In preterm neonates, physiologically based pharmacokinetic (PBPK) models are suited for studying the effects of maturational and non-maturational factors on the pharmacokinetics of drugs with complex age-dependent metabolic pathways like acetaminophen (APAP). The aim of this study was to determine the impact of drug metabolising enzymes ontogeny on the pharmacokinetics of APAP in preterm neonates and to study the effect of reduced cardiac output (CO) on its PK using PBPK modelling. A PBPK model for APAP was first developed and validated in adults and then scaled to paediatric age groups to account for the effect of enzyme ontogeny. In preterm neonates, CO was reduced by 10%, 20%, and 30% to determine how this might affect APAP PK in preterm neonates. In all age groups, the predicted concentration-time profiles of APAP were within 5th and 95th percentile of the clinically observed concentration-time profiles and the predicted Cmax and AUC were within 2-folds of the reported parameters in clinical studies. Sulfation accounted for most of APAP metabolism in children, with the highest contribution of 68% in preterm neonates. A reduction in CO by up to 30% did not significantly alter the clearance of APAP in preterm neonates. The model successfully incorporated the ontogeny of drug metabolising enzymes involved in APAP metabolism and adequately predicted the PK of APAP in preterm neonates. A reduction in hepatic perfusion as a result of up to 30% reduction in CO has no effect on the PK of APAP in preterm neonates.
Background
In addition to the maximum plasma concentration (C
max
) to the minimum inhibitory concentration (MIC) ratio, the 24-hour area under the concentration-time curve (AUC
24h
) to MIC has recently been suggested as pharmacokinetic/pharmacodynamic (PK/PD) targets for efficacy and safety in once-daily dosing of gentamicin (ODDG) in critically ill patients.
Purpose
This study aimed to predict the optimal effective dose and risk of nephrotoxicity for gentamicin in critically ill patients for two different PK/PD targets within the first 3 days of infection.
Methods
The gathered pharmacokinetic and demographic data in critically ill patients from 21 previously published studies were used to build a one-compartment pharmacokinetic model. The Monte Carlo Simulation (MCS) method was conducted with the use of gentamicin once-daily dosing ranging from 5–10 mg/kg. The percentage target attainment (PTA) for efficacy, C
max
/MIC ~8–10 and AUC
24h
/MIC ≥110 targets, were studied. The AUC
24h
>700 mg⋅h/L and C
min
>2 mg/L were used to predict the risk of nephrotoxicity.
Results
Gentamicin 7 mg/kg/day could achieve both efficacy targets for more than 90% when the MIC was <0.5 mg/L. When the MIC increased to 1 mg/L, gentamicin 8 mg/kg/day could reach the PK/PD and safety targets. However, for pathogens with MIC ≥2 mg/L, no studied gentamicin doses were sufficient to reach the efficacy target. The risk of nephrotoxicity using AUC
24h
>700 mg⋅h/L was small, but the risk was greater when applying a C
min
target >2 mg/L.
Conclusion
Considering both targets of Cmax/MIC ~8–10 and AUC
24h
/MIC ≥110, an initial gentamicin dose of 8 mg/kg/day should be recommended in critically ill patients for pathogens with MIC of ≤1 mg/L. Clinical validation of our results is essential.
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