Vincent Jullien (1),Ronit Pressler (2), Geraldine Boylan (3), Mats Blennow (4), Neil Marlow (2), Catherine Chiron (1), Gerard Pons (1)
(1) INSERM U1129, Paris, France, (2) University College London, UK, (3) University College Cork, Ireland, (4) Karolinska Institutet and University Hospital, Stockholm, Sweden
Objectives: Experimental data supported the use of bumetanide for the treatment of neonatal seizures due to hypoxic-ischaemic encephalopathy (HIE). The objectives of the study were to develop a population PK model of bumetanide in this population and to evaluate the possible relationship between the exposure to the drug and its efficacy/safety.
Methods: Infants with HIE and seizures not responding to a loading dose of 20 mg/kg IV phenobarbitone were included in the study. Bumetanide was administered by IV route every 12 hours for 48 hours. Four different unitary dose levels (0.05, 0.1, 0.2, and 0.3 mg/kg) were evaluated. Primary end point for efficacy was the reduction of electrographic seizure burden by ≥80% within hours 3 and 4 after the first bumetanide administration compared to the baseline without need for rescue AED over the next 48h. Screening for hearing impairment was performed for toxicity evaluation. Four blood samples of 500 µL were drawn per infant. The infants were randomly assigned to one of 2 sampling groups. Population PK analysis was performed using MONOLIX software (version 4.2). For each newborn, AUC after the first dose (AUC1) and the total cumulative AUC (AUC2) were calculated using individual estimates of clearance, and possible relationship between AUC1, AUC2 and efficacy or the occurrence of hearing loss was investigated.
Results: Fourteen newborn infants (4 girls) were included in the study. Four infants were allocated to dose level 0.05mg/kg, three to 0.1mg/kg, six to 0.2mg/kg and one to 0.3mg/kg. Only 2 infants met all criteria for a positive seizure outcome. Three infants died (due to the severity of HIE and/or comorbidities) and among the 11 survivors three were subsequently found to have hearing loss. Forty-nine blood samples were available for PK evaluation. The best structural PK model was a 2-compartment model with first-order elimination from the central compartment. BW was found to explain the IIV of the elimination clearance of bumetanide. Mean population parameters (% IIV) were: CL (L/h) = 0.063 x (BW/3.4)1.69(22 %), Vc (L) = 0.285, Vp (L) = 0.443 (42 %), Q (L/h) = 0.594. Eta shrinkage was 21 % for CL and 23 % for Vp. No trend was observed between AUC1 or AUC2 and efficacy/toxicity.
Conclusions: This is the first population PK model for bumetanide in newborn infants. Bumetanide was associated to an unfavorable efficacy/safety ratio for the treatment of neonatal seizure.
References:
[1] Pressler RM, Mangum B. Newly emerging therapies for neonatal seizures. Semin Fetal Neonatal Med. 2013;18(4): 216-223.
[2] Lopez-Samblas AM, Adams JA, Goldberg RN, Modi MW. The pharmacokinetics of bumetanide in the newborn infant. Biol Neonate. 1997;72(5): 265-272.
[3]Sullivan JE, Witte MK, Yamashita TS, Myers CM, Blumer JL. Pharmacokinetics of bumetanide in critically ill infants. Clin Pharmacol Ther. 1996;60(4): 405-413.
[4] Pressler RM, Boylan G, Blennow M, et al. Bumetanide for the treatment of seizures in newborn infants with hypoxic ischaemic encephalopathy: NEMO – a dose finding and feasability open-label trial. Lancet Neurology. 2015;In Press.
Reference: PAGE 24 (2015) Abstr 3367 [www.page-meeting.org/?abstract=3367]
Poster: Drug/Disease modeling - Paediatrics