• Danica Michaličková, Pavla Pokorná, Dick Tibboel, Ondřej Slanař, Knibbe Catherijne A J CAJ Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands. , and Krekels Elke H J EHJ Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands..
• Institute of Pharmacology, First Faculty of Medicine & General University Hospital, Charles University, Prague, Czech Republic.
• Pediatr Crit Care Me. 2020 Sep 1; 21 (9): e707-e715.

ObjectivesThis study characterizes the changes in the pharmacokinetics of phenobarbital associated with extracorporeal membrane oxygenation treatment in neonates, to illustrate our findings and provide guidance on dosing.DesignRetrospective pilot population pharmacokinetic analysis.SettingNeonatal ICU.PatientsThirteen critically ill neonates (birth body weight, 3.21 kg [2.65-3.72 kg]; postnatal age at start of treatment: 2 d [0-7 d]; gestational age: 38 wk [38-41 wk]) receiving venovenous or venoarterial extracorporeal membrane oxygenation.InterventionsPhenobarbital administered in a loading dose of 7.5 mg/kg (8.5-16 mg/kg) and maintenance dose of 6.9 mg/kg/d (4.5-8.5 mg/kg/d).Measurements And Main ResultsTherapeutic drug monitoring data were available, yielding 5, 31, and 19 phenobarbital concentrations before, during, and after extracorporeal membrane oxygenation, respectively. Population pharmacokinetic analysis was performed using NONMEM 7.3.0 (ICON Development Solutions, Ellicott City, MD). Maturation functions for clearance and volume of distribution were obtained from literature. In a one-compartment model, clearance and volume of distribution for a typical neonate off extracorporeal membrane oxygenation and with a median birth body weight (3.21 kg) at median postnatal age (2 d) were 0.0096 L/hr (relative SE = 11%)) and 2.72 L (16%), respectively. During extracorporeal membrane oxygenation, clearance was found to linearly increase with time. Upon decannulation, phenobarbital clearance initially decreased and subsequently increased slowly driven by maturation. Extracorporeal membrane oxygenation-related changes in volume of distribution could not be identified, possibly due to sparse data collection shortly after extracorporeal membrane oxygenation start. According to the model, target attainment is achieved in the first 12 days of extracorporeal membrane oxygenation with a regimen of a loading dose of 20 mg/kg and a maintenance dose of 4 mg/kg/d divided in two doses with an increase of 0.25 mg/kg every 12 hours during extracorporeal membrane oxygenation treatment.ConclusionsWe found a time-dependent increase in phenobarbital clearance during the first 12 days of extracorporeal membrane oxygenation treatment in neonates, which results in continuously decreasing phenobarbital exposure and increases the risk of therapeutic failure over time. Due to high unexplained variability, frequent and repeated therapeutic drug monitoring should be considered even with the model-derived regimen.

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