Drug disposition and clinical practice in neonates: cross talk between developmental physiology and pharmacology

Area of Science:

• Pharmacology
• Pediatrics
• Physiology

Background:

• Infant drug dosing is complex due to significant physiological maturation.
• Variability in drug response is a hallmark of pediatric clinical pharmacology.
• Developmental physiology directly influences developmental pharmacology in infants.

Purpose of the Study:

• To highlight the importance of integrating ontogeny-related knowledge for predicting drug behavior in infants.
• To emphasize the link between physiological maturation and drug elimination processes.
• To underscore the need for a comprehensive approach to understanding infant pharmacokinetics and pharmacodynamics.

Main Methods:

• Reviewing the relationship between renal/hepatic physiology and drug clearance/elimination.
• Analyzing maturational profiles of drug elimination at enzyme and transporter levels.
• Integrating in vivo observations with mechanistic and physiology-based pharmacokinetic (PBPK) models.

Main Results:

• Maturational changes in renal and hepatic systems significantly impact drug clearance and elimination.
• Individual elimination processes (enzyme and transporter levels) show distinct maturational trajectories.
• Discrepancies between mechanistic and PBPK models can reveal gaps in understanding maturational physiology and drug transport ontogeny.

Conclusions:

• Accurate drug dosing in infants necessitates a deep understanding of their unique physiological characteristics.
• Integrating knowledge of all elimination routes is essential for predicting drug pharmacokinetics and pharmacodynamics in this population.
• A combined approach using mechanistic and PBPK models aids in identifying critical knowledge gaps in infant pharmacology.