Severity parameters for asphyxia or hypoxic-ischemic encephalopathy do not explain inter-individual variability in the pharmacokinetics of phenobarbital in newborns treated with therapeutic hypothermia

Pavla Pokorná; Danica Michaličková; Swantje Völler; Karolina Hronová; Dick Tibboel; Ondřej Slanař; Elke H. Krekels

doi:10.23736/S2724-5276.20.05740-0

Severity parameters for asphyxia or hypoxic-ischemic encephalopathy do not explain inter-individual variability in the pharmacokinetics of phenobarbital in newborns treated with therapeutic hypothermia

Pavla Pokorná
, Danica Michaličková^*
, Swantje Völler
, Karolina Hronová
, Dick Tibboel
, Ondřej Slanař
, Elke H. Krekels

^*Corresponding author for this work

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

Abstract

BACKGROUND:

The current study uses a population modeling approach to evaluate and quantify the impact of severity of asphyxia and hypoxic-ischemic encephalopathy (HIE) on the pharmacokinetics of phenobarbital in asphyxiated newborns treated with therapeutic hypothermia.

METHODS:

Included newborns received phenobarbital (the TOBY trial protocol). 120 plasma samples were available from 50 newborns, median (IQR) weight 3.3 (2.8-3.5) kg and gestational age 39 (39-40) weeks. NONMEM^® version 7.2 was used for the data analysis. Age, body weight, sex, concomitant medications, kidney and liver function markers, as well as severity parameters of asphyxia and HIE were tested as potential covariates of pharmacokinetics of phenobarbital. Severe asphyxia was defined as pH of arterial umbilical cord blood ≤7.1 and Apgar 5 ≤5, and severe HIE was defined as time to normalization of amplitude-integrated electroencephalography (aEEG) >24 h.

RESULTS:

Weight was found to be the only statistically significant covariate for the volume of distribution. At weight of 1 kg volume of distribution was 0.91 L and for every additional kg it increased in 0.91 L. Clearance was 0.00563 L/h. No covariates were statistically significant for the clearance of phenobarbital.

CONCLUSIONS:

Phenobarbital dose adjustments are not indicated in the studied population, irrespective of the severity of asphyxia or HIE.

Original language	English
Pages (from-to)	107-115
Number of pages	9
Journal	Minerva Pediatrics
Volume	74
Issue number	2
DOIs	https://doi.org/10.23736/S2724-5276.20.05740-0
Publication status	Published - 1 Apr 2022

Bibliographical note

Funding Information:
Pavla Pokorna is supported by the General University Hospital RV-project (64-165/2012) and an unrestricted research grant of the Intensive Care of the Erasmus MC-Sophia Childrens Hospital. The work was supported by a Charles University project Progres Q25.

Publisher Copyright:
© 2020 EDIZIONI MINERVA MEDICA.

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10.23736/S2724-5276.20.05740-0

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Pokorná, P., Michaličková, D., Völler, S., Hronová, K., Tibboel, D., Slanař, O., & Krekels, E. H. (2022). Severity parameters for asphyxia or hypoxic-ischemic encephalopathy do not explain inter-individual variability in the pharmacokinetics of phenobarbital in newborns treated with therapeutic hypothermia. Minerva Pediatrics, 74(2), 107-115. https://doi.org/10.23736/S2724-5276.20.05740-0

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title = "Severity parameters for asphyxia or hypoxic-ischemic encephalopathy do not explain inter-individual variability in the pharmacokinetics of phenobarbital in newborns treated with therapeutic hypothermia",

abstract = "BACKGROUND: The current study uses a population modeling approach to evaluate and quantify the impact of severity of asphyxia and hypoxic-ischemic encephalopathy (HIE) on the pharmacokinetics of phenobarbital in asphyxiated newborns treated with therapeutic hypothermia. METHODS: Included newborns received phenobarbital (the TOBY trial protocol). 120 plasma samples were available from 50 newborns, median (IQR) weight 3.3 (2.8-3.5) kg and gestational age 39 (39-40) weeks. NONMEM{\textregistered} version 7.2 was used for the data analysis. Age, body weight, sex, concomitant medications, kidney and liver function markers, as well as severity parameters of asphyxia and HIE were tested as potential covariates of pharmacokinetics of phenobarbital. Severe asphyxia was defined as pH of arterial umbilical cord blood ≤7.1 and Apgar 5 ≤5, and severe HIE was defined as time to normalization of amplitude-integrated electroencephalography (aEEG) >24 h. RESULTS: Weight was found to be the only statistically significant covariate for the volume of distribution. At weight of 1 kg volume of distribution was 0.91 L and for every additional kg it increased in 0.91 L. Clearance was 0.00563 L/h. No covariates were statistically significant for the clearance of phenobarbital. CONCLUSIONS: Phenobarbital dose adjustments are not indicated in the studied population, irrespective of the severity of asphyxia or HIE.",

author = "Pavla Pokorn{\'a} and Danica Michali{\v c}kov{\'a} and Swantje V{\"o}ller and Karolina Hronov{\'a} and Dick Tibboel and Ond{\v r}ej Slana{\v r} and Krekels, \{Elke H.\}",

note = "Funding Information: Pavla Pokorna is supported by the General University Hospital RV-project (64-165/2012) and an unrestricted research grant of the Intensive Care of the Erasmus MC-Sophia Childrens Hospital. The work was supported by a Charles University project Progres Q25. Publisher Copyright: {\textcopyright} 2020 EDIZIONI MINERVA MEDICA.",

year = "2022",

month = apr,

day = "1",

doi = "10.23736/S2724-5276.20.05740-0",

language = "English",

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Pokorná, P, Michaličková, D, Völler, S, Hronová, K, Tibboel, D, Slanař, O & Krekels, EH 2022, 'Severity parameters for asphyxia or hypoxic-ischemic encephalopathy do not explain inter-individual variability in the pharmacokinetics of phenobarbital in newborns treated with therapeutic hypothermia', Minerva Pediatrics, vol. 74, no. 2, pp. 107-115. https://doi.org/10.23736/S2724-5276.20.05740-0

