The bioavailability and maturing clearance of doxapram in preterm infants

Robert B. Flint; Sinno H. P. Simons; Peter Andriessen; Kian D. Liem; Pieter L. J. Degraeuwe; Irwin K. M. Reiss; Rob Ter Heine; Aline G. J. Engbers; Birgit C. P. Koch; Ronald de Groot; David M. Burger; Catherijne A. J. Knibbe; Swantje Voller; DINO Research group

doi:10.1038/s41390-020-1037-9

The bioavailability and maturing clearance of doxapram in preterm infants

Robert B. Flint^*, Sinno H. P. Simons, Peter Andriessen, Kian D. Liem, Pieter L. J. Degraeuwe, Irwin K. M. Reiss, Rob Ter Heine, Aline G. J. Engbers, Birgit C. P. Koch, Ronald de Groot, David M. Burger, Catherijne A. J. Knibbe, Swantje Voller, DINO Research group

^*Corresponding author for this work

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

Abstract

Background Doxapram is used for the treatment of apnea of prematurity in dosing regimens only based on bodyweight, as pharmacokinetic data are limited. This study describes the pharmacokinetics of doxapram and keto-doxapram in preterm infants. Methods Data (302 samples) from 75 neonates were included with a median (range) gestational age (GA) 25.9 (23.9-29.4) weeks, bodyweight 0.95 (0.48-1.61) kg, and postnatal age (PNA) 17 (1-52) days at the start of continuous treatment. A population pharmacokinetic model was developed using non-linear mixed-effects modelling (NONMEM (R)). Results A two-compartment model best described the pharmacokinetics of doxapram and keto-doxapram. PNA and GA affected the formation clearance of keto-doxapram (CLFORMATION KETO-DOXAPRAM) and clearance of doxapram via other routes (CLDOXAPRAM OTHER ROUTES). For a median individual of 0.95 kg, GA 25.6 weeks, and PNA 29 days, CL(FORMATION KETO-DOXAPRAM)was 0.115 L/h (relative standard error (RSE) 12%) and CL(DOXAPRAM OTHER ROUTES)was 0.645 L/h (RSE 9%). Oral bioavailability was estimated at 74% (RSE 10%). Conclusions Dosing of doxapram only based on bodyweight results in the highest exposure in preterm infants with the lowest PNA and GA. Therefore, dosing may need to be adjusted for GA and PNA to minimize the risk of accumulation and adverse events. For switching to oral therapy, a 33% dose increase is required to maintain exposure. Impact

Current dosing regimens of doxapram in preterm infants only based on bodyweight result in the highest exposure in infants with the lowest PNA and GA. Dosing of doxapram may need to be adjusted for GA and PNA to minimize the risk of accumulation and adverse events. Describing the pharmacokinetics of doxapram and its active metabolite keto-doxapram following intravenous and gastroenteral administration enables to include drug exposure to the evaluation of treatment of AOP. The oral bioavailability of doxapram in preterm neonates is 74%, requiring a 33% higher dose via oral than intravenous administration to maintain exposure.

Original language	English
Pages (from-to)	1268-1277
Number of pages	10
Journal	Pediatric Research
Volume	89
Issue number	5
Early online date	22 Jul 2020
DOIs	https://doi.org/10.1038/s41390-020-1037-9
Publication status	Published - Apr 2021

Keywords

IDIOPATHIC APNEA
CAFFEINE THERAPY
PREMATURITY
PHARMACOTHERAPY
BRADYCARDIA
METABOLISM
DISABILITY
HYPOXEMIA
CHILDREN
WEIGHT

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10.1038/s41390-020-1037-9

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Flint, R. B., Simons, S. H. P., Andriessen, P., Liem, K. D., Degraeuwe, P. L. J., Reiss, I. K. M., Ter Heine, R., Engbers, A. G. J., Koch, B. C. P., de Groot, R., Burger, D. M., Knibbe, C. A. J., Voller, S., & DINO Research group (2021). The bioavailability and maturing clearance of doxapram in preterm infants. Pediatric Research, 89(5), 1268-1277. https://doi.org/10.1038/s41390-020-1037-9

