Laurent M A Favié1,2, Floris Groenendaal3,4, Marcel P H van den Broek5, Carin M A Rademaker6, Timo R de Haan7, Henrica L M van Straaten8, Peter H Dijk9, Arno van Heijst10, Sinno H P Simons11, Koen P Dijkman12, Monique Rijken13, Inge A Zonnenberg14, Filip Cools15, Alexandra Zecic16, Johanna H van der Lee17, Debbie H G M Nuytemans18, Frank van Bel3,4, Toine C G Egberts6,19, Alwin D R Huitema6,20. 1. Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands, L.M.A.Favie@umcutrecht.nl. 2. Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands, L.M.A.Favie@umcutrecht.nl. 3. Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands. 4. Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands. 5. Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands. 6. Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands. 7. Department of Neonatology, Emma Children's Hospital, Academic Medical Center, Amsterdam University Medical Center, Amsterdam, The Netherlands. 8. Department of Neonatology, Isala Clinics, Zwolle, The Netherlands. 9. Department of Neonatology, Groningen University Medical Centre, Groningen, The Netherlands. 10. Department of Neonatology, Radboud University Medical Center-Amalia Children's Hospital, Nijmegen, The Netherlands. 11. Division of Neonatology, Department of Pediatrics, Erasmus Medical Centre-Sophia Children's Hospital, Rotterdam, The Netherlands. 12. Department of Neonatology, Máxima Medical Center Veldhoven, Veldhoven, The Netherlands. 13. Department of Neonatology, Leiden University Medical Center, Leiden, The Netherlands. 14. Department of Neonatology, VU University Medical Center, Amsterdam University Medical Center, Amsterdam, The Netherlands. 15. Department of Neonatology, UZ Brussel - Vrije Universiteit Brussel, Brussels, Belgium. 16. Department of Neonatology, University Hospital Gent, Gent, Belgium. 17. Paediatric Clinical Research Office, Emma Children's Hospital, Academic Medical Center, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 18. Clinical Research Coordinator PharmaCool Study, Amsterdam University Medical Center, Amsterdam, The Netherlands. 19. Department of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Utrecht University, Utrecht, The Netherlands. 20. Department of Pharmacy and Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Abstract
BACKGROUND: Phenobarbital and midazolam are commonly used drugs in (near-)term neonates treated with therapeutic hypothermia for hypoxic-ischaemic encephalopathy, for sedation, and/or as anti-epileptic drug. Phenobarbital is an inducer of cytochrome P450 (CYP) 3A, while midazolam is a CYP3A substrate. Therefore, co-treatment with phenobarbital might impact midazolam clearance. OBJECTIVES: To assess pharmacokinetics and clinical anti-epileptic effectiveness of phenobarbital and midazolam in asphyxiated neonates and to develop dosing guidelines. METHODS: Data were collected in the prospective multicentre PharmaCool study. In the present study, neonates treated with therapeutic hypothermia and receiving midazolam and/or phenobarbital were included. Plasma concentrations of phenobarbital and midazolam including its metabolites were determined in blood samples drawn on days 2-5 after birth. Pharmacokinetic analyses were performed using non-linear mixed effects modelling; clinical effectiveness was defined as no use of additional anti-epileptic drugs. RESULTS: Data were available from 113 (phenobarbital) and 118 (midazolam) neonates; 68 were treated with both medications. Only clearance of 1-hydroxy midazolam was influenced by hypothermia. Phenobarbital co-administration increased midazolam clearance by a factor 2.3 (95% CI 1.9-2.9, p < 0.05). Anticonvulsant effectiveness was 65.5% for phenobarbital and 37.1% for add-on midazolam. CONCLUSIONS: Therapeutic hypothermia does not influence clearance of phenobarbital or midazolam in (near-)term neonates with hypoxic-ischaemic encephalopathy. A phenobarbital dose of 30 mg/kg is advised to reach therapeutic concentrations. Phenobarbital co-administration significantly increased midazolam clearance. Should phenobarbital be substituted by non-CYP3A inducers as first-line anticonvulsant, a 50% lower midazolam maintenance dose might be appropriate to avoid excessive exposure during the first days after birth.
BACKGROUND:Phenobarbital and midazolam are commonly used drugs in (near-)term neonates treated with therapeutic hypothermia for hypoxic-ischaemic encephalopathy, for sedation, and/or as anti-epileptic drug. Phenobarbital is an inducer of cytochrome P450 (CYP) 3A, while midazolam is a CYP3A substrate. Therefore, co-treatment with phenobarbital might impact midazolam clearance. OBJECTIVES: To assess pharmacokinetics and clinical anti-epileptic effectiveness of phenobarbital and midazolam in asphyxiated neonates and to develop dosing guidelines. METHODS: Data were collected in the prospective multicentre PharmaCool study. In the present study, neonates treated with therapeutic hypothermia and receiving midazolam and/or phenobarbital were included. Plasma concentrations of phenobarbital and midazolam including its metabolites were determined in blood samples drawn on days 2-5 after birth. Pharmacokinetic analyses were performed using non-linear mixed effects modelling; clinical effectiveness was defined as no use of additional anti-epileptic drugs. RESULTS: Data were available from 113 (phenobarbital) and 118 (midazolam) neonates; 68 were treated with both medications. Only clearance of 1-hydroxy midazolam was influenced by hypothermia. Phenobarbital co-administration increased midazolam clearance by a factor 2.3 (95% CI 1.9-2.9, p < 0.05). Anticonvulsant effectiveness was 65.5% for phenobarbital and 37.1% for add-on midazolam. CONCLUSIONS: Therapeutic hypothermia does not influence clearance of phenobarbital or midazolam in (near-)term neonates with hypoxic-ischaemic encephalopathy. A phenobarbital dose of 30 mg/kg is advised to reach therapeutic concentrations. Phenobarbital co-administration significantly increased midazolam clearance. Should phenobarbital be substituted by non-CYP3A inducers as first-line anticonvulsant, a 50% lower midazolam maintenance dose might be appropriate to avoid excessive exposure during the first days after birth.
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