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Effect of maturation on drug disposition in pediatric patients
1Department of Clinical Pharmacy, College of Pharmacy, University of Tennessee, Memphis 38163.
Insights
Pediatric drug disposition changes significantly with age due to maturational shifts in absorption, distribution, metabolism, and excretion. Understanding these pharmacokinetic variations is crucial for safe and effective pediatric medication use.
Area of Science:
- Pharmacology
- Pediatric Medicine
- Drug Metabolism
Background:
- Physiologic processes governing drug disposition undergo significant maturational changes in pediatric patients.
- Evaluating data from pediatric drug studies requires understanding these age-related pharmacokinetic alterations.
Purpose of the Study:
- To describe maturational changes in physiologic processes affecting drug disposition in pediatric patients.
- To discuss the evaluation of data from pediatric drug studies considering these developmental changes.
Main Methods:
- Review of physiological changes impacting drug absorption, distribution, metabolism, and excretion in pediatric populations.
- Discussion on the challenges and considerations in analyzing pediatric drug study data.
Main Results:
- Gastrointestinal absorption, skin permeability, drug distribution (volume of distribution), and plasma protein binding are altered with age.
- Biotransformation pathways (Phase 1 and Phase 2) show complex developmental trajectories, generally decreased in neonates and increasing through childhood.
- Renal drug elimination is inefficient in neonates, leading to prolonged half-lives, though infant clearance can sometimes exceed adult values.
Conclusions:
- Limited data exist on specific drug disposition changes across pediatric populations, highlighting a need for more research.
- Careful consideration of study design limitations is essential when developing research protocols for pediatric drug studies.
Abstract:
Maturational changes in the physiologic processes that govern drug disposition in pediatric patients are described, and evaluation of data from pediatric drug studies is discussed. Gastrointestinal absorption depends on gastric pH, gastric emptying time, intestinal transit time, and gastrointestinal enzymatic activity; the overall effect of age-related alterations in these variables is poorly understood. Maturational changes in the skin affect percutaneous absorption. Distribution of drugs is affected by alterations in vascular perfusion, body composition, tissue binding, and plasma protein binding. For most water-soluble drugs, volume of distribution is increased in neonates. Age-related changes in biotransformation are complex because the rate of development of phase 1 and phase 2 metabolic pathways varies and metabolic pathways may be induced by in utero exposure to inducing agents. For most drugs, biotransformation is decreased in the neonate, increases from one to five years of age, and decreases after puberty to adult values. The kidneys of neonates are inefficient at drug elimination, leading initially to prolonged elimination half-lives of many drugs. Clearance of some drugs may be greater in infants than in older children and adults because of disproportionate development of renal filtration and secretion in relation to reabsorption. Few data on maturational changes in physiologic processes that affect drug disposition are available for any one drug in a specific pediatric population. In the development of research protocols, careful attention should be paid to the design limitations of published studies.