Phenobarbital, Midazolam Pharmacokinetics, Effectiveness, and Drug-Drug Interaction in Asphyxiated Neonates Undergoing Therapeutic Hypothermia

on behalf of the PharmaCool study group; Laurent M A Favié; Floris Groenendaal; Marcel P H van den Broek; Carin M A Rademaker; Timo R de Haan; Henrica L M van Straaten; Peter H Dijk; Arno van Heijst; Sinno H P Simons; Koen P Dijkman; Monique Rijken; Inge A Zonnenberg; Filip Cools; Alexandra Zecic; Johanna H van der Lee; Debbie H G M Nuytemans; Frank van Bel; Toine C G Egberts; Alwin D R Huitema

doi:10.1159/000499330

Phenobarbital, Midazolam Pharmacokinetics, Effectiveness, and Drug-Drug Interaction in Asphyxiated Neonates Undergoing Therapeutic Hypothermia

on behalf of the PharmaCool study group, Laurent M A Favié, Floris Groenendaal, Marcel P H van den Broek, Carin M A Rademaker, Timo R de Haan, Henrica L M van Straaten, Peter H Dijk, Arno van Heijst, Sinno H P Simons, Koen P Dijkman, Monique Rijken, Inge A Zonnenberg, Filip Cools, Alexandra Zecic, Johanna H van der Lee, Debbie H G M Nuytemans, Frank van Bel, Toine C G Egberts, Alwin D R Huitema

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	154-162
Number of pages	9
Journal	Neonatology
Volume	116
Issue number	2
DOIs	https://doi.org/10.1159/000499330
Publication status	Published - 2019

Keywords

Phenobarbital
midazolam
pharmacokinetics
hypoxic-ischaemic encephalopathy
neonates

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on behalf of the PharmaCool study group, Favié, L. M. A., Groenendaal, F., van den Broek, M. P. H., Rademaker, C. M. A., de Haan, T. R., van Straaten, H. L. M., Dijk, P. H., van Heijst, A., Simons, S. H. P., Dijkman, K. P., Rijken, M., Zonnenberg, I. A., Cools, F., Zecic, A., van der Lee, J. H., Nuytemans, D. H. G. M., van Bel, F., Egberts, T. C. G., & Huitema, A. D. R. (2019). Phenobarbital, Midazolam Pharmacokinetics, Effectiveness, and Drug-Drug Interaction in Asphyxiated Neonates Undergoing Therapeutic Hypothermia. Neonatology, 116(2), 154-162. https://doi.org/10.1159/000499330

@article{a34fc21bf40a4c179b17046c0a5d9b71,

title = "Phenobarbital, Midazolam Pharmacokinetics, Effectiveness, and Drug-Drug Interaction in Asphyxiated Neonates Undergoing Therapeutic Hypothermia",

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.",

keywords = "Phenobarbital, midazolam, pharmacokinetics, hypoxic-ischaemic encephalopathy, neonates",

author = "on behalf of the PharmaCool study group and Favi{\'e}, {Laurent M A} and Floris Groenendaal and {van den Broek}, {Marcel P H} and Rademaker, {Carin M A} and {de Haan}, {Timo R} and {van Straaten}, {Henrica L M} and Dijk, {Peter H} and {van Heijst}, Arno and Simons, {Sinno H P} and Dijkman, {Koen P} and Monique Rijken and Zonnenberg, {Inge A} and Filip Cools and Alexandra Zecic and {van der Lee}, {Johanna H} and Nuytemans, {Debbie H G M} and {van Bel}, Frank and Egberts, {Toine C G} and Huitema, {Alwin D R}",

note = "{\textcopyright} 2019 The Author(s) Published by S. Karger AG, Basel.",

year = "2019",

doi = "10.1159/000499330",

language = "English",

volume = "116",

pages = "154--162",

journal = "Neonatology",

issn = "1661-7800",

publisher = "S. Karger AG",

number = "2",

}

on behalf of the PharmaCool study group, Favié, LMA, Groenendaal, F, van den Broek, MPH, Rademaker, CMA, de Haan, TR, van Straaten, HLM, Dijk, PH, van Heijst, A, Simons, SHP, Dijkman, KP, Rijken, M, Zonnenberg, IA, Cools, F, Zecic, A, van der Lee, JH, Nuytemans, DHGM, van Bel, F, Egberts, TCG & Huitema, ADR 2019, 'Phenobarbital, Midazolam Pharmacokinetics, Effectiveness, and Drug-Drug Interaction in Asphyxiated Neonates Undergoing Therapeutic Hypothermia', Neonatology, vol. 116, no. 2, pp. 154-162. https://doi.org/10.1159/000499330

Phenobarbital, Midazolam Pharmacokinetics, Effectiveness, and Drug-Drug Interaction in Asphyxiated Neonates Undergoing Therapeutic Hypothermia. / on behalf of the PharmaCool study group; Favié, Laurent M A; Groenendaal, Floris et al.
In: Neonatology, Vol. 116, No. 2, 2019, p. 154-162.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Phenobarbital, Midazolam Pharmacokinetics, Effectiveness, and Drug-Drug Interaction in Asphyxiated Neonates Undergoing Therapeutic Hypothermia

AU - on behalf of the PharmaCool study group

AU - Favié, Laurent M A

AU - Groenendaal, Floris

AU - van den Broek, Marcel P H

AU - Rademaker, Carin M A

AU - de Haan, Timo R

AU - van Straaten, Henrica L M

AU - Dijk, Peter H

AU - van Heijst, Arno

AU - Simons, Sinno H P

AU - Dijkman, Koen P

AU - Rijken, Monique

AU - Zonnenberg, Inge A

AU - Cools, Filip

AU - Zecic, Alexandra

AU - van der Lee, Johanna H

AU - Nuytemans, Debbie H G M

AU - van Bel, Frank

AU - Egberts, Toine C G

AU - Huitema, Alwin D R

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

KW - Phenobarbital

KW - midazolam

KW - pharmacokinetics

KW - hypoxic-ischaemic encephalopathy

KW - neonates

U2 - 10.1159/000499330

DO - 10.1159/000499330

M3 - Article

C2 - 31256150

SN - 1661-7800

VL - 116

SP - 154

EP - 162

JO - Neonatology

JF - Neonatology

IS - 2

ER -

Phenobarbital, Midazolam Pharmacokinetics, Effectiveness, and Drug-Drug Interaction in Asphyxiated Neonates Undergoing Therapeutic Hypothermia

Abstract

Keywords

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