Morris Muliaditan (1), Mary Wire (3), Kimberly Adkison (3), David Burger (4), Evelyne Jacqz-Aigrain (5), Courtney V. Fletcher (6), Oscar Della Pasqua (1,2)
(1) UCL School of Life and Medical Sciences, London, UK, (2) GlaxoSmithKline, Uxbridge, UK, (3) GlaxoSmithKline, Research Triangle Park, USA, (4) Radboud University Medical Centre, Nijmegen, The Netherlands (5) Paediatric Pharmacology, Hospital Robert Debré, Paris, France, (6) University of Nebraska Medical Center, Omaha, NE USA.
Objectives: Abacavir (ABC) is one of the recommended nucleoside reverse transcriptase inhibitor (NRTI) against human immunodeficiency virus (HIV); ABC is presently approved for twice daily administration in HIV-infected children of at least 3 months. A model-based approach has been applied during the course of drug development and post-approval to obtain a deeper understanding of the oral pharmacokinetic properties of ABC in children [1]. Given the availability of additional paediatric PK data, a meta-analysis was performed with the objective of validating and refining the previously published PK model [1].
Methods: ABC concentration-time data from 169 paediatric HIV-infected patients enrolled in six clinical trials were included in the population PK analysis. Parameters were first re-estimated using data from the three initially available studies to confirm consistency of the structural model and covariate effects with previously published PK models [1]. This model was subsequently used to predict ABC 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 ABC following oral administration were well-described by a 2-compartmental model with first order absorption and elimination, as published earlier [1]. Weight was a significant covariate on CL/F and V/F. A study-specific relative bioavailability term (F1) for tablet and solution was introduced in the PK model to describe substantially higher observed exposure in ARROW Substudy Part 2 compared to other studies despite administration of similar doses/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 ABC, 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] Zhao W, Piana C, Danhof M, Burger D, Della Pasqua O, Jacqz-Aigrain E. Population pharmacokinetics of abacavir in infants, toddlers and children. Br J Clin Pharmacol (2013) 75(6):1525-35
Reference: PAGE 23 () Abstr 3305 [www.page-meeting.org/?abstract=3305]
Poster: Drug/Disease modeling - Paediatrics