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

Yunda Huang, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Global Health, University of Washington, Seattle, WA, USA. Electronic address: yunda@fredhutch.org.
Lily Zhang, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Huub Gelderblom, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Kelly E. Seaton, Department of Surgery, Integrative Immunobiology, Molecular Genetics and Microbiology, Duke Center for Human Systems Immunology, Durham, NC, USA.
Nicole L. Yates, Department of Surgery, Integrative Immunobiology, Molecular Genetics and Microbiology, Duke Center for Human Systems Immunology, Durham, NC, USA.
Carmen A. Paez, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Shelly T. Karuna, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Philip Andrew, HPTN Leadership and Operations Center, FHI 360, Durham, NC, USA.
Theresa Gamble, HPTN Leadership and Operations Center, FHI 360, Durham, NC, USA.
Samuel T. Robinson, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Julie E. Ledgerwood, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Ollivier Hyrien, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Stephen R. Walsh, Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Cynthia L. Gay, Institute for Global Health and Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Jane A. Gwira, Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
Hans M. Spiegel, Kelly Government Solutions, Contractor to NIAID/NIH/HHS, Rockville, MD, USA.
Magdalena E. Sobieszczyk, Columbia University Irving Medical Center, New York, NY, USA.
Sharon B. Mannheimer, Columbia University Irving Medical Center, New York, NY, USA.
Srilatha Edupuganti, Division of Infectious Diseases, Department of Medicine, Emory University, Atlanta, GA, USA.
Christopher B. Hurt, Institute for Global Health and Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Kathryn E. Stephenson, Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Chenchen Yu, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Colleen F. Kelley, Division of Infectious Diseases, Department of Medicine, Emory University, Atlanta, GA, USA.
Sharana Mahomed, Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa.
Marc Siegel, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Margaret Yacovone, Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
Michael N. Pensiero, Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
Deborah Donnell, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Myron S. Cohen, Institute for Global Health and Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Lawrence Corey, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Peter B. Gilbert, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Richard A. Koup, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Document Type

Journal Article

Publication Date

6-13-2025

Journal

EBioMedicine

Volume

117

DOI

10.1016/j.ebiom.2025.105804

Keywords

Dosing strategy; Exponent of body weight; HIV prevention; Population pharmacokinetics model; Two-compartment; Variability in exposure

Abstract

BACKGROUND: Pharmacokinetic (PK) modelling 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 adults without HIV-1, we compared fixed and weight-based dosing strategies for three HIV-1 broadly neutralising mAbs planned for prevention efficacy evaluation: 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) subcutaneously or intravenously. 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-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, areas under the time-concentration curves (AUC), and predicted neutralisation titres against representative HIV-1 virus strains. FINDINGS: For all three mAbs, we observed a modest effect of body weight on clearance rate and volumes of the central and peripheral compartments. The population-level magnitude and variability in time-specific concentrations, AUC, and predicted neutralisation titres were comparable between the two dosing strategies for both sexes. 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. For lower weight individuals, fixed dosing improved AUC, potentially correcting the underdosing seen in the previous weight-based mAb efficacy trials. For higher weight individuals (e.g., >100 kg), body weight-based dosing or a higher fixed dose may be preferred. INTERPRETATION: For HIV-1 prophylactic mAbs, a fixed-dose approach, possibly banded by weight categories may be advantageous over weight-based dosing, as it offers increased operational efficiency while maintaining comparable pharmacokinetics and inter-individual consistency. FUNDING: NIAID.

Department

Medicine

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