Abstract
Fentanyl is widely used for analgesia, sedation, and anesthesia both in adult and pediatric populations. Yet, only few pharmacokinetic studies of fentanyl in pediatrics exist as conducting clinical trials in this population is especially challenging. Physiologically-based pharmacokinetic (PBPK) modeling is a mechanistic approach to explore drug pharmacokinetics and allows extrapolation from adult to pediatric populations based on age-related physiological differences. The aim of this study was to develop a PBPK model of fentanyl and norfentanyl for both adult and pediatric populations. The adult PBPK model was established in PK-Sim® using data from 16 clinical studies and was scaled to several pediatric subpopulations. ~93% of the predicted AUClast values in adults and ~88% in pediatrics were within 2-fold of the corresponding value observed. The adult PBPK model predicted a fraction of fentanyl dose metabolized to norfentanyl of ~33% and a fraction excreted in urine of ~7%. In addition, the pediatric PBPK model was used to simulate differences in peak plasma concentrations after bolus injections and short infusions. The novel PBPK models could be helpful to further investigate fentanyl pharmacokinetics in both adult and pediatric populations.
Highlights
Fentanyl is a strong opioid—approximately 50- to 100-fold more potent compared to morphine—and is extensively used in the therapeutic fields of analgesia, sedation, and anesthesia both in adult and pediatric patients [1,2,3]
The adult Physiologically-based pharmacokinetic (PBPK) model predicts the fraction of fentanyl dose metabolized to norfentanyl of ~33% and the fraction of fentanyl eliminated via an unspecific hepatic clearance of ~60%
This study demonstrates the applicability of PBPK modeling to predict both clearance values as well as plasma concentration–time profiles and the corresponding AUCs for the analgesic drug fentanyl for preterm neonates to up to 3-year-old children within a whole-body PBPK framework
Summary
Fentanyl is a strong opioid—approximately 50- to 100-fold more potent compared to morphine—and is extensively used in the therapeutic fields of analgesia, sedation, and anesthesia both in adult and pediatric patients [1,2,3]. Recent research activities have suggested a strong involvement of additional metabolic pathways and hypothesized unknown metabolites [5,6]. Fentanyl is the opioid analgesic most frequently used in neonatal intensive care units [1], which highlights the importance of fentanyl in pediatrics. The desired analgesic and sedating effects resulting from administration of fentanyl usually lead to an improvement of respiratory compliance [7,8]. A recent meta-analysis by Ziesenitz and colleagues concluded the need for further research on fentanyl, especially in larger cohorts and special subpopulations such as preterm neonates and children with hepatic or renal impairment [2]. Pediatric PK studies are difficult to conduct and are often impeded by ethical and logistic challenges, many of which are unique to pediatrics [9]
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