Academic Lead: Dr. Catherine Chiron (INSERM)
WP partner: AP-HP
Bumetanide is currently considered for the treatment of neonatal seizures that are not responding to phenobarbitone. However, the pharmacokinetics of this drug in neonates has been poorly investigated so far and the relationship between drug exposure and efficacy is still unknown. As a consequence, the dose used may not be optimal for efficacy and/or safety of the drug. Similarly, midazolam and lignocaine have been previously investigated on only a limited number of newborn infants.
The aim of WP 09 will be to establish the dosing recommendations of bumetanide and to validate the current dosing recommendations of midazolam, lignocaine and phenobarbitone that will provide the highest probability of efficacy and optimal therapeutic interval in this population.
Task 1: Determination of the optimal sampling design for the study.
The number and the sampling-times will be determined in order to allow the estimation of the pharmacokinetic parameters with the minimal uncertainty.
Task 2: Development and validation of the analytical methods of the assays.
In order to quantify the 3 drugs of interest in a volume of plasma as low as possible (e.g. 100 µl), a simultaneous assay will be developed for the 3 drugs by liquid chromatography with tandem mass spectrometry.
Task 3: Determination of storage and shipment conditions for the samples.
The temperature for storage and shipment and the possible necessity for prior separation of plasma will be determined according to the stability of the compounds.
Task 4: Standard operating procedure (SOP).
An SOP including details on sampling frequency, sample volume, sampling technique, storage and shipping of blood samples will be sent all recruiting centres (WP 04) and to the SC for filing in the Master Trial File (WP 01).
Task 5: Performance of the assays.
Concentration of bumetanide will be determined using liquid chromatography with optimal methods. All the babies included in the clinical study will also be included in the PK/PD study to elicit the best statistical power for the determination of the concentration/effect relationship. The first sample will be drawn at the end of the evaluation of phenobarbitone efficacy, before the administration of bumetanide and a further two samples will be drawn over a 3 day period, after the administration of bumetanide. The drawn volume will not exceed 1 % of the total blood volume over the time of the study. This is well under the limits recommended by EMEA: Guidelines on the investigation of medicinal products in the term and preterm infant (Doc. Ref. EMEA/267484/2007). Every effort will be made to take these samples together with routine blood samples in order to minimise pain and blood loss.
Task 6: Data modelling.
The data will be analyzed by a population approach which will allow us to determine the covariates (post-natal age, body weight, body surface area, cooling for HIE) explaining the interindividual variability of the PK/PD parameters of the drugs studied. PK/PD models will be developed and used to perform simulation calculations to determine the optimal dose for each drug and each individual in this population.