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J Clin Pharmacol. 2016 Mar;56(3):284-90. doi: 10.1002/jcph.596. Epub 2015 Sep 14.

Pilot evaluation of the population pharmacokinetics of bumetanide in term newborn infants with seizures.

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INSERM U1129 "Infantile Epilepsies and Brain Plasticity," Paris, France; Paris Descartes University; CEA, Gif sur Yvette, France.
Service de Pharmacologie, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France.
Neuroscience Unit (ICH) and Neonatal Unit (IWH), University College London, London, UK.
INFANT Research Centre & Neonatal Intensive Care Unit, University College Cork, Cork, Ireland.
Neonatology, Karolinska Institutet and University Hospital, Stockholm, Sweden.


Recent experimental data suggest bumetanide as a possible therapeutic option in newborn infants with seizures after birth asphyxia. Because pharmacokinetic (PK) data are lacking in this population, who very often benefit from therapeutic cooling, which can modify the PK behavior of a drug, a PK study was conducted in term infants with seizures caused by hypoxic-ischemic encephalopathy. Fourteen infants were included, 13 of them being cooled. Forty-nine blood samples were available for the determination of the plasma concentration of bumetanide. Concentration-time data were analyzed by the use of a population approach performed with Monolix Software. Bumetanide was found to follow a 2-compartment model. The mean values were 0.063 L/h for clearance, 0.28 and 0.44 L for the central and peripheral distribution volumes, respectively, and 0.59 L/h for the distribution clearance. Birth body weight explained the interindividual variability of bumetanide clearance via an allometric model. No relationship was found between bumetanide exposure and its efficacy (reduction in seizure burden) or its toxicity (hearing loss). This study describes the first PK model of bumetanide in hypothermia-treated infants with seizures.


central nervous system; neonatology; population pharmacokinetics

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