Factors Contributing to Fentanyl Pharmacokinetic Variability Among Diagnostically Diverse Critically Ill Children
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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.
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.
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.
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.
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.
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.
- 2.Sullivan KR, Cammarano WB, Wiener-Kronish JP. Analgesics, tranquilizers, and sedatives. Card intensive care. 2nd ed. Philadelphia: Elsevier/Saunders; 2010. p. 504–15. https://www.clinicalkey.com/#!/content/book/3-s2.0-B9781416037736100412?scrollTo=%23hl0000403. Accessed 19 Mar 2018.
- 5.Peng PWH, Sandler AN. A review of the use of fentanyl analgesia in the management of acute pain in adults. Anesthesiol J Am Soc Anesthesiol. 1999;90:576–99.Google Scholar
- 21.Friis-Hansen B. Body composition during growth. In vivo measurements and biochemical data correlated to differential anatomical growth. Pediatrics. 1971;47(1 Suppl 2):264–72.Google Scholar
- 22.Weber DR, Leonard MB, Zemel BS. Body composition analysis in the pediatric population. Pediatr Endocrinol Rev PER. 2012;10:130–9.Google Scholar
- 27.Feierman DE, Lasker JM. Metabolism of fentanyl, a synthetic opioid analgesic, by human liver microsomes. Role of CYP3A4. Drug Metab Dispos Biol Fate Chem. 1996;24:932–9.Google Scholar
- 28.Tateishi T, Krivoruk Y, Ueng YF, Wood AJ, Guengerich FP, Wood M. Identification of human liver cytochrome P-450 3A4 as the enzyme responsible for fentanyl and sufentanil N-dealkylation. Anesth Analg. 1996;82:167–72.Google Scholar
- 32.Burk O, Koch I, Raucy J, Hustert E, Eichelbaum M, Brockmöller J, et al. The induction of cytochrome P450 3A5 (CYP3A5) in the human liver and intestine is mediated by the xenobiotic sensors pregnane X receptor (PXR) and constitutively activated receptor (CAR). J Biol Chem. 2004;279:38379–85.CrossRefGoogle Scholar
- 33.Wortham M, Czerwinski M, He L, Parkinson A, Wan Y-JY. Expression of constitutive androstane receptor, hepatic nuclear factor 4 alpha, and P450 oxidoreductase genes determines interindividual variability in basal expression and activity of a broad scope of xenobiotic metabolism genes in the human liver. Drug Metab Dispos Biol Fate Chem. 2007;35:1700–10.CrossRefGoogle Scholar
- 39.Olsen L, Aisner D, McGinnis JM, Institute of Medicine (U.S.), editors. The learning healthcare system: workshop summary. Washington, DC: National Academies Press; 2007.Google Scholar