Morris Muliaditan (1), Mary Wire (3), Kimberly Adkison (3), David Burger (4), Evelyne Jacqz-Aigrain (5), Oscar Della Pasqua (1,2)
(1) UCL School of Life and Medical Sciences, London, UK, (2) GlaxoSmithKline, London, UK, (3) GlaxoSmithKline, Research Triangle Park, USA, (4) Radboud Univ. Med. Ctr, Nijmegen, the Netherlands, (5) Paediatric Pharmacology, Hospital Robert Debré, Paris, France
Objectives: Lamivudine (3TC), a key nucleoside reverse transcriptase inhibitor (NRTI) against human immunodeficiency virus (HIV), is currently approved for twice daily administration in HIV-infected children of at least 3 months. A model-based approach was applied during the course of drug development and post-approval [1] to obtain a deeper understanding of the oral pharmacokinetic properties of 3TC in children. Given the availability of additional oral and intravenous paediatric PK data, a meta-analysis was performed with the objective of validating and refining the previously published PK model [1].
Methods: 3TC concentration-time data from 209 paediatric HIV-infected patients enrolled in six clinical trials were included in the population PK analysis. Parameters were first estimated using data from the three initially available studies to confirm consistency of the structural model and covariate effects with a previously published PK model [1]. This initial model was subsequently used to predict 3TC PK in three external studies followed by a meta-analysis of all available studies for model refinement. Model performance was based on secondary PK parameters (AUC0-24h, Cmax and Cτ). The analysis was performed using a non-linear mixed effect approach, as implemented in NONMEM 7.0.
Results: The pharmacokinetics of 3TC following oral administration were well-described by a one-compartment model with first order absorption and elimination, as published earlier [1]. Weight was a significant covariate on CL and V. Absolute bioavailability (F1) for tablet and solution was introduced in the PK model to account for differences between formulations. The predictive ability of the model was confirmed and diagnostic plots showed good agreement of predicted and observed secondary PK parameters.
Conclusion: Our analysis provided a robust set of parameters to describe the population PK of 3TC, which can be used to evaluate prospective study design, dosing regimens and covariate effects in children. The analysis also confirms the suitability of the model to inform the potential of a once daily dosing regimen in children of at least 3 months of age, as currently prescribed in adults.
References:
[1] Piana C, Zhao W, Adkison K, Burger D, Jacqz-Aigrain E, Danhof M, Della Pasqua O. Covariate effects and population pharmacokinetics of lamivudine in HIV-infected children. Br J Clin Pharmacol (2013) doi: 10.1111/bcp.12246
Reference: PAGE 23 (2014) Abstr 3304 [www.page-meeting.org/?abstract=3304]
Poster: Drug/Disease modeling - Paediatrics