Physiologically-Based Pharmacokinetic (PBPK) Modeling Providing Insights into Fentanyl Pharmacokinetics in Adults and Pediatric Patients
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) mode...
Main Authors: | , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
MDPI AG
2020-09-01
|
Series: | Pharmaceutics |
Subjects: | |
Online Access: | https://www.mdpi.com/1999-4923/12/10/908 |
id |
doaj-5b434bd5d61e4392b35ce8cbc6571013 |
---|---|
record_format |
Article |
spelling |
doaj-5b434bd5d61e4392b35ce8cbc65710132020-11-25T03:53:44ZengMDPI AGPharmaceutics1999-49232020-09-011290890810.3390/pharmaceutics12100908Physiologically-Based Pharmacokinetic (PBPK) Modeling Providing Insights into Fentanyl Pharmacokinetics in Adults and Pediatric PatientsLukas Kovar0Andreas Weber1Michael Zemlin2Yvonne Kohl3Robert Bals4Bernd Meibohm5Dominik Selzer6Thorsten Lehr7Department of Clinical Pharmacy, Saarland University, 66123 Saarbrücken, GermanyDepartment of Clinical Pharmacy, Saarland University, 66123 Saarbrücken, GermanyDepartment of General Pediatrics and Neonatology, Saarland University Medical Center, 66421 Homburg, GermanyFraunhofer Institute for Biomedical Engineering IBMT, 66280 Sulzbach, GermanyDepartment of Internal Medicine V, Saarland University, 66421 Homburg, GermanyDepartment of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, TN 38163, USADepartment of Clinical Pharmacy, Saarland University, 66123 Saarbrücken, GermanyDepartment of Clinical Pharmacy, Saarland University, 66123 Saarbrücken, GermanyFentanyl 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<sup>®</sup> using data from 16 clinical studies and was scaled to several pediatric subpopulations. ~93% of the predicted AUC<sub>last</sub> 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.https://www.mdpi.com/1999-4923/12/10/908physiologically-based pharmacokinetic (PBPK) modelingfentanylneonatesnorfentanylpediatric scalingdrug–drug interaction (DDI) |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Lukas Kovar Andreas Weber Michael Zemlin Yvonne Kohl Robert Bals Bernd Meibohm Dominik Selzer Thorsten Lehr |
spellingShingle |
Lukas Kovar Andreas Weber Michael Zemlin Yvonne Kohl Robert Bals Bernd Meibohm Dominik Selzer Thorsten Lehr Physiologically-Based Pharmacokinetic (PBPK) Modeling Providing Insights into Fentanyl Pharmacokinetics in Adults and Pediatric Patients Pharmaceutics physiologically-based pharmacokinetic (PBPK) modeling fentanyl neonates norfentanyl pediatric scaling drug–drug interaction (DDI) |
author_facet |
Lukas Kovar Andreas Weber Michael Zemlin Yvonne Kohl Robert Bals Bernd Meibohm Dominik Selzer Thorsten Lehr |
author_sort |
Lukas Kovar |
title |
Physiologically-Based Pharmacokinetic (PBPK) Modeling Providing Insights into Fentanyl Pharmacokinetics in Adults and Pediatric Patients |
title_short |
Physiologically-Based Pharmacokinetic (PBPK) Modeling Providing Insights into Fentanyl Pharmacokinetics in Adults and Pediatric Patients |
title_full |
Physiologically-Based Pharmacokinetic (PBPK) Modeling Providing Insights into Fentanyl Pharmacokinetics in Adults and Pediatric Patients |
title_fullStr |
Physiologically-Based Pharmacokinetic (PBPK) Modeling Providing Insights into Fentanyl Pharmacokinetics in Adults and Pediatric Patients |
title_full_unstemmed |
Physiologically-Based Pharmacokinetic (PBPK) Modeling Providing Insights into Fentanyl Pharmacokinetics in Adults and Pediatric Patients |
title_sort |
physiologically-based pharmacokinetic (pbpk) modeling providing insights into fentanyl pharmacokinetics in adults and pediatric patients |
publisher |
MDPI AG |
series |
Pharmaceutics |
issn |
1999-4923 |
publishDate |
2020-09-01 |
description |
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<sup>®</sup> using data from 16 clinical studies and was scaled to several pediatric subpopulations. ~93% of the predicted AUC<sub>last</sub> 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. |
topic |
physiologically-based pharmacokinetic (PBPK) modeling fentanyl neonates norfentanyl pediatric scaling drug–drug interaction (DDI) |
url |
https://www.mdpi.com/1999-4923/12/10/908 |
work_keys_str_mv |
AT lukaskovar physiologicallybasedpharmacokineticpbpkmodelingprovidinginsightsintofentanylpharmacokineticsinadultsandpediatricpatients AT andreasweber physiologicallybasedpharmacokineticpbpkmodelingprovidinginsightsintofentanylpharmacokineticsinadultsandpediatricpatients AT michaelzemlin physiologicallybasedpharmacokineticpbpkmodelingprovidinginsightsintofentanylpharmacokineticsinadultsandpediatricpatients AT yvonnekohl physiologicallybasedpharmacokineticpbpkmodelingprovidinginsightsintofentanylpharmacokineticsinadultsandpediatricpatients AT robertbals physiologicallybasedpharmacokineticpbpkmodelingprovidinginsightsintofentanylpharmacokineticsinadultsandpediatricpatients AT berndmeibohm physiologicallybasedpharmacokineticpbpkmodelingprovidinginsightsintofentanylpharmacokineticsinadultsandpediatricpatients AT dominikselzer physiologicallybasedpharmacokineticpbpkmodelingprovidinginsightsintofentanylpharmacokineticsinadultsandpediatricpatients AT thorstenlehr physiologicallybasedpharmacokineticpbpkmodelingprovidinginsightsintofentanylpharmacokineticsinadultsandpediatricpatients |
_version_ |
1724476984497537024 |