Foetal and neonatal exposure prediction and dosing evaluation for ampicillin using a physiologically‐based pharmacokinetic modelling approach

Aims Ampicillin is frequently used in neonates for the treatment of sepsis and as an intrapartum prophylaxis option for Group B Streptococcus. Pharmacokinetic data to guide ampicillin dosing in neonates and during the intrapartum period are limited. The objective of this study was to build a physiologically‐based pharmacokinetic (PBPK) model to characterize the disposition of ampicillin in neonates and foetuses and to inform corresponding optimal dosing regimens. Methods An adult ampicillin PBPK model was first developed using the Simcyp® simulator. The adult model was then scaled to neonates by accounting for maturational changes in physiological parameters and age‐dependent drug disposition or extended to a pregnancy model for mothers and foetuses. Models were verified using collected mean or individual‐level concentration data from the literature. Results The developed adult PBPK model included elimination via glomerular filtration, OAT3‐mediated tubular secretion and biliary excretion as well as hepatic metabolism, and 89.8% of the observed mean concentrations in adults were within a 2‐fold range of model mean predictions. Most of the observed individual‐level observations in neonates (78.4%) and foetuses (about 65% in two studies) were within the 90% prediction intervals. The recommended 50 mg/kg every 8 h (q8h) ampicillin regimen achieved the 75% fraction time of total drug concentration above minimum inhibitory concentration (T > MIC) target for an MIC ≤8 mg/L in >90% virtual neonates, and 1 g ampicillin for pregnant women provided adequate foetal exposure (>0.25 mg/L) for 4 h prior to delivery. Conclusions A PBPK model was developed to characterize ampicillin's disposition in neonates, pregnant women, and foetuses, and the model supported optimal dosing evaluation in these vulnerable populations.