The bioavailability and maturing clearance of doxapram in preterm infants

• Published in: Pediatric research 2021-04, Vol.89 (5), p.1268-1277
• Main Authors: Flint, Robert B., Simons, Sinno H. P., Andriessen, Peter, Liem, Kian D., Degraeuwe, Pieter L. J., Reiss, Irwin K. M., Ter Heine, Rob, Engbers, Aline G. J., Koch, Birgit C. P., Groot, Ronald de, Burger, David M., Knibbe, Catherijne A. J., Völler, Swantje
• Format: Article
• Language: English
• Subjects: Administration, Oral; Bioavailability; Body Weight; Clinical Research Article; Doxapram - pharmacokinetics; Female; Gestational Age; Humans; Infant; Infant, Low Birth Weight; Infant, Newborn; Infant, Newborn, Diseases - drug therapy; Infant, Premature; Infant, Premature, Diseases - drug therapy; Male; Medicine; Medicine & Public Health; Newborn babies; Nonlinear Dynamics; Pediatric Surgery; Pediatrics; Pharmacokinetics; Premature babies; Reproducibility of Results; Risk; Sleep Apnea, Central - drug therapy
• ISSN: 0031-3998; 1530-0447
• DOI: 10.1038/s41390-020-1037-9

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 (CL FORMATION KETO-DOXAPRAM ) and clearance of doxapram via other routes (CL DOXAPRAM 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.