@article{6a14fbd8ba0546d994457aa0d6f0149d,

title = "The bioavailability and maturing clearance of doxapram in preterm infants",

abstract = "Background Doxapram is used for the treatment of apnea of prematurity in dosing regimens only based on bodyweight, as pharmacokinetic data are limited. This study describes the pharmacokinetics of doxapram and keto-doxapram in preterm infants. Methods Data (302 samples) from 75 neonates were included with a median (range) gestational age (GA) 25.9 (23.9-29.4) weeks, bodyweight 0.95 (0.48-1.61) kg, and postnatal age (PNA) 17 (1-52) days at the start of continuous treatment. A population pharmacokinetic model was developed using non-linear mixed-effects modelling (NONMEM (R)). Results A two-compartment model best described the pharmacokinetics of doxapram and keto-doxapram. PNA and GA affected the formation clearance of keto-doxapram (CLFORMATION KETO-DOXAPRAM) and clearance of doxapram via other routes (CLDOXAPRAM OTHER ROUTES). For a median individual of 0.95 kg, GA 25.6 weeks, and PNA 29 days, CL(FORMATION KETO-DOXAPRAM)was 0.115 L/h (relative standard error (RSE) 12%) and CL(DOXAPRAM OTHER ROUTES)was 0.645 L/h (RSE 9%). Oral bioavailability was estimated at 74% (RSE 10%). Conclusions Dosing of doxapram only based on bodyweight results in the highest exposure in preterm infants with the lowest PNA and GA. Therefore, dosing may need to be adjusted for GA and PNA to minimize the risk of accumulation and adverse events. For switching to oral therapy, a 33% dose increase is required to maintain exposure. ImpactCurrent dosing regimens of doxapram in preterm infants only based on bodyweight result in the highest exposure in infants with the lowest PNA and GA. Dosing of doxapram may need to be adjusted for GA and PNA to minimize the risk of accumulation and adverse events. Describing the pharmacokinetics of doxapram and its active metabolite keto-doxapram following intravenous and gastroenteral administration enables to include drug exposure to the evaluation of treatment of AOP. The oral bioavailability of doxapram in preterm neonates is 74%, requiring a 33% higher dose via oral than intravenous administration to maintain exposure.",

keywords = "IDIOPATHIC APNEA, CAFFEINE THERAPY, PREMATURITY, PHARMACOTHERAPY, BRADYCARDIA, METABOLISM, DISABILITY, HYPOXEMIA, CHILDREN, WEIGHT",

author = "Flint, {Robert B.} and Simons, {Sinno H. P.} and Peter Andriessen and Liem, {Kian D.} and Degraeuwe, {Pieter L. J.} and Reiss, {Irwin K. M.} and {Ter Heine}, Rob and Engbers, {Aline G. J.} and Koch, {Birgit C. P.} and {de Groot}, Ronald and Burger, {David M.} and Knibbe, {Catherijne A. J.} and Swantje Voller and {DINO Research group}",

note = "Funding Information: This study was enabled by funding from the Netherlands Organization for Health Research and Development ZonMw (Grant number: 80-83600-98-10190). Publisher Copyright: {\textcopyright} 2020, International Pediatric Research Foundation, Inc.",

year = "2021",

month = apr,

doi = "10.1038/s41390-020-1037-9",

language = "English",

volume = "89",

pages = "1268--1277",

journal = "Pediatric Research",

issn = "0031-3998",

publisher = "Springer",

number = "5",

}

TY - JOUR

T1 - The bioavailability and maturing clearance of doxapram in preterm infants

AU - Flint, Robert B.

AU - Simons, Sinno H. P.

AU - Andriessen, Peter

AU - Liem, Kian D.

AU - Degraeuwe, Pieter L. J.

AU - Reiss, Irwin K. M.

AU - Ter Heine, Rob

AU - Engbers, Aline G. J.

AU - Koch, Birgit C. P.

AU - de Groot, Ronald

AU - Burger, David M.

AU - Knibbe, Catherijne A. J.

AU - Voller, Swantje

AU - DINO Research group

N1 - Funding Information: This study was enabled by funding from the Netherlands Organization for Health Research and Development ZonMw (Grant number: 80-83600-98-10190). Publisher Copyright: © 2020, International Pediatric Research Foundation, Inc.

