NDLI: Pharmacokinetic design optimization in children and estimation of maturation parameters: example of cytochrome P450 3A4

Content Provider	Springer Nature Link
Author	Bouillon Pichault, Marion Jullien, Vincent Bazzoli, Caroline Pons, Gérard Tod, Michel
Copyright Year	2010
Abstract	The aim of this work was to determine whether optimizing the study design in terms of ages and sampling times for a drug eliminated solely via cytochrome P450 3A4 (CYP3A4) would allow us to accurately estimate the pharmacokinetic parameters throughout the entire childhood timespan, while taking into account age- and weight-related changes. A linear monocompartmental model with first-order absorption was used successively with three different residual error models and previously published pharmacokinetic parameters (“true values”). The optimal ages were established by D-optimization using the CYP3A4 maturation function to create “optimized demographic databases.” The post-dose times for each previously selected age were determined by D-optimization using the pharmacokinetic model to create “optimized sparse sampling databases.” We simulated concentrations by applying the population pharmacokinetic model to the optimized sparse sampling databases to create optimized concentration databases. The latter were modeled to estimate population pharmacokinetic parameters. We then compared true and estimated parameter values. The established optimal design comprised four age ranges: 0.008 years old (i.e., around 3 days), 0.192 years old (i.e., around 2 months), 1.325 years old, and adults, with the same number of subjects per group and three or four samples per subject, in accordance with the error model. The population pharmacokinetic parameters that we estimated with this design were precise and unbiased (root mean square error [RMSE] and mean prediction error [MPE] less than 11% for clearance and distribution volume and less than 18% for k$_{a}$), whereas the maturation parameters were unbiased but less precise (MPE < 6% and RMSE < 37%). Based on our results, taking growth and maturation into account a priori in a pediatric pharmacokinetic study is theoretically feasible. However, it requires that very early ages be included in studies, which may present an obstacle to the use of this approach. First-pass effects, alternative elimination routes, and combined elimination pathways should also be investigated.
Starting Page	25
Ending Page	40
Page Count	16
File Format	PDF
ISSN	1567567X
Journal	Journal of Pharmacokinetics and Pharmacodynamics
Volume Number	38
Issue Number	1
e-ISSN	15738744
Language	English
Publisher	Springer US
Publisher Date	2010-11-04
Publisher Place	Boston
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Population pharmacokinetics Protocol optimisation Children Maturation function Biochemistry Biomedical Engineering Veterinary Medicine Pharmacy Pharmacology/Toxicology
Content Type	Text
Resource Type	Article
Subject	Pharmacology

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