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
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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.
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Dosing of doxapram may need to be adjusted for GA and PNA to minimize the risk of accumulation and adverse events.
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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.
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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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Acknowledgements
This study was enabled by funding from the Netherlands Organization for Health Research and Development ZonMw (Grant number: 80-83600-98-10190).
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R.d.G. initiated the application of the grant that enabled the DINO study. R.B.F., S.H.P.S., R.d.G, D.M.B., and C.A.J.K. designed the study. P.L.J.D., P.A., K.D.L., I.K.M.R., and S.H.P.S. were local coordinating investigators and recruited subjects. B.C.P.K. facilitated the measurement of the plasma concentrations doxapram and keto-doxapram. R.B.F., A.G.J.E., R.t.H., C.A.J.K., and S.V. performed the population PK analyses. All authors have read and approved the final version of the paper.
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The Erasmus MC ethics review board approved the protocol and written informed consent from parents/legal guardians was obtained prior to study initiation (MEC-2014-067).
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Flint, R.B., Simons, S.H.P., Andriessen, P. et al. The bioavailability and maturing clearance of doxapram in preterm infants. Pediatr Res 89, 1268–1277 (2021). https://doi.org/10.1038/s41390-020-1037-9
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DOI: https://doi.org/10.1038/s41390-020-1037-9
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