PY - 2021/4

Y1 - 2021/4

N2 - Background Doxapram is used for the treatment of apnea of prematurity in dosing regimens only based on bodyweight, as pharmacokinetic data are limited. This study describes the pharmacokinetics of doxapram and keto-doxapram in preterm infants. Methods Data (302 samples) from 75 neonates were included with a median (range) gestational age (GA) 25.9 (23.9-29.4) weeks, bodyweight 0.95 (0.48-1.61) kg, and postnatal age (PNA) 17 (1-52) days at the start of continuous treatment. A population pharmacokinetic model was developed using non-linear mixed-effects modelling (NONMEM (R)). Results A two-compartment model best described the pharmacokinetics of doxapram and keto-doxapram. PNA and GA affected the formation clearance of keto-doxapram (CLFORMATION KETO-DOXAPRAM) and clearance of doxapram via other routes (CLDOXAPRAM OTHER ROUTES). For a median individual of 0.95 kg, GA 25.6 weeks, and PNA 29 days, CL(FORMATION KETO-DOXAPRAM)was 0.115 L/h (relative standard error (RSE) 12%) and CL(DOXAPRAM OTHER ROUTES)was 0.645 L/h (RSE 9%). Oral bioavailability was estimated at 74% (RSE 10%). Conclusions Dosing of doxapram only based on bodyweight results in the highest exposure in preterm infants with the lowest PNA and GA. Therefore, dosing may need to be adjusted for GA and PNA to minimize the risk of accumulation and adverse events. For switching to oral therapy, a 33% dose increase is required to maintain exposure. ImpactCurrent dosing regimens of doxapram in preterm infants only based on bodyweight result in the highest exposure in infants with the lowest PNA and GA. Dosing of doxapram may need to be adjusted for GA and PNA to minimize the risk of accumulation and adverse events. Describing the pharmacokinetics of doxapram and its active metabolite keto-doxapram following intravenous and gastroenteral administration enables to include drug exposure to the evaluation of treatment of AOP. The oral bioavailability of doxapram in preterm neonates is 74%, requiring a 33% higher dose via oral than intravenous administration to maintain exposure.

AB - Background Doxapram is used for the treatment of apnea of prematurity in dosing regimens only based on bodyweight, as pharmacokinetic data are limited. This study describes the pharmacokinetics of doxapram and keto-doxapram in preterm infants. Methods Data (302 samples) from 75 neonates were included with a median (range) gestational age (GA) 25.9 (23.9-29.4) weeks, bodyweight 0.95 (0.48-1.61) kg, and postnatal age (PNA) 17 (1-52) days at the start of continuous treatment. A population pharmacokinetic model was developed using non-linear mixed-effects modelling (NONMEM (R)). Results A two-compartment model best described the pharmacokinetics of doxapram and keto-doxapram. PNA and GA affected the formation clearance of keto-doxapram (CLFORMATION KETO-DOXAPRAM) and clearance of doxapram via other routes (CLDOXAPRAM OTHER ROUTES). For a median individual of 0.95 kg, GA 25.6 weeks, and PNA 29 days, CL(FORMATION KETO-DOXAPRAM)was 0.115 L/h (relative standard error (RSE) 12%) and CL(DOXAPRAM OTHER ROUTES)was 0.645 L/h (RSE 9%). Oral bioavailability was estimated at 74% (RSE 10%). Conclusions Dosing of doxapram only based on bodyweight results in the highest exposure in preterm infants with the lowest PNA and GA. Therefore, dosing may need to be adjusted for GA and PNA to minimize the risk of accumulation and adverse events. For switching to oral therapy, a 33% dose increase is required to maintain exposure. ImpactCurrent dosing regimens of doxapram in preterm infants only based on bodyweight result in the highest exposure in infants with the lowest PNA and GA. Dosing of doxapram may need to be adjusted for GA and PNA to minimize the risk of accumulation and adverse events. Describing the pharmacokinetics of doxapram and its active metabolite keto-doxapram following intravenous and gastroenteral administration enables to include drug exposure to the evaluation of treatment of AOP. The oral bioavailability of doxapram in preterm neonates is 74%, requiring a 33% higher dose via oral than intravenous administration to maintain exposure.

KW - IDIOPATHIC APNEA

KW - CAFFEINE THERAPY

KW - PREMATURITY

KW - PHARMACOTHERAPY

KW - BRADYCARDIA

KW - METABOLISM

KW - DISABILITY

KW - HYPOXEMIA

KW - CHILDREN

KW - WEIGHT

U2 - 10.1038/s41390-020-1037-9

DO - 10.1038/s41390-020-1037-9

M3 - Article

C2 - 32698193

SN - 0031-3998

VL - 89

SP - 1268

EP - 1277

JO - Pediatric Research

JF - Pediatric Research

IS - 5

ER -

The bioavailability and maturing clearance of doxapram in preterm infants

Abstract

Keywords

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