Yunjiao Wu (1), Swantje Völler (1), Robert Flint (2,3), Sinno Simons (2), Karel Allegaert (4), Vineta Fellman (5,6,7), Catherijne Knibbe (1,3,8)
(1) Division of Pharmacology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands, (2) Department of Pediatrics, Division of Neonatology, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands, (3) Department of Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands, (4) University of Leuven, Belgium and Erasmus MC, Rotterdam, the Netherlands (5) Lund University, Department of Clinical Sciences, Lund, Pediatrics, Lund, Sweden, (6) Folkhälsan Research Center, Helsinki, Finland, (7) Children's Hospital, University of Helsinki, Helsinki, Finland, (8) Department of Clinical Pharmacy, St Antonius Hospital, Nieuwegein, The Netherlands
Objectives: Fentanyl is a synthetic opioid with strong analgestic and sedative effects. It is a commonly used opioid in neonatal intensive care units (NICU) to prevent and ameliorate severe pain. Currently, the information on the pharmacokinetics of fentanyl is limited in very preterm, but also in term newborn infants. Still, the use of fentanyl in this population is off-label and mostly based on bodyweight.
Pharmacokinetics of fentanyl in preterm neonates (gestational age 24-32 weeks) has been studied by Völler et al.[1], who showed that fentanyl clearance (CL) rapidly increases with both gestational age (GA) and postnatal age (PNA). However, whether GA and PNA also influence clearance maturation in term neonates is still unknown. The aim of this study is to determine the pharmacokinetics of fentanyl in preterm and term neonates from 24-42 weeks of gestation.
Methods: After combining the dataset from Saarenmaa et al., which partly was published as non-compartmental pharmacokinetic study [2] and the dataset from Völler et al. [1], we developed a population pharmacokinetic model using NONMEM® 7.4. In total, the dataset contained a total of 677 observations of 164 infants with a median GA of 29.0 (range 23.9 – 42.3) weeks, birth weight of 1.1 (range 0.4 – 4.2) kg, current weight of 1.1 (range 0.4-4.2) kg, PNA of 14.5 (range 0.0 – 101.0) days and calculated postmenstrual age (PMA) of 30.0 (range 23.9 – 42.3) weeks. The CIs of the bootstrap analysis in PsN (n=1000) were used to evaluate the precision of the estimated parameters.
Results: The data was best described by a two-compartment model. For a typical newborn infant (birthweight 1060 g, current weight 1097 g and 1 day old), CL was 0.49 L/h, volume of distribution for the central compartment (V1) was 6.80 L and volume of distribution for the peripheral compartment (V2) was 4.49 L, intercompartmental clearance (Q) was 0.76 L/h. A fixed exponent of 1 was sufficient to describe the effect of current weight on V1. Although PMA was the most significant covariate on clearance, the combination of birthweight and PNA (exponent 1.74 and 0.339, respectively) proved to be superior to PMA alone (ΔOFV is -40.0). CL for neonates with birthweght of 2000 g and 3000 g are 2.34-fold and 5.76-fold higher compared with that of 1000 g, respectively. Infants with a postnatal age of 1 week, 2 weeks and 3 weeks have a 1.43-fold, 2.07-fold and 2.53-fold higher CL than that of infants at birth. Goodness of fit plots and bootstrap results did not show obvious bias.
Conclusions: A popPK model describing the PK of fentanyl in preterm and term neonates was successfully developed. The results shows that CL was best descibed by birthweight and PNA. Völler et al.[1] found that GA and PNA influenced CL in preterm neonates. In this dataset, the fit for GA and PNA was very similar to that for birthweight and PNA (ΔOFV is 6.67). These findings support that antenatal and postnatal maturation influnce the CL of fentanyl in both term and preterm infants. Therefore, dosing based on current bodyweight is suboptimal in this population.
References:
[1] Voller S et al. Arch Dis Child Fetal Neonatal Ed. (2019) Nov;104(6):F598-F603.
[2] Saarenmaa E et al. J Pediatr. (2000) Jun;136(6):767-70.
Reference: PAGE () Abstr 9496 [www.page-meeting.org/?abstract=9496]
Poster: Drug/Disease Modelling - Paediatrics