Population pharmacokinetic analysis of lamivudine (3TC) in HIV-exposed neonates and pediatric participants living with HIV-1 from the IMPAACT 2019 and PETITE studies

ABSTRACT Lamivudine is a nucleoside reverse transcriptase inhibitor widely used in combination antiretroviral therapy for the treatment of human immunodeficiency virus infection. Accurate dose selection in neonates and young children remains challenging because of rapid developmental changes in renal clearance. We updated an existing pediatric population pharmacokinetic (PopPK) model, previously developed using data from 210 participants across five studies, by incorporating a maturation function and integrating pharmacokinetic data from two additional studies, IMPAACT 2019 ( n = 55) and PETITE ( n = 24, all neonates), for a total of 289 participants aged 0.0137 (~5 days) to 19.1 years. Unlike the prior model, which did not include a maturation function, the refined PopPK model incorporates a sigmoid Emax maturation function on clearance (postmenstrual age at which clearance reaches 50% of its mature [adult] value (TM50) 51.4 weeks postmenstrual age; Hill coefficient 4.81), reflecting developmental immaturity of clearance mechanisms in early life. The PopPK model retained a one-compartment structure with first-order absorption and linear elimination. Estimation of allometric exponents for body weight further improved model fit, and inter-individual and inter-occasion variability were included in clearance, volume, and absorption rate constant. Model performance was assessed using standard goodness-of-fit diagnostics and visual predictive checks, which demonstrated good agreement between observed and model-predicted concentrations across the pediatric age and weight range. In conclusion, incorporation of a maturation function on clearance successfully extended the pediatric lamivudine PopPK model to term neonates and infants, with parameter estimates remaining consistent with the original model, supporting model-informed dose selection in this understudied population.

Authors

Institutions

Publication Details

Journal
Antimicrobial Agents and Chemotherapy
Published
2026-11-10
DOI
https://doi.org/10.1128/aac.00701-26
Primary Topic
Pharmaceutical studies and practices
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
NOV
article

Population pharmacokinetic analysis of lamivudine (3TC) in HIV-exposed neonates and pediatric participants living with HIV-1 from the IMPAACT 2019 and PETITE studies

Patricia Michele Flynn, Rashmi J. Mehta, Tim Roy Cressey, Mark Fredric Cotton et al.
Antimicrobial Agents and Chemotherapy
Pharmaceutical studies and practices
article

Population pharmacokinetic analysis of lamivudine (3TC) in HIV-exposed neonates and pediatric participants living with HIV-1 from the IMPAACT 2019 and PETITE studies

Patricia Michele Flynn, Rashmi J. Mehta, Tim Roy Cressey, Mark Fredric Cotton, Adrie Bekker, Kelly Colsh, Isabelle Déprez, Jon W. Collins, S. Y. Amy Cheung, Ann M. Buchanan, Samantha du Toit, Yasha Rani, Lauren Ziemba, Edmund V. Capparelli, Hardik Chandasana, Mark R. Bush, Anne Coletti, Iris Mustich, Helena Rabie, Sai Majji, Kristina M. Brooks, Ratchada Cressey, Kyle Whitson, Sara Zabih, Nicolas Salvadori, Barbara E. Heckman, Rose Lagattuta, Yu‐Wei Lin, A. Costa, Marisa M. Groenewald, Marc J. Lallemant, Kanchana Than-in-at, Cynthia H. Brothers, Ellen Townley, Chelsea Stotz, John H Moye, Shahadah Bailey, Shawn Ward, Dwight Yin, James Nielsen, PETITE study Team, IMPAACT 2019 Team
article en

Abstract

ABSTRACT Lamivudine is a nucleoside reverse transcriptase inhibitor widely used in combination antiretroviral therapy for the treatment of human immunodeficiency virus infection. Accurate dose selection in neonates and young children remains challenging because of rapid developmental changes in renal clearance. We updated an existing pediatric population pharmacokinetic (PopPK) model, previously developed using data from 210 participants across five studies, by incorporating a maturation function and integrating pharmacokinetic data from two additional studies, IMPAACT 2019 ( n = 55) and PETITE ( n = 24, all neonates), for a total of 289 participants aged 0.0137 (~5 days) to 19.1 years. Unlike the prior model, which did not include a maturation function, the refined PopPK model incorporates a sigmoid Emax maturation function on clearance (postmenstrual age at which clearance reaches 50% of its mature [adult] value (TM50) 51.4 weeks postmenstrual age; Hill coefficient 4.81), reflecting developmental immaturity of clearance mechanisms in early life. The PopPK model retained a one-compartment structure with first-order absorption and linear elimination. Estimation of allometric exponents for body weight further improved model fit, and inter-individual and inter-occasion variability were included in clearance, volume, and absorption rate constant. Model performance was assessed using standard goodness-of-fit diagnostics and visual predictive checks, which demonstrated good agreement between observed and model-predicted concentrations across the pediatric age and weight range. In conclusion, incorporation of a maturation function on clearance successfully extended the pediatric lamivudine PopPK model to term neonates and infants, with parameter estimates remaining consistent with the original model, supporting model-informed dose selection in this understudied population.

Antimicrobial Agents and Chemotherapy
Family Health International 360 (US), National Institutes of Health (US), St. Jude Children's Research Hospital (US), Harvard University (US), University of Liverpool (GB), University of California, Los Angeles (US), GlaxoSmithKline (United Kingdom) (GB), Stellenbosch University (ZA), University of California San Diego (US), NYU Langone Health (US), ViiV Healthcare (United Kingdom) (GB), Certara (United States) (US), National Institute of Allergy and Infectious Diseases (US), Frontier Science & Technology Research Foundation, Inc. (US), Eunice Kennedy Shriver National Institute of Child Health and Human Development (US), Chiang Mai University (TH), University of Colorado Anschutz Medical Campus (US)
Pharmaceutical studies and practices
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.

Laika access coming soon