Model-Informed Dose Optimization of Spironolactone in Neonates and Infants

Area of Science:

• Pharmacokinetics
• Pediatric Pharmacology
• Drug Metabolism

Background:

• Spironolactone (SP) use in pediatrics is common but lacks robust pharmacokinetic (PK) data.
• Limited PK data in children hinders optimal spironolactone dosing and therapeutic outcomes.

Purpose of the Study:

• To develop physiologically based pharmacokinetic (PBPK) models for spironolactone and its metabolites.
• To predict spironolactone PK in pediatric populations, including infants and neonates.
• To establish a basis for optimizing spironolactone dosing in children.

Main Methods:

• Developed PBPK models for spironolactone (SP), canrenone (CAN), and 7α thio-methyl spironolactone (TMS) in adults.
• Incorporated CES1-mediated metabolism and ontogeny for CES1 and CYP3A4.
• Integrated age-related physiological changes for pediatric PK prediction.

Main Results:

• PBPK models accurately predicted SP, CAN, and TMS PK in adults, including food effects.
• Pediatric PBPK model simulations proposed doses of 2.5 mg/kg (6mo-2yr) and 2 mg/kg (1-6mo) for infants.
• These simulated infant doses match adult systemic exposure for edema treatment.

Conclusions:

• The PBPK model offers valuable insights for spironolactone dosing in pediatric populations.
• Optimized dosing strategies can improve therapeutic outcomes in children.
• The model is particularly useful for populations where clinical PK studies are difficult.