lancet-header

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 These preprints are early-stage research papers that have not been peer-reviewed.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

See all articles by Yunda Huang

Yunda Huang

Fred Hutchinson Cancer Research Center - Vaccine and Infectious Disease Division

Lily Zhang

Fred Hutchinson Cancer Research Center - Vaccine and Infectious Disease Division

Huub Gelderblom

Fred Hutchinson Cancer Research Center - Vaccine and Infectious Disease Division

Kelly E. Seaton

Duke University - Departments of Surgery, Immunology, Molecular Genetics and Microbiology

Nicole L. Yates

Duke University - Departments of Surgery, Immunology, Molecular Genetics and Microbiology

Carmen A. Paez

Fred Hutchinson Cancer Research Center - Vaccine and Infectious Disease Division

Shelly T. Karuna

Fred Hutchinson Cancer Research Center - Vaccine and Infectious Disease Division

Philip Andrew

Family Health International

Theresa Gamble

HPTN Leadership and Operations Center

Samuel T. Robinson

Fred Hutchinson Cancer Research Center - Vaccine and Infectious Disease Division

Julie E. Ledgerwood

Government of the United States of America - National Institute of Allergy and Infectious Diseases

Ollivier Hyrien

Fred Hutchinson Cancer Research Center

Stephen R. Walsh

Harvard University - Brigham and Women’s Hospital

Cynthia L. Gay

University of North Carolina (UNC) at Chapel Hill - School of Medicine

Jane A. Gwira

Government of the United States of America - National Institute of Allergy and Infectious Diseases

Hans Spiegel

Kelly Government Solutions

Magdalena Sobieszczyk

Columbia University - Aaron Diamond AIDS Research Center; Columbia University - Division of Infectious Diseases

Sharon Mannheimer

Columbia University - Irving Medical Center

Srilatha Edupuganti

Emory University - School of Medicine

Christopher B. Hurt

University of North Carolina (UNC) at Chapel Hill

Kathryn E. Stephenson

Harvard University - Beth Israel Deaconess Medical Center

Chenchen Yu

Fred Hutchinson Cancer Research Center - Vaccine and Infectious Disease Division

Colleen F. Kelley

Emory University - Division of Infectious Diseases

Sharana Mahomed

University of KwaZulu-Natal - Centre for the AIDS Programme of Research in South Africa (CAPRISA)

Marc Siegel

George Washington University - School of Medicine and Health Sciences

Margaret Yacovone

National Institutes of Health

Michael N. Pensiero

Government of the United States of America - National Institute of Allergy and Infectious Diseases

Deborah Donnell

Fred Hutchinson Cancer Research Center - Vaccine and Infectious Disease Division

Myron Cohen

University of North Carolina (UNC) at Chapel Hill - Department of Medicine

Lawrence Corey

Fred Hutchinson Cancer Research Center - Vaccine and Infectious Disease Division

Peter B. Gilbert

Fred Hutchinson Cancer Research Center - Vaccine and Infectious Disease Division

Richard A. Koup

National Institutes of Health - Vaccine Research Center

Georgia D. Tomaras

Duke University - Departments of Surgery, Immunology, Molecular Genetics and Microbiology

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

Huang, Yunda and Zhang, Lily and Gelderblom, Huub and Seaton, Kelly E. and Yates, Nicole L. and Paez, Carmen A. and Karuna, Shelly T. and Andrew, Philip and Gamble, Theresa and Robinson, Samuel T. and Ledgerwood, Julie E. and Hyrien, Ollivier and Walsh, Stephen R. and Gay, Cynthia L. and Gwira, Jane A. and Spiegel, Hans and Sobieszczyk, Magdalena and Mannheimer, Sharon and Edupuganti, Srilatha and Hurt, Christopher B. and Stephenson, Kathryn E. and Yu, Chenchen and Kelley, Colleen F. and Mahomed, Sharana and Siegel, Marc and Yacovone, Margaret and Pensiero, Michael N. and Donnell, Deborah and Cohen, Myron and Corey, Lawrence and Gilbert, Peter B. and Koup, Richard A. and Tomaras, Georgia D., Fixed Dosing Versus Weight-Based Dosing of HIV-1 Prophylactic Monoclonal Antibodies in Adults: A Pharmacokinetics Modeling Study. Available at SSRN: https://ssrn.com/abstract=5091691 or http://dx.doi.org/10.2139/ssrn.5091691

