Dose evaluation of lamivudine in human immunodeficiency virus-infected children aged 5 months to 18 years based on a population pharmacokinetic analysis
Aim: 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. Methods: Population pharmacokinetic modelling was performed in NONMEM using data from two model-building datasets and two external datasets [n = 180 (age 0.4–18 years, body weight 3.4–60.5 kg); 2061 samples (median 12 per child); daily oral dose 60–300 mg (3.9–17.6 mg kg–1)]. Steady state AUC0–24h was calculated per individual (adult target 8.9 mg·h l–1). Results: 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 13.2 l h–1 (4.2%) and 38.9 l (7.0%) for a median individual of 16.6 kg, 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 >14 kg and <14 kg, respectively, the target AUC0–24h was reached. Conclusion: Bodyweight best predicted the developmental changes in apparent lamivudine clearance and volume of distribution. For children aged 5 months–18 years with a body weight <14 kg, the dose should be increased from 8 to 10 mg kg–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.
|Keywords||human immunodeficiency virus/acquired immune deficiency syndrome, modelling and simulation, paediatrics, pharmacotherapy, therapeutic drug monitoring|
|Persistent URL||dx.doi.org/10.1111/bcp.13227, hdl.handle.net/1765/108160|
|Journal||British Journal of Clinical Pharmacology|
Janssen, E.J.H, Bastiaans, D.E.T. (Diane E. T.), Välitalo, P.A.J, van Rossum, A.M.C, Jacqz-Aigrain, E, Lyall, H, … Burger, D.M. (2017). Dose evaluation of lamivudine in human immunodeficiency virus-infected children aged 5 months to 18 years based on a population pharmacokinetic analysis. British Journal of Clinical Pharmacology, 83(6), 1287–1297. doi:10.1111/bcp.13227