Dose evaluation of lamivudine in human immunodeficiency virus-infected children aged 5months to 18years based on a population pharmacokinetic analysis.

Abstract

The objectives of this study were to characterize age-related changes in lamivudine pharmacokinetics in children and evaluate lamivudine exposure, followed by dose recommendations for subgroups in which target steady state area under the daily plasma concentration-time curve (AUC0-24h ) is not reached. Population pharmacokinetic modelling was performed in NONMEM using data from two model-building datasets and two external datasets [n=180 (age 0.4-18years, body weight 3.4-60.5kg); 2061 samples (median 12 per child); daily oral dose 60-300mg (3.9-17.6mgkg-1 )]. Steady state AUC0-24h was calculated per individual (adult target 8.9mg·hl-1 ). A two-compartment model with sequential zero order and first order absorption best described the data. Apparent clearance and central volume of distribution (% RSE) were 13.2lh-1 (4.2%) and 38.9l (7.0%) for a median individual of 16.6kg, respectively. Bodyweight was identified as covariate on apparent clearance and volume of distribution using power functions (exponents 0.506 (20.2%) and 0.489 (32.3%), respectively). The external evaluation supported the predictive ability of the final model. In 94.5% and 35.8% of the children with a body weight >14kg and <14kg, respectively, the target AUC0-24h was reached. Bodyweight best predicted the developmental changes in apparent lamivudine clearance and volume of distribution. For children aged 5months-18years with a body weight <14kg, the dose should be increased from 8 to 10mgkg-1 day-1 if the adult target for AUC0-24h is aimed for. In order to identify whether bodyweight influences bioavailability, clearance and/or volume of distribution, future analysis including data on intravenously administered lamivudine is needed.