Yunjiao Wu (1), Swantje Völler (1,2,3), Robert B. Flint (3,4), Sinno H.P. Simons (3), Karel Allegaert (4,5), Vineta Fellman (6,7,8), Catherijne A.J. Knibbe (1,3,9)*
(1) Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands, (2) Division of BioTherapeutics, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands, (3) Department of Pediatrics, Division of Neonatology, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands, (4) Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands, (5) KU Leuven, Departments of Development and Regeneration and Pharmaceutical and Pharmacological Sciences, Belgium, (6) Department of Clinical Sciences, Lund, Pediatrics, Lund University, Lund, Sweden, (7) Folkhälsan Research Center, Helsinki, Finland, (8) Children's Hospital, University of Helsinki, Helsinki. Finland, (9) Department of Clinical Pharmacy, St Antonius Hospital, Nieuwegein, The Netherlands.
Objectives: Fentanyl is a commonly used opioid in neonatal intensive care units (NICU) to prevent and ameliorate severe pain. Given the limited pharmacokinetic information across the entire neonatal age range, its neonatal use is off-label and mostly bodyweight-based.
The pharmacokinetics of fentanyl in preterm neonates (gestational age 24-32 weeks) have 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: We pooled data from the study of Völler et al.[1] and Saarenmaa et al. [2] on 164 newborns with median (range) GA of 29.0 (23.9-42.3) weeks, birthweight of 1,055 (390-4,245) grams and PNA of 1 (0-68) days. In total, 678 plasma samples upon bolus dosing (69 patients, median dose 2.1 mcg/kg, median 2 boluses per patient) or continuous infusions (95 patients, median dose 1.1 mcg/kg/h for 30 hours) with and without boluses were used for population pharmacokinetic modeling in NONMEM® 7.4. Goodness-of-fit plots and normalized prediction distribution errors (NPDEs) based on 1000 simulations were used for model evaluation.
Results: The combined dataset was best described by a two-compartment model with first-order elimination. Separated combined additive and proportional error functions for the different datasets was used as residual model.
Implementation of the combination of PNA and birthweight on clearance (CL) was superior to implementation of postmenstrual age (PMA) (ΔOFV=-91), and the relationship between birthweight, PNA and CL was best described by a power function (exponent 1.47 and 0.505, respectively). CL is 0.31 L/h for a typical newborn infant with birthweight of 1055 g and PNA of 1 day. CL of a 2000 g and 3000 g-birthweight neonate was 1.8 and 4.0-fold higher compared to a 1000 g-birthweight neonate, respectively; CL of a 7, 14 and 21 days-PNA neonates was 1.7-fold, 2.8-fold and 3.6-fold higher compared to 1 day, respectively.
The relationship between central distribution volume (V1) and current body weight (CW) was bset desribed by a bodyweight dependent-exponent function[3], which allows the scaling exponent of CW on V1 change with CW. V1 is 10.6 L for a typical newborn infant with CW of 1165 g, and the exponent varied between 1.66 for neonates of 1000g CW and 1.05 for neonates of 3000g CW.
Goodness of fit plots and NPDEs results did not show any misspecification.
Conclusions: A popPK model describing the PK of fentanyl in preterm and term neonates was successfully developed. The results shows that CLwas best descibed by birthweight and PNA. In preterm neonates, Völler et al. [1] found GA and PNA as covariates for CL. In the current dataset, the result for GA and PNA was very similar to that for birthweight and PNA (ΔOFV of 0.475). These findings show that antenatal and postnatal maturation influnce the CL of fentanyl in both preterm and term infants. Therefore, dosing based on current bodyweight is suboptimal in this population.
References:
[1] Voller S, Flint RB, Andriessen P, Allegaert K, Zimmermann LJI, Liem KD, et al. Rapidly maturing fentanyl clearance in preterm neonates. Arch Dis Child Fetal Neonatal Ed. 2019 Nov;104(6):F598-F603.
[2] Saarenmaa E, Neuvonen PJ, Fellman V. Gestational age and birth weight effects on plasma clearance of fentanyl in newborn infants. J Pediatr. 2000 Jun;136(6):767-70.
[3] De Cock RF, Allegaert K, Brussee JM, Sherwin CM, Mulla H, de Hoog M, et al. Simultaneous pharmacokinetic modeling of gentamicin, tobramycin and vancomycin clearance from neonates to adults: towards a semi-physiological function for maturation in glomerular filtration. Pharm Res. 2014;31(10):2643-54.
Reference: PAGE 29 (2021) Abstr 9594 [www.page-meeting.org/?abstract=9594]
Poster: Drug/Disease Modelling - Paediatrics