Robert B Flint1,2,3, Sinno H P Simons4, Peter Andriessen5, Kian D Liem6, Pieter L J Degraeuwe7, Irwin K M Reiss4, Rob Ter Heine8, Aline G J Engbers9, Birgit C P Koch10, Ronald de Groot11, David M Burger8, Catherijne A J Knibbe9,12, Swantje Völler9. 1. Department of Pediatrics, Division of Neonatology, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands. r.flint@erasmusmc.nl. 2. Department of Hospital Pharmacy, Erasmus Medical Center, Rotterdam, The Netherlands. r.flint@erasmusmc.nl. 3. Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. r.flint@erasmusmc.nl. 4. Department of Pediatrics, Division of Neonatology, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands. 5. Department of Pediatrics, Division of Neonatology, Máxima Medical Center, Veldhoven, The Netherlands. 6. Department of Pediatrics, Division of Neonatology of the Radboudumc, Nijmegen, The Netherlands. 7. Department of Pediatrics, Maastricht University Medical Center, School of Oncology and Developmental Biology, School of Mental Health and Neuroscience, Maastricht, The Netherlands. 8. Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. 9. Leiden Amsterdam Center for Drug Research (LACDR), Division of Pharmacology, LACDR, Leiden University, Leiden, The Netherlands. 10. Department of Hospital Pharmacy, Erasmus Medical Center, Rotterdam, The Netherlands. 11. Laboratory of Pediatric Infectious Diseases, Department of Pediatrics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. 12. Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands.
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®). 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, CLFORMATION KETO-DOXAPRAM was 0.115 L/h (relative standard error (RSE) 12%) and CLDOXAPRAM 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.
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®). 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, CLFORMATION KETO-DOXAPRAM was 0.115 L/h (relative standard error (RSE) 12%) and CLDOXAPRAM 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.
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Authors: Christian F Poets; Robin S Roberts; Barbara Schmidt; Robin K Whyte; Elizabeth V Asztalos; David Bader; Aida Bairam; Diane Moddemann; Abraham Peliowski; Yacov Rabi; Alfonso Solimano; Harvey Nelson Journal: JAMA Date: 2015-08-11 Impact factor: 56.272