individuals, potentially correcting the underdosing seen in the previous weight-based mAb efficacy trials.
Interpretation: For HIV-1 prophylactic mAbs, a fixed-dose approach is recommended over weight-based dosing, as it offers advantages of reduced vial wastage and increased operational efficiency while maintaining comparable pharmacokinetics and inter-individual consistency.
Funding: The HIV Vaccine Trials Network (HVTN) is funded by the NIH/NIAID: UM1AI068618 (Lab), UM1AI068635 (Statistical and Data Management Center), UM1 AI068614 (Leadership and Operations Center). Overall support for the HIV Prevention Trials Network (HPTN) is provided by the National Institute of Allergy and Infectious Diseases (NIAID), Office of the Director (OD), National Institutes of Health (NIH), National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) under Award Numbers UM1AI068619 (HPTN Leadership and Operations Center), UM1AI068617 (HPTN Statistical and Data Management Center), and UM1AI068613 (HPTN Laboratory Center). We acknowledge the Duke Center for AIDS Research (NIH NIAID P30AI064518). We also hereby acknowledge the contribution of the VRC 605, HVTN 127/HPTN 087, HVTN 130/HPTN 089, HVTN 136/HPTN 091, and HVTN 140/HPTN 101 study teams, study participants, and site investigators/research teams.
Declaration of Interest: SRW has received institutional grants or contracts from Sanofi Pasteur, Janssen Vaccines/Johnson & Johnson, Moderna Tx, Pfizer, Vir Biotechnology, AbbVie, and Worcester HIV Vaccine; has participated on data safety monitoring or advisory boards for Janssen Vaccines/Johnson & Johnson and BioNTech; and his spouse holds stock/stock options in Regeneron Pharmaceuticals. CFK has received research grants to her institution from Gilead Sciences, Viiv, Moderna, Novavax, and Humanigen.
Keywords: HIV prevention, dosing strategy, exponent of body weight, two-compartment, population pharmacokinetics model, variability in exposure
Suggested Citation: Suggested Citation