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

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.