Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Fentanyl dosage for preterm infants suggested by a pharmacokinetic, -dynamic, and -genetic model

Bardol, Maddlie LU ; Norman, Elisabeth LU ; Lagercrantz, Hugo ; Fellman, Vineta LU orcid and Standing, Joseph F. (2024) In Pediatric Research
Abstract

Background: Fentanyl is commonly administered for procedural pain management in preterm infants, but target concentrations have not yet been defined. Methods: To investigate pharmacokinetics (PK), -dynamics (PD), and -genetics (PG), 25 infants (gestational age 23.3–34.1 weeks) received a fentanyl dose before a skin-breaking procedure (0.5 µg/kg) or tracheal intubation (2 µg/kg). Four pain scales were used as a PD endpoint to evaluate efficacy. The impact of polymorphism in genes encoding enzymes (UGT2B7, CYP3A7, CYP3A4, COMT, CYP2D6, KCNJ6), transporters (SLC22A1, ABCC1, ABCC3) and receptor (OPRM1) on PK parameters was explored. Results: A two-compartment PK model adequately described the fentanyl concentration. The effects of weight... (More)

Background: Fentanyl is commonly administered for procedural pain management in preterm infants, but target concentrations have not yet been defined. Methods: To investigate pharmacokinetics (PK), -dynamics (PD), and -genetics (PG), 25 infants (gestational age 23.3–34.1 weeks) received a fentanyl dose before a skin-breaking procedure (0.5 µg/kg) or tracheal intubation (2 µg/kg). Four pain scales were used as a PD endpoint to evaluate efficacy. The impact of polymorphism in genes encoding enzymes (UGT2B7, CYP3A7, CYP3A4, COMT, CYP2D6, KCNJ6), transporters (SLC22A1, ABCC1, ABCC3) and receptor (OPRM1) on PK parameters was explored. Results: A two-compartment PK model adequately described the fentanyl concentration. The effects of weight and maturity on the clearance were included as covariates in the model. One genetic variant encoding the ABCC1 transporter (rs111517339 T/TA) and two encoding the ABCC3 transporter (rs11079921 T/C and rs8077268 C/T) had a significant effect on fentanyl elimination that explained 15% of the interindividual variability on the clearance. A proportional odds PK/PD model was used to describe the concentration-effect relationship of fentanyl using the Échelle de douleur et d’inconfort du nouveau-né (EDIN) pain score. Conclusion: The simulations suggest that an intravenous dose of 2 µg/kg would be appropriate in preterm infants for a clearly painful procedure, such as an intubation. Impact: Design of personalized analgesia with fentanyl for newborn infants should consider maturation and genetic variants of opioid transporters affecting drug elimination. The results indicate that an intravenous dose of 2 μg/kg fentanyl would be suitable before a clearly painful procedure in preterm infants. Genetic variants encoding ABCC1 and ABCC3 transporters increase the clearance of fentanyl, which is a novel finding.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Pediatric Research
publisher
International Pediatric Foundation Inc.
external identifiers
  • pmid:39025933
  • scopus:85198924239
ISSN
0031-3998
DOI
10.1038/s41390-024-03404-z
language
English
LU publication?
yes
additional info
Publisher Copyright: © The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc 2024.
id
8d5e6be3-f801-4ce5-bcf8-8d58dbc2753f
date added to LUP
2024-11-27 12:56:15
date last changed
2025-07-24 08:39:11
@article{8d5e6be3-f801-4ce5-bcf8-8d58dbc2753f,
  abstract     = {{<p>Background: Fentanyl is commonly administered for procedural pain management in preterm infants, but target concentrations have not yet been defined. Methods: To investigate pharmacokinetics (PK), -dynamics (PD), and -genetics (PG), 25 infants (gestational age 23.3–34.1 weeks) received a fentanyl dose before a skin-breaking procedure (0.5 µg/kg) or tracheal intubation (2 µg/kg). Four pain scales were used as a PD endpoint to evaluate efficacy. The impact of polymorphism in genes encoding enzymes (UGT2B7, CYP3A7, CYP3A4, COMT, CYP2D6, KCNJ6), transporters (SLC22A1, ABCC1, ABCC3) and receptor (OPRM1) on PK parameters was explored. Results: A two-compartment PK model adequately described the fentanyl concentration. The effects of weight and maturity on the clearance were included as covariates in the model. One genetic variant encoding the ABCC1 transporter (rs111517339 T/TA) and two encoding the ABCC3 transporter (rs11079921 T/C and rs8077268 C/T) had a significant effect on fentanyl elimination that explained 15% of the interindividual variability on the clearance. A proportional odds PK/PD model was used to describe the concentration-effect relationship of fentanyl using the Échelle de douleur et d’inconfort du nouveau-né (EDIN) pain score. Conclusion: The simulations suggest that an intravenous dose of 2 µg/kg would be appropriate in preterm infants for a clearly painful procedure, such as an intubation. Impact: Design of personalized analgesia with fentanyl for newborn infants should consider maturation and genetic variants of opioid transporters affecting drug elimination. The results indicate that an intravenous dose of 2 μg/kg fentanyl would be suitable before a clearly painful procedure in preterm infants. Genetic variants encoding ABCC1 and ABCC3 transporters increase the clearance of fentanyl, which is a novel finding.</p>}},
  author       = {{Bardol, Maddlie and Norman, Elisabeth and Lagercrantz, Hugo and Fellman, Vineta and Standing, Joseph F.}},
  issn         = {{0031-3998}},
  language     = {{eng}},
  publisher    = {{International Pediatric Foundation Inc.}},
  series       = {{Pediatric Research}},
  title        = {{Fentanyl dosage for preterm infants suggested by a pharmacokinetic, -dynamic, and -genetic model}},
  url          = {{http://dx.doi.org/10.1038/s41390-024-03404-z}},
  doi          = {{10.1038/s41390-024-03404-z}},
  year         = {{2024}},
}