Article date: September 2011
By: Massimo Cella, Wei Zhao, Evelyne Jacqz‐Aigrain, David Burger, Meindert Danhof, Oscar Della Pasqua, in Volume 72, Issue 3, pages 454-464
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• In paediatric development, initial estimation of the paediatric dose is obtained by extrapolation. This is usually performed using the dosing regimen in another population as reference. However, no consensus on dose selection methodologies has been reached so far.
• The paradigm compound identified to illustrate these concepts is a nucleoside reverse transcriptase inhibitor (NRTI) used to treat HIV infection. The recommended paediatric dose of abacavir is 8 mg kg−1 twice daily up to a maximum of 300 mg twice daily.
WHAT THIS STUDY ADDS
• Our findings show that the use of a population model may not suffice to predict parameter distributions and drug exposure across paediatric populations.
• Estimation of covariate effects is critical, but not sufficient to extrapolate pharmacokinetics from a reference population to another population.
• Covariate‐parameter correlations may not remain constant beyond the range of observations. Exponential relationships used by allometry do not correct for these discrepancies.
AIMS To assess the predictive value of a model‐based approach for dose selection across paediatric populations in early clinical drug development.
METHODS Abacavir was selected as a paradigm compound using data across a wide age range. Abacavir pharmacokinetics (PK) in children were analysed separately from infants and toddlers. Two independent models were obtained, and systemic exposure (AUC) was then simulated across populations based on the estimates from each model. Drug exposures in infants and toddlers were predicted using pharmacokinetic parameter distributions obtained from children, and the other way around.
RESULTS The pharmacokinetic models (a two‐compartment PK model for infants and toddlers and a one compartment PK model for children) accurately described the exposure in the population from which they were built. However, neither model predicted exposure in a different population: in infants, the median AUC (95%‐CI) was estimated at 7.03 (6.72, 7.48) µg ml−1 h, whilst it was predicted at 5.75 (4.82, 6.26) µg ml−1 h; in children, the estimated median AUC was 6.96 (5.85, 7.91) µg ml−1 h, whilst the predicted value was 6.45 (5.80, 7.01) µg ml−1 h.
CONCLUSIONS These findings suggest that the assumption of an identical (linear or nonlinear) correlation between pharmacokinetic parameters and demographic factors may not hold true across age groups. Whilst the use of modelling enables accurate characterization of pharmacokinetic properties, extrapolations based on such parameter estimates may have limited value due to differences in the impact of developmental growth across populations.
DOI: 10.1111/j.1365-2125.2011.03992.x
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