Population pharmacokinetics and dosing of amoxicillin in (pre)term neonates

Area of Science:

• Neonatal pharmacology
• Clinical pharmacy
• Pediatric infectious diseases

Background:

• Amoxicillin is frequently prescribed for neonatal infections.
• Optimizing amoxicillin dosing in neonates is crucial due to their unique physiology.
• Understanding pharmacokinetic variability is essential for safe and effective drug use.

Purpose of the Study:

• To characterize amoxicillin pharmacokinetics in neonates.
• To identify factors influencing amoxicillin clearance and volume of distribution.
• To propose an optimized dosing regimen to ensure therapeutic drug concentrations and minimize toxicity.

Main Methods:

• Plasma amoxicillin concentrations were measured using reversed-phase HPLC in 150 neonates.
• Population pharmacokinetic analysis was performed, including regression analysis to identify significant covariates.
• Gestational age (GA) and co-administered gentamicin parameters were assessed as predictors.
• A new dosage regimen was simulated and evaluated.

Main Results:

• Mean amoxicillin clearance (CL/W) was 0.096 L/kg/h, elimination half-life (t(1/2)) was 5.2 hours, and volume of distribution (V/W) was 0.65 L/kg.
• Gentamicin CL/W, gentamicin V/W, and GA were significant predictors of amoxicillin CL/W.
• The current dosage regimen resulted in toxic plasma concentrations in some neonates.
• The proposed new regimen (15 mg/kg q8h for GA ≤34 weeks, 20 mg/kg q8h for GA >34 weeks) achieved satisfactory concentrations in simulations.

Conclusions:

• Current amoxicillin dosing may lead to toxicity in neonates.
• A revised, GA-stratified dosing regimen is proposed to optimize therapeutic concentrations.
• The new regimen is expected to ensure satisfactory amoxicillin levels, potentially reducing the need for therapeutic drug monitoring.