Extrapolation of midazolam disposition in neonates using physiological based pharmacokinetic/pharmacodynamic (PBPK/PD) modelling

Abstract

Objective: To explore the feasibility of model simulation research strategies for dose optimization in the neonatal populations. Using midazolam as a model drug, a PBPK/PD model was established to simulated and optimize the dosing regimen for sedation in the neonatal population. Methods: Firstly, an adult PBPK/PD model was established. Secondly, the research strategy of extrapolating adult drug use data to newborns was applied. The adult PBPK/PD model was extrapolated to the neonatal population according to the maturation formula of plasma albumin and metabolic enzyme CYP3A4/5. The robustness of the neonatal model was evaluated using clinical data from different age stratification. The neonatal PBPK/PD model was then used to simulate the dosage regimen of midazolam for sedation in newborns. Results: Individualized validation in adults showed that 95.1% of the predicted concentration values were within two-fold, and all the predicted AUC values were within two-fold; the extrapolated neonatal model showed that about 84.4% of the predicted concentration values were within two-fold, the AAFE value of the overall model was < 2, and the AFE value was between 0.5–1.5; the validated neonatal PBPK/PD model showed that virtual term neonates maintained a target plasma concentration range within 26 hours when using the dosage regimen recommended on the product label (0.06 mg/kg/h, iv infusion 12 hours), the optimal dose for premature infants to reach the target plasma concentration range may need to be slightly higher than the recommended dose on the product label (0.03mg/kg/h, iv infusion 12h). Conclusion: We successfully established a neonatal PBPK/PD model of midazolam by referring to extrapolated-based research strategy and integrating the influence of human physiological development on drug disposal. Finally, the model was validated with the dosage of midazolam in the product specification, and reliable results were obtained.