Aline G.J. Engbers (1,2), Swantje Völler (1,3), Christian F. Poets (4), Catherijne A.J. Knibbe (1,5), Irwin K.M. Reiss (2), Birgit C.P Koch (6), Robert B. Flint (2,6), Sinno H.P. Simons (2)
(1) Division of Systems Biomedicine & Pharmacology, LACDR, Leiden University, Leiden, the Netherlands, (2) Department of Paediatrics, Division of Neonatology, Erasmus UMC - Sophia Children’s Hospital, Rotterdam, the Netherlands, (3) Division of BioTherapeutics, LACDR, Leiden University, Leiden, the Netherlands, (4) Department of Neonatology, Tübingen University Hospital, Tübingen, Germany, (5) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, the Netherlands, (6) Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands
Objectives: Caffeine is the standard treatment to stimulate breathing of preterm neonates. If apneas persist despite caffeine treatment, co-administration with doxapram may be initiated. While in small studies the use of doxapram in addition to caffeine has been found to be successful in preventing the need for endotracheal intubation[1,2], these results need to be validated in a further prospective study. At this point, it is unknown whether observed effects of doxapram can be attributed to doxapram itself, or to a pharmacokinetic (PK) interaction between caffeine and doxapram. Therefore, we performed a PK study to examine a potential pharmacokinetic interaction between caffeine and doxapram. Patients in the study population all received caffeine, and were co-medicated with doxapram where needed, resulting in caffeine concentrations in absence or presence of doxapram treatment.
Methods: Caffeine concentrations from patients in the DINO study (NCT02421068) who received caffeine with or without doxapram were analyzed using NONMEM V7.3. A population PK model for caffeine was developed, in which the patient characteristics postnatal age (PNA), gestational age (GA), birth weight (WTB) and current weight (WT) and co-administration of doxapram were tested as covariates. Concomitant use of doxapram was defined as a caffeine plasma sample being taken during doxapram infusion. To prevent overlooking a slower-onset interaction we also tested whether a sample was taken 24, 48 or 72 hour after a doxapram infusion event. The rate of caffeine absorption was fixed to 4.0 h-1, and bioavailability was assumed to be 100%.[3]
Results: In 39 preterm infants 174 samples were collected in which caffeine plasma levels were determined. Median gestational age (GA) was 25.6 (range 24.0 – 28.0) weeks, PNA during treatment was 20 (0 – 61) days, birth weight was 0.8 (0.5 – 1.3) kg and current weight was 1.0 (0.5 – 2.2) kg. Patients received a median loading dose of caffeine of 10 (range 5 – 11) mg/kg orally or intravenously, followed by a median daily maintenance dose of 5 (3 – 11) mg/kg over a median duration of 48 (3 – 61) treatment days. In 27 (69%) patients doxapram treatment was initiated because of apnea persistence, resulting in 65 (39%) samples that were taken during doxapram infusion. An extra 23 (13%) samples were taken within 72 after a doxapram administration, of which 10 (6%) and 21 (12%) taken within 24 and 48 hour after a doxapram administration.
A one-compartment model fitted the data best, with estimated clearance (CL) of 9.37 mL/h (RSE 4%) and volume of distribution (V) of 612 mL (RSE 14%) for a preterm infant with a birth weight of 0.8 kg, a current weight of 1.0 kg and a PNA of 20 days. Interindividual variability was identified on CL (22.7%, RSE 11%, shrinkage 10%). PNA and birth weight were identified as covariates for CL described by a power model, with estimated exponents of 0.54 (RSE 13%) and 0.83 (RSE 19%), respectively. No interaction between doxapram use and caffeine could be identified, regardless the time after doxapram administration.
Conclusions: In this pharmacokinetic study in preterm infants receiving caffeine only or caffeine combined with doxapram, no pharmacokinetic interaction between caffeine and doxapram CL was identified. Estimated CL and V are in good agreement with previously reported values.[3] The lack of a pharmacokinetic interaction implies that previously reported effects of doxapram are the result of an additive effect on the respiratory system of preterm neonates by doxapram itself, but this effect needs further prospective analysis.
References:
[1] Flint, R. et al. Retrospective study shows that doxapram therapy avoided the need for endotracheal intubation in most premature neonates. Acta Paediatr. Int. J. Paediatr. 106, 733–739 (2017).
[2] Flint, R. B. et al. Big Data Analyses for Continuous Evaluation of Pharmacotherapy: A Proof of Principle with Doxapram in Preterm Infants. Curr. Pharm. Des. 23, 5919–5927 (2018).
[3] Patel, P. et al. Dried blood spots and sparse sampling: A practical approach to estimating pharmacokinetic parameters of caffeine in preterm infants. Br. J. Clin. Pharmacol. 75, 805–813 (2013).
Reference: PAGE () Abstr 9377 [www.page-meeting.org/?abstract=9377]
Poster: Drug/Disease Modelling - Paediatrics