Yunda Huang (Contact Author)

Fred Hutchinson Cancer Research Center - Vaccine and Infectious Disease Division ( email )

Seattle, WA 98109-1024
United States

Lily Zhang

Fred Hutchinson Cancer Research Center - Vaccine and Infectious Disease Division ( email )

Huub Gelderblom

Fred Hutchinson Cancer Research Center - Vaccine and Infectious Disease Division ( email )

Kelly E. Seaton

Duke University - Departments of Surgery, Immunology, Molecular Genetics and Microbiology ( email )

United States

Nicole L. Yates

Duke University - Departments of Surgery, Immunology, Molecular Genetics and Microbiology ( email )

United States

Carmen A. Paez

Fred Hutchinson Cancer Research Center - Vaccine and Infectious Disease Division ( email )

Shelly T. Karuna

Fred Hutchinson Cancer Research Center - Vaccine and Infectious Disease Division ( email )

Seattle, WA 98109-1024
United States

Philip Andrew

Family Health International ( email )

Durham, NC
United States

Theresa Gamble

HPTN Leadership and Operations Center ( email )

Samuel T. Robinson

Fred Hutchinson Cancer Research Center - Vaccine and Infectious Disease Division ( email )

Julie E. Ledgerwood

Government of the United States of America - National Institute of Allergy and Infectious Diseases ( email )

Ollivier Hyrien

Fred Hutchinson Cancer Research Center ( email )

1100 Fairview Avenue North
M2-C206
Seattle, WA 98109-1024
United States

Stephen R. Walsh

Harvard University - Brigham and Women’s Hospital

Cynthia L. Gay

University of North Carolina (UNC) at Chapel Hill - School of Medicine ( email )

Jane A. Gwira

Government of the United States of America - National Institute of Allergy and Infectious Diseases ( email )

Bethesda
United States

Hans Spiegel

Kelly Government Solutions

Magdalena Sobieszczyk

Columbia University - Aaron Diamond AIDS Research Center ( email )

Columbia University - Division of Infectious Diseases ( email )

United States

Sharon Mannheimer

Columbia University - Irving Medical Center ( email )

Srilatha Edupuganti

Emory University - School of Medicine

1364 Clifton Rd. NE
Atlanta, GA 30322
United States

Christopher B. Hurt

University of North Carolina (UNC) at Chapel Hill ( email )

Kathryn E. Stephenson

Harvard University - Beth Israel Deaconess Medical Center ( email )

330 Brookline Avenue
Boston, MA 02115
United States

Chenchen Yu

Fred Hutchinson Cancer Research Center - Vaccine and Infectious Disease Division ( email )

Colleen F. Kelley

Emory University - Division of Infectious Diseases ( email )

United States

Sharana Mahomed

University of KwaZulu-Natal - Centre for the AIDS Programme of Research in South Africa (CAPRISA) ( email )

Marc Siegel

George Washington University - School of Medicine and Health Sciences ( email )

Margaret Yacovone

National Institutes of Health ( email )

Michael N. Pensiero

Government of the United States of America - National Institute of Allergy and Infectious Diseases ( email )

Bethesda
United States

Deborah Donnell

Fred Hutchinson Cancer Research Center - Vaccine and Infectious Disease Division ( email )

Myron Cohen

University of North Carolina (UNC) at Chapel Hill - Department of Medicine ( email )

Chapel Hill, NC
United States

Lawrence Corey

Fred Hutchinson Cancer Research Center - Vaccine and Infectious Disease Division ( email )

Peter B. Gilbert

Fred Hutchinson Cancer Research Center - Vaccine and Infectious Disease Division ( email )

Richard A. Koup

National Institutes of Health - Vaccine Research Center ( email )

Bethesda, MD 20892-9806
United States

Georgia D. Tomaras

Duke University - Departments of Surgery, Immunology, Molecular Genetics and Microbiology ( email )

United States