Phenobarbital for neonatal seizures in hypoxic ischemic encephalopathy: A pharmacokinetic study during whole body hypothermia

Abstract

SUMMARYPurpose: Therapeutic hypothermia has recently been introduced to treat term newborns with hypoxic-ischemic encephalopathy, of whom more than half have seizures. Phenobarbital is widely used to treat neonatal seizures, but it is unknown whether its pharmacokinetics is affected by hypothermia. We evaluated the influence of hypothermia on phenobarbital pharmacokinetics in asphyxiated newborns. Methods: Nineteen term asphyxiated newborns treated with mild whole body hypothermia, started within 6 h after birth and protracted for 72 h, received phenobarbital for clinical seizures. Treatment schedule consisted of a loading dose of 20 mg/kg, titrated to response, up to a maximum dose of 40 mg/kg, followed by a maintenance dose of 2.5 or 1.5 mg/kg every 12 h. Phenobarbital concentrations were measured on 28 dried blood spots in each newborn. Key Findings: Eighteen newborns showed plasma concentrations within the reference range after receiving a loading dose of 20 mg/kg. In the remaining newborn, who had received a loading dose of 35 mg/kg, phenobarbital concentrations exceeded the upper reference limit. Phenobarbital concentrations reached a virtual steady state in all newborns. Pharmacokinetic parameters were then calculated. Minimum and maximum concentration (24.7 ± 8.8 and 30.63 ± 10.3 mg/L), average plasma concentration (27.37 ± 9.4 mg/L), and half-life (173.9 ± 62.5 h) were considerably higher than reported in literature for normothermic newborns. Pharmacokinetic parameters did not differ significantly between infants receiving different maintenance doses. Significance: Phenobarbital administered to newborns under whole body hypothermia results in higher plasma concentrations and longer half-lives than expected in normothermic newborns.

Effect of Hypothermia and Targeted Temperature Management on Drug Disposition and Response Following Cardiac Arrest: A Comprehensive Review of Preclinical and Clinical Investigations

“…Van den Broek et al (2012) postulated that the effect of asphyxia could be predominately driving changes in the PB CL, and the effect of temperature may not have an additional contributing effect. Since the effect of asphyxia on PB PK was not tested by Filippi et al (2011), this could be the main covariate contributing to the discrepancies in conclusions between these two studies. Shellhaas et al (2013) also found no effect of TTM on the clearance of PB in neonates with HIE.…”

“…In contrast to Filippi et al (2011), a clinical study performed by van den Broek et al (2012) reported no effect of hypothermia (33.5°C) for 72 hours on PB PK in asphyxiated neonates. This retrospective study identified 31 neonates with HIE who were administered an intravenous loading dose of PB of 20 mg/kg with additional doses administered as needed in subsequent days.…”

“…However, the driving force behind that change in PK, and the interplay of disease versus temperature, remains to be determined. It appears that the initial findings reported by Filippi et al (2011), which attribute temperature to changes in PB PK, may be confounded by the effect of asphyxia. More recent population PK studies have failed to show an effect of temperature on PB Cl or V D .…”

“…Three clinical studies have investigated the effects of hypothermia on PB PK in neonates, a population where PB is commonly used as a first-line agent to prevent neonatal seizures (Filippi et al, 2011;van den Broek et al, 2012;Shellhaas et al, 2013). Filippi et al (2011) investigated PB PK at two different doses in 19 asphyxiated newborns who were undergoing 72 hours of mild hypothermia to 33.5°C. Noncompartmental analysis of steady-state PB concentrations demonstrated a higher C avg , C min , and C max in the hypothermic neonates as compared with literature values reported for normothermic neonates.…”

Therapeutic drug monitoring of carbamazepine and its metabolite in children from dried blood spots using liquid chromatography and tandem mass spectrometry

“…An additional major practical advantage of DBS sampling is the feasibility of sample collection by patients or their parents/guardians at home, and its shipping to the lab by mail. Therefore, DBS has been regarded as a very popular sample collection technique for pharmacokinetic studies [16,17].…”