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Protein binding predictions in infants
Patrick J McNamara1, Jane Alcorn
1Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, USA. pmcnamar@uky.edu
Insights
Drug binding in newborns differs due to lower plasma protein levels. A predictive model accurately estimates drug binding fractions in infants and children based on age-related protein changes.
Area of Science:
- Pharmacology
- Neonatal Physiology
- Drug Metabolism
Background:
- Plasma protein concentrations, crucial for drug binding, vary significantly between newborns and adults.
- Human serum albumin (HSA) levels are near adult concentrations at birth, while alpha 1-acid glycoprotein (AAG) levels are substantially lower.
- This difference impacts how drugs bind, affecting their availability and efficacy in neonates.
Purpose of the Study:
- To investigate the impact of age-dependent plasma protein concentration changes on drug binding in infants and children.
- To develop and validate a predictive model for estimating unbound drug fractions in pediatric populations.
Main Methods:
- Comparison of plasma binding protein concentrations (HSA and AAG) in newborns versus adults.
- Utilizing a mathematical model incorporating adult unbound fractions and infant-to-adult protein concentration ratios.
- Validation of the model's predictions against observed unbound drug fractions in infants and children.
Main Results:
- Newborns exhibit lower plasma binding protein levels compared to adults, which increase with age.
- Drugs primarily bound to HSA show binding closer to adult levels in newborns, unlike drugs bound to AAG.
- The developed model successfully predicted the fraction of unbound drugs in infants and children.
Conclusions:
- Age-related changes in plasma protein concentrations significantly influence drug binding in pediatric populations.
- A predictive model utilizing protein concentration ratios can accurately estimate unbound drug fractions in neonates and children.
- This model aids in optimizing pediatric drug dosing and understanding drug disposition in early life stages.
Abstract:
Plasma binding protein levels are lower in the newborn than in the adult and gradually increase with age. At birth, human serum albumin (HSA) concentrations are close to adult levels (75%-80%), while alpha 1-acid glycoprotein (AAG) is initially half the adult concentration. As a result, the extent of drug binding to HSA is closer to that of the adult than are those drugs bound largely to AAG. A model that incorporates the fraction unbound in adults and the ratio of the binding protein concentration between infants and adults successfully predicted the fraction unbound in infants and children.