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.