Semi-Mechanistic Model for Predicting the Dosing Rate in Children and Neonates for Drugs Mainly Eliminated by Cytochrome Metabolism
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Background and Objective
A simple approach is proposed to predict drug clearance in children when no paediatric data are available for drugs metabolised by cytochromes.
The maturation functions of cytochrome activity and binding proteins in plasma were combined with several measures of body size to describe drug clearance increase with age. The complete model and different reduced models were evaluated on a large panel of drug clearance data in children. The parameters of the models were estimated by nonlinear regression. Bias and precision of predictions were determined.
Two hundred and ten clearance ratios were available for the analysis, corresponding to 53 drugs mainly eliminated by cytochrome metabolism. The age range was 1.5 day to 16 years and there were 30 values for children aged less than 2 years. Fat-free mass at power 0.75 yielded better results than the other body size descriptor tested. The model with the best fit was based on the fat-free mass ratio, the unbound fraction ratio, maturation functions for cytochromes and no maturation function for clearance by other routes. In children aged less than 2 years, the predictive performances were much better with the final model than with the model based on body surface area. The final model was almost unbiased.
This model allows the calculation of the maintenance dose of drugs eliminated mainly by cytochromes. After external validation, it could be used in children aged less than 2 years. In older children, the model reduces to a simple approach based on body surface area or preferably on fat-free mass at power 0.75. The model is not suitable for preterm neonates.
Compliance with Ethical Standards
No external funding was used in the conduct of this study.
Conflict of interest
Lena Cerruti, Nathalie Bleyzac and Michel Tod have no conflicts of interest directly relevant to the contents of this article.
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