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Clinical Pharmacokinetics

, Volume 57, Issue 7, pp 831–841 | Cite as

Semi-Mechanistic Model for Predicting the Dosing Rate in Children and Neonates for Drugs Mainly Eliminated by Cytochrome Metabolism

  • Lena Cerruti
  • Nathalie Bleyzac
  • Michel Tod
Original Research Article

Abstract

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.

Methods

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.

Results

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.

Conclusions

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.

Notes

Compliance with Ethical Standards

Funding

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.

Supplementary material

40262_2017_596_MOESM1_ESM.doc (708 kb)
Supplementary material 1 (DOC 708 kb)

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Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Pharmacie, Groupement Hospitalier NordHospices Civils de LyonLyonFrance
  2. 2.EMR3738, Faculté de médecine Lyon-sudUniversité Lyon 1LyonFrance
  3. 3.Faculté de pharmacieUniversité Lyon 1LyonFrance
  4. 4.EMR3738, Faculté de médecine Lyon-sudOullinsFrance

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