Prediction of Clearance and Dose of Midazolam in Preterm and Term Neonates: A Comparative Study Between Allometric Scaling and Physiologically Based Pharmacokinetic Modeling

Abstract

Children are not small adults because besides size there are subtle physiological and biochemical differences between children and adults. Like adults, children also require medicine for the management or cure for the underlying diseases. To select a right dose in children, pharmacokinetic (PK) information is warranted. However, in many instances, a PK study in neonates and infants may not be possible. Therefore, various methods are used to predict PK parameters in this group of population, and these predicted parameters may help to calculate a safe dose for the very young children. Allometry is widely used for the prediction of PK parameters in children and subsequently one can predict dose from these predicted PK parameters. Physiologically based pharmacokinetic modeling (PBPK) has also become a useful tool to achieve these goals. Therefore, the objective of this study was to compare the predictive performance of allometry and PBPK for a test compound, midazolam in preterm, and term neonates. In this study, there were 5 preterm neonates (gestational age ranging from 34 to 37 weeks) and 5 term neonates (gestational age ranging from 38 to 41 weeks). PBPK modeling was performed using PK-Sim 6.0 and clearance, as well as midazolam dose in neonates was predicted. Clearance and midazolam dose in neonates was also predicted by allometric scaling. In this study, the allometric exponents for the prediction of midazolam clearance in preterm neonates and term neonates were 1.2 and 1.1, respectively. Similarly, for the prediction of midazolam neonatal dose, the exponent of allometry was either 0.9 or 1.0. The predicted midazolam clearance and dose by both methods were then compared with observed midazolam clearance and dose in neonates. The results of the study showed a slightly better prediction of midazolam clearance in neonates by PBPK than allometric scaling. However, the projected dose of midazolam in neonates was comparable between the 2 methods. Overall, it was noted that both PBPK and allometric model can be used to predict clearance and dose of midazolam in neonates.