Population pharmacokinetic modeling of abacavir in HIV-exposed neonates and children with HIV-1 using data from the IMPAACT 2019 and PETITE studies.

Abstract

Abacavir (ABC) is one of the primary HIV nucleoside reverse transcriptase inhibitors used in pediatric antiretroviral therapy, yet optimal dosing in neonates and infants is challenging because of rapid developmental changes that influence its pharmacokinetics (PK). In this work, a previously developed pediatric population pharmacokinetic (PopPK) model for ABC was refined to extend its applicability to neonates and young infants by incorporating maturation-related processes and newly available clinical data. PK data from the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) 2019 and PETITE studies, which included term neonates (<28 days of life) and infants (<2 years), were integrated into a historical pooled data set of five pediatric studies. Multiple maturation functions and body weight scaling approaches were systematically evaluated to describe developmental changes in ABC disposition. Model performance was assessed using standard goodness-of-fit diagnostics and prediction-corrected visual predictive checks. The final PopPK model incorporated a sigmoid Emax maturation function on oral clearance together with an age-dependent absorption rate constant, providing an accurate description of ABC PK across the full pediatric age range. The updated model successfully captured the higher systemic exposures observed in neonates and infants with immature metabolic capacity during early life. The ABC PK model supports evidence-based dosing guidance for term neonates and young infants.