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Factors Contributing to Fentanyl Pharmacokinetic Variability Among Diagnostically Diverse Critically Ill Children

  • Fanuel T. Hagos
  • Christopher M. HorvatEmail author
  • Alicia K. Au
  • Yvette P. Conley
  • Lingjue Li
  • Samuel M. Poloyac
  • Patrick M. Kochanek
  • Robert S. B. Clark
  • Philip E. Empey
Original Research Article
  • 18 Downloads

Abstract

Objective

The objective of this study was to characterize the population pharmacokinetics of fentanyl and identify factors that contribute to exposure variability in critically ill pediatric patients.

Methods

We conducted a single-center, retrospective cohort study using electronic record data and remnant blood samples in the setting of a mixed medical/surgical intensive care unit (ICU) at a quaternary children’s hospital. Children with a predicted ICU length of stay of at least 3 days and presence of an indwelling central venous or arterial line were included. Serum fentanyl measurements were performed for 278 unique remnant samples from 66 patients. Both one- and two-compartment models were evaluated to describe fentanyl disposition. Covariates were introduced into the model in a forward/backward, stepwise approach and included age, sex, race, weight, cytochrome P450 (CYP) 3A5 genotype, and the presence of CYP3A4 or CYP3A5 inducers or inhibitors. Simulations were performed using the successful model to depict the influence of inducers on fentanyl concentrations.

Results

A two-compartment base model best described the data. There was good agreement between observed and predicted concentrations in the final model. The typical fentanyl clearance for 70 kg (reference weight) and 20.1 kg (median weight) patients were 34.6 and 13.6 L/h, respectively. The magnitude of the unexplained random inter-individual variability was high for both clearance (60.7%) and apparent volume of the central compartment (V1) (107.2%). Coadministration of the known CYP3A4/5 inducers fosphenytoin and/or phenobarbital was associated with significantly increased fentanyl clearance. Simulations demonstrate that the effect of inducer administration was most pronounced following discontinuation of a fentanyl infusion.

Conclusions

In this study we show the feasibility and utility of using electronic record data and remnant blood samples to successfully construct population pharmacokinetic models for a heterogeneous cohort of critically ill children. A clinically relevant effect of concomitant CYP3A4/5 inducers was identified. Scaling this population pharmacokinetic approach is necessary to craft precision approaches to fentanyl administration for critically ill children.

Notes

Compliance with Ethical Standards

Conflict of interest

Fanuel T. Hagos, Christopher M. Horvat, Alicia K. Au, Yvette Conley, Lingjue Li, Samuel M. Poloyac, Patrick M. Kochanek, Robert S. B. Clark, and Philip E. Empey have no conflicts of interest relating to this article.

Funding

This work was supported by NIH Grants 1TL1 TR001858-01 (FTH) and NICHD T32 HD 040686 (CMH, PMK), the Children’s Hospital of Pittsburgh Trust Young Investigator Award (CMH), and the Children’s Hospital of Pittsburgh Scientific Fund (CMH). No sponsors were involved in the study design, collection, analysis, or interpretation of data, the writing of the report, or the decision to submit the manuscript for publication. Christopher M. Horvat wrote the first draft of this manuscript and no honorarium, grant, or other form of payment was given to produce this manuscript.

Supplementary material

40262_2019_773_MOESM1_ESM.docx (49 kb)
Supplementary material 1 (DOCX 49 kb)

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Fanuel T. Hagos
    • 1
  • Christopher M. Horvat
    • 2
    • 3
    Email author
  • Alicia K. Au
    • 2
    • 3
  • Yvette P. Conley
    • 4
    • 5
  • Lingjue Li
    • 3
    • 6
  • Samuel M. Poloyac
    • 3
    • 6
  • Patrick M. Kochanek
    • 2
    • 3
  • Robert S. B. Clark
    • 2
    • 3
  • Philip E. Empey
    • 3
    • 6
  1. 1.Center for Clinical Pharmaceutical SciencesUniversity of Pittsburgh School of PharmacyPittsburghUSA
  2. 2.Department of Critical Care MedicineUniversity of Pittsburgh, School of Medicine and Children’s Hospital of Pittsburgh of UPMCPittsburghUSA
  3. 3.Safar Center for Resuscitation ResearchUniversity of PittsburghPittsburghUSA
  4. 4.Department of Health Promotion and DevelopmentUniversity of Pittsburgh School of NursingPittsburghUSA
  5. 5.Department of Human GeneticsUniversity of Pittsburgh Graduate School of Public HealthPittsburghUSA
  6. 6.Division of Pharmacy and TherapeuticsUniversity of Pittsburgh School of PharmacyPittsburghUSA

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