Severity parameters for asphyxia or hypoxic-ischemic encephalopathy do not explain inter-individual variability in the pharmacokinetics of phenobarbital in newborns treated with therapeutic hypothermia. / Pokorná, Pavla; Michaličková, Danica; Völler, Swantje et al.
In: Minerva Pediatrics, Vol. 74, No. 2, 01.04.2022, p. 107-115.

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

TY - JOUR

T1 - Severity parameters for asphyxia or hypoxic-ischemic encephalopathy do not explain inter-individual variability in the pharmacokinetics of phenobarbital in newborns treated with therapeutic hypothermia

AU - Pokorná, Pavla

AU - Michaličková, Danica

AU - Völler, Swantje

AU - Hronová, Karolina

AU - Tibboel, Dick

AU - Slanař, Ondřej

AU - Krekels, Elke H.

N1 - Funding Information: Pavla Pokorna is supported by the General University Hospital RV-project (64-165/2012) and an unrestricted research grant of the Intensive Care of the Erasmus MC-Sophia Childrens Hospital. The work was supported by a Charles University project Progres Q25. Publisher Copyright: © 2020 EDIZIONI MINERVA MEDICA.

PY - 2022/4/1

Y1 - 2022/4/1

N2 - BACKGROUND: The current study uses a population modeling approach to evaluate and quantify the impact of severity of asphyxia and hypoxic-ischemic encephalopathy (HIE) on the pharmacokinetics of phenobarbital in asphyxiated newborns treated with therapeutic hypothermia. METHODS: Included newborns received phenobarbital (the TOBY trial protocol). 120 plasma samples were available from 50 newborns, median (IQR) weight 3.3 (2.8-3.5) kg and gestational age 39 (39-40) weeks. NONMEM® version 7.2 was used for the data analysis. Age, body weight, sex, concomitant medications, kidney and liver function markers, as well as severity parameters of asphyxia and HIE were tested as potential covariates of pharmacokinetics of phenobarbital. Severe asphyxia was defined as pH of arterial umbilical cord blood ≤7.1 and Apgar 5 ≤5, and severe HIE was defined as time to normalization of amplitude-integrated electroencephalography (aEEG) >24 h. RESULTS: Weight was found to be the only statistically significant covariate for the volume of distribution. At weight of 1 kg volume of distribution was 0.91 L and for every additional kg it increased in 0.91 L. Clearance was 0.00563 L/h. No covariates were statistically significant for the clearance of phenobarbital. CONCLUSIONS: Phenobarbital dose adjustments are not indicated in the studied population, irrespective of the severity of asphyxia or HIE.

AB - BACKGROUND: The current study uses a population modeling approach to evaluate and quantify the impact of severity of asphyxia and hypoxic-ischemic encephalopathy (HIE) on the pharmacokinetics of phenobarbital in asphyxiated newborns treated with therapeutic hypothermia. METHODS: Included newborns received phenobarbital (the TOBY trial protocol). 120 plasma samples were available from 50 newborns, median (IQR) weight 3.3 (2.8-3.5) kg and gestational age 39 (39-40) weeks. NONMEM® version 7.2 was used for the data analysis. Age, body weight, sex, concomitant medications, kidney and liver function markers, as well as severity parameters of asphyxia and HIE were tested as potential covariates of pharmacokinetics of phenobarbital. Severe asphyxia was defined as pH of arterial umbilical cord blood ≤7.1 and Apgar 5 ≤5, and severe HIE was defined as time to normalization of amplitude-integrated electroencephalography (aEEG) >24 h. RESULTS: Weight was found to be the only statistically significant covariate for the volume of distribution. At weight of 1 kg volume of distribution was 0.91 L and for every additional kg it increased in 0.91 L. Clearance was 0.00563 L/h. No covariates were statistically significant for the clearance of phenobarbital. CONCLUSIONS: Phenobarbital dose adjustments are not indicated in the studied population, irrespective of the severity of asphyxia or HIE.

UR - https://www.scopus.com/pages/publications/85129997611

U2 - 10.23736/S2724-5276.20.05740-0

DO - 10.23736/S2724-5276.20.05740-0

M3 - Article

C2 - 33107271

AN - SCOPUS:85129997611

SN - 2724-5276

VL - 74

SP - 107

EP - 115

JO - Minerva Pediatrics

JF - Minerva Pediatrics

IS - 2

ER -

Severity parameters for asphyxia or hypoxic-ischemic encephalopathy do not explain inter-individual variability in the pharmacokinetics of phenobarbital in newborns treated with therapeutic hypothermia

Abstract

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