ALESSANDRO Di Deo1, Licia Lugli2, Bianca Maria Goffredo3, Raffaele Simeoli3, Oscar Della Pasqua1
1Clinical Pharmacology & Therapeutics, 2Neonatal Intensive Care Unit, Women’s and Children’s Health Department, University Hospital of Modena, 3Bambino Gesù Children's Hospital IRCCS
Introduction: Therapeutic hypothermia (TH) is the standard of care for newborns with moderate to severe hypoxic-ischaemic encephalopathy (HIE) following peripartum asphyxia [1-3]. TH has been shown to improve survival in infants, however pain during treatment may affect its effectiveness. Thus, to mitigate the negative long-term effects on neurodevelopment and quality of life, pain management through analgosedation is required [4-5]. Currently, there is no consensus regarding the dosing requirements for neonatal analgosedation undergoing TH. Despite its wide clinical use [6], the pharmacokinetics and pharmacodynamics of fentanyl have not been characterised in this setting. Therefore, FentanylTH (EUDRACT: 2020-000836-23) was set up to investigate the pharmacokinetics of fentanyl in full-term newborns with HIE who require TH. Following administration of a 2 µg/kg bolus and subsequent IV infusion of 1 µg/kg/h over 72 h. It has been anticipated that changes in pharmacokinetics were expected due to vasoconstriction, reduced heart rate, decreased hepatic blood flow, and metabolic activity (i.e., CYP3A4). Objectives: The primary aim of this study was to characterise TH-induced changes in the disposition properties of fentanyl in neonatal patients and explore the relationship between plasma exposure and the Neonatal Pain, Agitation, and Sedation Scale (N-PASS). Methods: A total of 17 newborns with gestational age ranging from 37 to 41 weeks were available for the purpose of this analysis. A nonlinear mixed effects modelling approach was implemented in NONMEM 7.5. Pharmacokinetic data were analysed based on a previously published model, including the effect of maturation and body weight. Moreover, an attempt was made to describe the change in systemic clearance related to the TH taking into account the time course of body temperature during and after TH. Subsequently, individual predicted measures of exposure were correlated with the N-PASS sedation/agitation scores. Simulations were then implemented considering fentanyl concentrations between 3 ng/mL and 5 ng/mL to be adequate for analgosedation. Alternative doses and dosing regimens were evaluated to maximise the proportion of subjects reaching the target concentrations and reducing the time to reach the putative therapeutic target. Results: The time course of fentanyl concentrations in neonatal patients was described by a two-compartment pharmacokinetic model, with allometric scaling based on body weight identified as the most relevant covariate factor influencing clearance and volume of distribution. Consistent with previously published data on therapeutic hypothermia (TH), the volume of distribution in newborns undergoing TH was significantly lower (approximately threefold) compared to newborns receiving standard analgosedation therapy. No relevant differences in systemic clearance were observed due to TH. Body weight and postnatal age (PNA) did not explain intraindividual variability in this group of neonates. The analysis of the N-PASS scores revealed that inadequate analgosedation (N-PASS Score >3) was observed in almost 50% of the patients within the first 24 hours. In addition, the correlation between systemic exposure and N-PASS score showed that concentrations above 3 ng/mL were associated with satisfactory pain management. Considering the therapeutic range identified in the PKPD analysis, a loading bolus of 3 up to 4 µg/kg followed by an IV infusion of 2 µg/kg/h should be used. Conclusion: The effect of TH on the pharmacokinetics of fentanyl was successfully described using a nonlinear mixed effects modelling approach. Model parameters indicate that TH reduces the volume of distribution without significant effect on clearance. The model also provided the basis for optimisation of the dosing regimen (i.e., 3 or 4 µg/kg bolus). The proposed dose should ensure a faster onset of analgosedation without compromising the safety profile of fentanyl in this population. Ethical Requirements: This study has been approved by the Ethics Committee (protocol number: 152/2020/FARM/AOUMO) and the Italian Institute of Health (ISS: 20405(2020)-PRE21-1812). The study was implemented in accordance with the Declaration of Helsinki and the Good Clinical Practices guidelines [ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996 Directive 91/507/EEC; D.M. 15.7.1997].
[1] Lee AC, Kozuki N, Blencowe H, Vos T, Bahalim A, Darmstadt GL, et al. Intrapartum-related neonatal encephalopathy incidence and impairment at regional and global levels for 2010 with trends from 1990. Pediatric Research 2013;74(Suppl 1):50-72. [2] Gunn A, Laptook A, Robertson N, Barks J, Thoresen M, Wassink G, et al. Therapeutic hypothermia translates from ancient history in to practice. Pediatric Research 2017;81(1-2):202-9. [3] Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database of Systematic Reviews 2013, Issue 1. Art. No: CD003311. [4] U¨ner IL, Johansen T, Dahle J, Persson M, Stiris T, Andresen JH. Therapeutic hypothermia and N-PASS; results from implementation in a level 3 NICU. Early Human Development 2019;137:104828. [5] McPherson C, O’Mara K. Provision of sedation and treatment of seizures during neonatal therapeutic hypothermia. Neonatal Network 2020;39(4):227-35. [6]Lago P, Spada C, Lugli L, Garetti E, Pirelli A, Savant Levet P, Ancora G, Merazzi D; Pain Study Group of Italian Society of Neonatology. Pain management during therapeutic hypothermia in newborn infants with hypoxic-ischaemic encephalopathy. Acta Paediatr. 2020 Mar;109(3):628-629.
Reference: PAGE 33 (2025) Abstr 11405 [www.page-meeting.org/?abstract=11405]
Poster: Drug/Disease Modelling - Other Topics