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Published on: June 18, 2013
Determinants of variability in clearance of exogenous compounds in neonates
K Allegaert1, J N Van Den Anker, C Tayman
1Neonatal Intensive Care Unit, UZ Gasthuisberg, Leuven.
Insights
Neonatal drug disposition and elimination show significant maturation, especially in the first year of life. Tailored approaches considering patient-specific factors are crucial for safe and effective medication use in infants.
Area of Science:
- Pharmacology
- Neonatal Medicine
- Drug Metabolism
Background:
- Drug disposition and elimination principles apply to neonates but require a tailored approach due to specific maturational characteristics.
- Drug disposition undergoes significant maturation in children, most notably within the first year of life.
- Elimination clearance in neonates is primarily driven by metabolic and renal pathways.
Purpose of the Study:
- To explore the impact of maturational changes and covariates on drug disposition and elimination in neonates.
- To highlight the importance of patient-specific factors in neonatal pharmacokinetics and pharmacodynamics.
- To illustrate how factors like age, disease state, and genetics influence drug clearance.
Main Methods:
- Analysis of "probe" drugs (paracetamol, tramadol, propofol) in critically ill neonates to assess metabolic clearance.
- Evaluation of renal elimination clearance, focusing on glomerular filtration in early life.
- Observation of drug disposition (amikacin, vancomycin, cefazolin) in perinatal life to understand renal clearance variability.
Main Results:
- Phase I and II metabolic processes exhibit ontogeny in an iso-enzyme specific manner, with variations influenced by constitutional, environmental, and genetic factors.
- Renal elimination clearance is low in early life, primarily dependent on glomerular filtration, with extensive interindividual variability.
- Covariates such as postmenstrual age, postnatal age, disease state, polymorphisms, and co-administered drugs significantly impact drug clearance and variability.
Conclusions:
- Maturational changes in drug disposition and elimination significantly affect pharmacokinetics and pharmacodynamics in neonates.
- A personalized approach, considering the "patient" beyond just the dose, is essential for optimizing drug therapy in neonates.
- Understanding these developmental changes is critical for safe and effective drug use in the neonatal population.
Abstract:
Although the general principles of disposition and elimination of exogenous compounds apply in neonates, their specific characteristics warrant a tailored approach. Children display maturation in drug disposition, and these maturational changes are most prominent in the first year of life. Elimination clearance is mainly either through metabolic or renal elimination clearance. Almost all phase I and phase II metabolic processes display ontogeny in a iso-enzyme specific pattern. Variation in phenotypic metabolic clearance is based on constitutional, environmental and genetics factors. In early life, it mainly reflects ontogeny, but other covariates may also become relevant. The impact of various covariates like postmenstrual age, postnatal age, disease state characteristics and polymorphisms are illustrated based or 'probe' drugs (paracetamol, tramadol, propofol) administered as part of their medical treatment in critically ill neonates. Renal elimination clearance in early life is low and almost completely depends on glomerular filtration. Despite this overall low clearance, interindividual variability is already extensive and can be explained by covariates like postmenstrual age, postnatal age, co-administration of a non-selective cyclo-oxygenase inhibitor or growth restriction. These findings are illustrated by observations on amikacin, vancomycin and cefazolin disposition in perinatal life. These maturational changes all have impact on the pharmaco/toxicokinetics and -dynamics. We hereby would like to extent the adagio of Paracelsus that 'all is toxic, it only depends on the dose' by making the point that the 'patient' is also relevant.
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