title: Pilot evaluation of the population pharmacokinetics of bumetanide in term newborn infants with seizures.
abstract: 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.
authors.affiliation: 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.
authors.forename: Vincent
authors.initials: V
authors.lastname: Jullien
authors.affiliation: Neuroscience Unit (ICH) and Neonatal Unit (IWH), University College London, London, UK.
authors.forename: Ronit M
authors.initials: RM
authors.lastname: Pressler
authors.affiliation: INFANT Research Centre & Neonatal Intensive Care Unit, University College Cork, Cork, Ireland.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Boylan
authors.affiliation: Neonatology, Karolinska Institutet and University Hospital, Stockholm, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Blennow
authors.affiliation: Neuroscience Unit (ICH) and Neonatal Unit (IWH), University College London, London, UK.
authors.forename: Neil
authors.initials: N
authors.lastname: Marlow
authors.affiliation: INSERM U1129 "Infantile Epilepsies and Brain Plasticity," Paris, France; Paris Descartes University; CEA, Gif sur Yvette, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Chiron
authors.affiliation: INSERM U1129 "Infantile Epilepsies and Brain Plasticity," Paris, France; Paris Descartes University; CEA, Gif sur Yvette, France.
authors.forename: Gerard
authors.initials: G
authors.lastname: Pons
mesh_terms: D000927:Anticonvulsants / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use; D001237:Asphyxia / Q000150:complications; D002034:Bumetanide / Q000009:adverse effects / Q000097:blood* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D034381:Hearing Loss / Q000139:chemically induced; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008954:Models, Biological; D010865:Pilot Projects; D012640:Seizures / Q000097:blood* / Q000151:congenital* / Q000188:drug therapy / Q000209:etiology
chemical_list: D000927:Anticonvulsants; D002034:Bumetanide
keywords: central nervous system; neonatology; population pharmacokinetics