W.Z. and C.P. contributed equally to this work.
Paediatric clinical pharmacology
Population pharmacokinetics of abacavir in infants, toddlers and children
Article first published online: 20 MAY 2013
© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society
British Journal of Clinical Pharmacology
Volume 75, Issue 6, pages 1525–1535, June 2013
How to Cite
Zhao, W., Piana, C., Danhof, M., Burger, D., Della Pasqua, O. and Jacqz-Aigrain, E. (2013), Population pharmacokinetics of abacavir in infants, toddlers and children. British Journal of Clinical Pharmacology, 75: 1525–1535. doi: 10.1111/bcp.12024
- Issue published online: 20 MAY 2013
- Article first published online: 20 MAY 2013
- Accepted manuscript online: 5 NOV 2012 07:11AM EST
- Manuscript Accepted: 12 OCT 2012
- Manuscript Received: 9 JUL 2012
- GlaxoSmithKline, UK
- UK Medical Research Council
- UK Department for International Development (DFID)
- developmental pharmacokinetics;
- paediatric pharmacology;
- population pharmacokinetics
To characterize the pharmacokinetics of abacavir in infants, toddlers and children and to assess the influence of covariates on drug disposition across these populations.
Abacavir concentration data from three clinical studies in human immunodeficiency virus-infected children (n = 69) were used for model building. The children received either a weight-normalized dose of 16 mg kg−1 day−1 or the World Health Organization recommended dose based on weight bands. A population pharmacokinetic analysis was performed using nonlinear mixed effects modelling VI. The influence of age, gender, bodyweight and formulation was evaluated. The final model was selected according to graphical and statistical criteria.
A two-compartmental model with first-order absorption and first-order elimination best described the pharmacokinetics of abacavir. Bodyweight was identified as significant covariate influencing the apparent oral clearance and volume of distribution. Predicted steady-state maximal plasma concentration and area under the concentration–time curve from 0 to 12 h of the standard twice daily regimen were 2.5 mg l−1 and 6.1 mg h l−1 for toddlers and infants, and 3.6 mg l−1 and 8.7 mg h l−1 for children, respectively. Model-based predictions showed that equivalent systemic exposure was achieved after once and twice daily dosing regimens. There were no pharmacokinetic differences between the two formulations (tablet and solution). The model demonstrated good predictive performance for dosing prediction in individual patients and, as such, can be used to support therapeutic drug monitoring in conjunction with sparse sampling.
The disposition of abacavir in children appears to be affected only by differences in size, irrespective of the patient's age. Maturation processes of abacavir metabolism in younger infants should be evaluated in further studies to demonstrate the potential impact of ontogeny.