Population pharmacokinetics of phenobarbital in infants with neonatal encephalopathy treated with therapeutic hypothermia

Abstract

Objective: Phenobarbital is the first-line treatment for neonatal seizures. Many neonates with hypoxic ischemic encephalopathy are treated with therapeutic hypothermia, and about 40% have clinical seizures. Little is known about the pharmacokinetics of phenobarbital in infants with hypoxic ischemic encephalopathy who undergo therapeutic hypothermia. The objective of this study was to determine the effect of therapeutic hypothermia on phenobarbital pharmacokinetics, taking into account maturational changes.

Setting: Level 3 neonatal ICU.

Patients: Infants with hypoxic ischemic encephalopathy and suspected seizures, all treated with phenobarbital. Some of these infants also received treatment with therapeutic hypothermia.

Interventions: None.

Design: A retrospective cohort study of 39 infants with hypoxic ischemic encephalopathy treated with phenobarbital (20 were treated with therapeutic hypothermia and 19 were not).

Measurements and main results: Data on phenobarbital plasma concentrations were collected in 39 subjects with hypoxic ischemic encephalopathy with or without therapeutic hypothermia. Using nonlinear mixed-effects modeling, population pharmacokinetics of phenobarbital were developed with a total of 164 plasma concentrations. A one-compartment model best described the pharmacokinetics. The clearance of phenobarbital was linearly related to body weight and matured with increasing age with a maturation half-life of 22.1 days. Therapeutic hypothermia did not influence the pharmacokinetic parameters of phenobarbital.

Conclusions: Therapeutic hypothermia does not influence the clearance of phenobarbital after accounting for weight and age. Standard phenobarbital dosing is appropriate for the initial treatment of seizures in neonates with hypoxic ischemic encephalopathy treated with therapeutic hypothermia.

Figure 1

Temperatures recorded nearest to the phenobarbital plasma concentration measurements are presented for the hypothermia and normothermia (control) groups. Panel A demonstrates the range of temperatures at which the phenobarbital concentrations were sampled. In the hypothermia group, there are three groups of several data points: there is a cluster less than 32°C, suggesting over-cooling that may have occurred during the initial phases of hypothermia (for example during transport); there are many data points between 33°C and 35°C, implying the interval during hypothermia in our NICU; finally, there are data points above 36°C, which represent the rewarming period. Panel B displays boxplots of the same temperature data. The length of the boxes represents the interquartile range, while the horizontal line in the box is the median value and the whiskers indicate the minimum and maximum data points.

Figure 2

Maturational changes in phenobarbital clearance with postnatal age (PNA) are presented for a reference subject with median body weight of 3.47 kg, based on data obtained from the studied population.

Figure 3

Individual observed phenobarbital concentration-time profiles and model prediction from A) hypothermia and B) normothermia subjects. Open circle – observed phenobarbital concentrations; solid line – model predicted phenobarbital concentrations; solid circle with dashed line – body core temperature of hypothermia subject; dotted line – normal core temperature.

Figure 4

Standard Model Diagnostic Plot. IPERD – individual predicted concentrations; DV – observed concentrations; IWRES – individual weighted residuals; PRED – population predicted concentrations; CWRES – conditional weighted residuals. Standard model diagnostic plots reveal no significant systematic bias in the prediction of plasma phenobarbital concentrations.