Considering Age Variation When Coining Drugs as High versus Low Hepatic Extraction Ratio

The hepatic extraction ratio (EH) is commonly considered an “inherent attribute” of drug. It determines the main physiological and biological elements of the system (patient attributes) that are most significant in interindividual variability of clearance. The EH consists of three age-dependent parameters: fraction of unbound drug in blood (fu.B), hepatic intrinsic clearance of unbound drug […]

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Prediction of Voriconazole Non-Linear Pharmacokinetics Using a Pediatric Physiologically Based Pharmacokinetic Modeling Approach

We read with interest the report by Zane and Thakker entitled ‘‘A PBPK model for voriconazole disposition predicts intestinal first-pass metabolism in children’’. We believe the authors should be congratulated for tackling the complex case of voriconazole, as this is a drug with non-linear pharmacokinetics where clinical trials have shown a marked difference between adults […]

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Age related changes in fractional elimination pathways for drugs: assessing the impact of variable ontogeny on metabolic drug-drug interactions.

The magnitude of any metabolic drug-drug interactions (DDIs) depends on fractional importance of inhibited pathway which may not necessarily be the same in young children when compared to adults. The ontogeny pattern of cytochrome P450 (CYP) enzymes (CYPs 1A2, 2B6, 2C8, 2C9, 2C18/19, 2D6, 2E1, 3A4) and renal function were analyzed systematically. Bootstrap methodology was […]

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Do children have the same vulnerability to metabolic drug-drug interactions as adults? A critical analysis of the literature.

Many drug–drug interactions (DDIs) in the pediatric population are managed based on data generated in adults. However, due to developmental changes in elimination pathways from birth to adolescence, and variable weight-adjusted dose of interacting drugs, the assumption of DDIs being similar in adults and pediatrics might not be correct. This study compares the magnitude of […]

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Precision criteria to derive sample size when designing pediatric pharmacokinetics studies: which measure of variability should be used?

A new approach for calculation of sample size in pediatric clinical pharmacokinetic studies was suggested based on desired precision for a pharmacokinetic parameter of interest. The estimate of variability for sample size calculations could be obtained from different sources. It is not known whether these sources constantly show higher/lower variability across compounds and age groups. We obtained estimates of variability for clearance, volume of distribution and area under the plasma concentration-time […]

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Considering Age Variation when Coining Drugs as High vs Low Hepatic Extraction Ratio.

Hepatic extraction ratio (EH) is commonly considered as ‘an inherent attribute’ of drug. It determines the main physiological and biological elements of the system (patient attributes) which are most significant in inter-individual variability of clearance. EH consists of three age-dependent parameters: fraction of unbound drug in blood (fu.B), hepatic intrinsic clearance of unbound drug (CLu.int,H) and hepatic blood flow (QH). When age-effects on these elements […]

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A Re-evaluation and Validation of Ontogeny Functions for CYPs 1A2 and 3A4 Based on In Vivo Data

Current cytochrome P450 (CYP) 1A2 and 3A4 ontogeny profiles, which are derived mainly from in vitro studies and incorporated in pediatric physiologically based pharmacokinetic models, have been reported to under-predict the in vivo clearances of some model substrates in neonates and infants. We report ontogeny functions for these enzymes as pediatric to adult relative intrinsic […]

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