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 and Pharmacology, LACDR, Leiden University, Leiden, The Netherlands; (2) Division of Neonatology, Department of Paediatrics, 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 confirmed in larger studies. To date, it is unknown whether the 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 for an interaction when the caffeine 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 166 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. 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%) were taken within 24 and 48 hour after a doxapram administration.
A one-compartment model fitted the data best, with an estimated clearance (CL) of 9.99 mL/h (RSE 4%) and volume of distribution (V) of 513 mL (RSE 16%) for a preterm infant with a birth weight of 0.8 kg, a current weight of 1.0 kg and a PNA of 23 days. Interindividual variability was identified on CL (20.5%, RSE 11%, shrinkage 11%). PNA and birth weight were identified as covariates for CL using a power model, with estimated exponents of 0.51 (RSE 16%) and 0.71 (RSE 20%), respectively.
Comparison of doxapram naïve versus doxapram treated caffeine clearance suggested a 17% higher caffeine clearance in doxapram treated patients, but this effect did not meet the significance and precision criteria (dOFV −3.5 [p > 0.05] and RSE 99%). When concomitant use was defined for samples taken during doxapram infusion only dOFV was -4.7, which increased to -3.6 when samples taken up to 72 h after stopping doxapram infusion were also considered as concomitant doxapram. Therefore, 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. As current guidelines do not adjust the caffeine dose with postnatal age, decreased exposure to caffeine might partly explain the need for doxapram therapy after the first week of life.
The final, published version of this article is available at https://www.karger.com/?doi=10.1159/000513413.
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 29 (2021) Abstr 9692 [www.page-meeting.org/?abstract=9692]
Poster: Drug/Disease Modelling - Paediatrics