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Published on: August 19, 2020
Factors Contributing to Fentanyl Pharmacokinetic Variability Among Diagnostically Diverse Critically Ill Children
Fanuel T Hagos1, Christopher M Horvat2,3, Alicia K Au4,5
1Center for Clinical Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA.
Insights
This study characterized fentanyl pharmacokinetics in critically ill children, finding that CYP3A4/5 inducers significantly increase fentanyl clearance. This highlights the need for precision dosing in pediatric intensive care units (ICUs).
Area of Science:
- Pharmacology
- Pediatric Critical Care
- Pharmacokinetics
Background:
- Fentanyl is commonly used for analgesia and sedation in critically ill children.
- Significant variability exists in fentanyl exposure, necessitating population pharmacokinetic (PopPK) modeling.
Purpose of the Study:
- To characterize the population pharmacokinetics of fentanyl in critically ill pediatric patients.
- To identify factors contributing to fentanyl exposure variability.
Main Methods:
- Retrospective cohort study using electronic health records and remnant blood samples from a pediatric ICU.
- Developed and validated a two-compartment PopPK model for fentanyl.
- Evaluated covariates including age, weight, and CYP450 genotype/inducer status.
Main Results:
- A two-compartment model adequately described fentanyl disposition.
- High inter-individual variability was observed for fentanyl clearance and volume of distribution.
- Coadministration of CYP3A4/5 inducers (fosphenytoin, phenobarbital) significantly increased fentanyl clearance.
Conclusions:
- Population pharmacokinetic modeling is feasible and useful in critically ill children using electronic data and remnant samples.
- Concomitant CYP3A4/5 inducers have a clinically significant impact on fentanyl clearance.
- Precision dosing strategies for fentanyl in critically ill children are warranted.
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.
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