Pharmacokinetics of Phenobarbitone in Neonates – A Population Model Based on Routine Therapeutic Drug Monitoring Data

Background: Phenobarbitone is a commonly used first-line agent for treatment of neonatal seizures of varying causes. A significant proportion of neonatal seizures are due to Hypoxic-Ischaemic Encephalopathy (HIE). Babies with HIE who are treated with 72 hours of therapeutic hypothermia have an improved chance of survival without major disability. However, there is limited information regarding how therapeutic hypothermia affects drug disposition in these infants, and much of what is published appears to be contradictory.
Aim: The objective of this study was to develop a population pharmacokinetic model for phenobarbitone and to identify relevant covariates in a historical group of infants receiving standard care, which might be used as a basis for developing future models of phenobarbitone disposition during therapeutic hypothermia.
Methods: Phenobarbitone plasma concentrations (N=305) were taken for routine therapeutic drug monitoring of 112 infants (median gestational age of 38.7 weeks) treated in the Neonatal Intensive Care Unit at the Royal Brisbane and Women’s Hospital. Pharmacokinetic analyses were performed using non-linear mixed effects modelling in NONMEM( v.7.2) together with R (v. 2.15.1) and Xpose (v.4) for data visualisation, and Pirana for run management.
Results: The pharmacokinetics of phenobarbitone were best described by a one-compartment distribution model after oral and intravenous administration. Weight allometrically scaled was added on both clearance and volume of distribution. Furthermore, gestational age and postnatal age were included on clearance to describe the maturation changes in these premature infants. Even though the covariates improved the model the between-subject variability (CV%) on clearance and volume remained at approximately 33%.
Conclusions: This model can now serve as prior information when trying to establish the pharmacokinetics of phenobarbitone in neonates treated with therapeutic hypothermia.