Physiologically based pharmacokinetic modeling providing insights into the pharmacokinetics of Buprenorphine, Fentanyl and Nicotine in adult and pediatric patients

The drugs buprenorphine, fentanyl and nicotine are frequently applied for the treatment of pain and smoking cessation, respectively. However, several pharmacokinetic (PK) characteristics are still unclear in both adult and particularly pediatric patients, calling for more research in this field. Here, physiologically based pharmacokinetic (PBPK) modeling represents a valuable tool to enhance the understanding of a drug’s PK which may lead to optimization in dosing regimens and pharmacotherapy. Thus, this work aimed to gain insights into the PK of buprenorphine and fentanyl as well as to investigate nicotine brain tissue concentrations by leveraging PBPK modeling. Additionally, the ability of PBPK modeling to predict plasma concentrations and PK parameters in pediatric populations of different age groups was studied. For this purpose, PBPK models of the three drugs were built and evaluated with clinical data from adult patients. Buprenorphine and fentanyl models were extrapolated to successfully predict mean and individual plasma concentration-time profiles and PK parameters in children, full-term neonates and preterm neonates. Furthermore, the nicotine PBPK model was applied to simulate and evaluate brain tissue concentrations and was extended to model the positive chronotropic effect of nicotine. In conclusion, the work provides new insights into the PK of buprenorphine, fentanyl and nicotine and supports the use of PBPK modeling to predict a drug’s PK in pediatric patients.Die Arzneistoffe Buprenorphin, Fentanyl und Nikotin werden häufig in der Schmerztherapie bzw. zur Raucherentwöhnung eingesetzt, während einige ihrer pharmakokinetischen (PK) Eigenschaften weiterhin unerforscht sind. Ein besseres Verständnis der PK dieser Arzneistoffe könnte Anreize zur Therapieoptimierung in erwachsenen und pädiatrischen Patienten geben. Die Physiologie-basierte pharmakokinetische (PBPK) Modellierung besitzt das Potential, hierbei entscheidend zu helfen und offene Fragestellungen zu beantworten. Ziel dieser Arbeit war es, neue Erkenntnisse über die PK von Buprenorphin und Fentanyl sowie über Nikotinhirnkonzentrationen zu erlangen. Zudem wurden die prädiktiven Eigenschaften der PBPK Modellierung für pädiatrische Patientenpopulationen untersucht. Hierfür wurden PBPK Modelle für Buprenorphin, Fentanyl und Nikotin mit Daten von erwachsenen Patienten entwickelt und evaluiert. Anschließend wurden die Modelle für Buprenorphin und Fentanyl auf pädiatrische Patientengruppen extrapoliert und Plasmakonzentrations-Zeit-Profile sowie PK Parameter von Kindern, Neu- und Frühgeborenen erfolgreich vorhergesagt. Das Nikotin PBPK Modell wurde für Simulationen von Hirnkonzentrationen verwendet und um den positiv chronotropen Effekt von Nikotin erweitert. Schlussfolgernd liefert die Arbeit neue Erkenntnisse über die PK von Buprenorphin, Fentanyl und Nikotin und bekräftigt die Verwendbarkeit der PBPK Modellierung, die PK eines Arzneistoffs in pädiatrischen Patienten vorherzusagen

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) 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

Measurement campaign on the JRC Ispra decommissioning site

The purpose of this document is to describe the measurement campaign with the Free Release Measurement Facility (FRMF) at building 41m “Interim Storage Facility” (ISF) of material clearable according to existing licenses as part of the collaborative research project MetroDecom. The description of the measurement campaign includes the technical requirements and safety implementations necessary for carrying out this project. The Free Release Measurement Facility (FRMF) was designed as a state of the art facility for measurement of low gamma-ray activity waste packages. Gamma spectrometric method for free release measurment was developed. The complemented with passive neutron counting method. The both methods are used for different nuclide contents in the waste and are complementary. For this purpose the instrument incorporates: — Three passive neutron counters (design of JRC) — A gamma-ray detection system HPGe Interchangeable Detector Module IDM-200-V (ORTEC) — NuDET Plastic Scintillation Detectors (design of NUVIA) Decommissioning unit delivered seventy containers with material clearable according to existing JRC licenses. JRC G.II.7 performed the testing of the free release measurement system. The document contains the overview of that measurement campaign. The detailed measurement protocols, spectra generated by FRMF software are shared with MetroDecom Partners.JRC.G.II.7-Nuclear securit

Influence of Physicochemical Characteristics and Stability of Gold and Silver Nanoparticles on Biological Effects and Translocation across an Intestinal Barrier—A Case Study from In Vitro to In Silico

A better understanding of their interaction with cell-based tissue is a fundamental prerequisite towards the safe production and application of engineered nanomaterials. Quantitative experimental data on the correlation between physicochemical characteristics and the interaction and transport of engineered nanomaterials across biological barriers, in particular, is still scarce, thus hampering the development of effective predictive non-testing strategies. Against this background, the presented study investigated the translocation of gold and silver nanoparticles across the gastrointestinal barrier along with related biological effects using an in vitro 3D-triple co-culture cell model. Standardized in vitro assays and quantitative polymerase chain reaction showed no significant influence of the applied nanoparticles on both cell viability and generation of reactive oxygen species. Transmission electron microscopy indicated an intact cell barrier during the translocation study. Single particle ICP-MS revealed a time-dependent increase of translocated nanoparticles independent of their size, shape, surface charge, and stability in cell culture medium. This quantitative data provided the experimental basis for the successful mathematical description of the nanoparticle transport kinetics using a non-linear mixed effects modeling approach. The results of this study may serve as a basis for the development of predictive tools for improved risk assessment of engineered nanomaterials in the future

Physiologically-Based Pharmacokinetic (PBPK) Modeling of Buprenorphine in Adults, Children and Preterm Neonates

Buprenorphine plays a crucial role in the therapeutic management of pain in adults, adolescents and pediatric subpopulations. However, only few pharmacokinetic studies of buprenorphine in children, particularly neonates, are available as conducting clinical trials in this population is especially challenging. Physiologically-based pharmacokinetic (PBPK) modeling allows the prediction of drug exposure in pediatrics based on age-related physiological differences. The aim of this study was to predict the pharmacokinetics of buprenorphine in pediatrics with PBPK modeling. Moreover, the drug-drug interaction (DDI) potential of buprenorphine with CYP3A4 and P-glycoprotein perpetrator drugs should be elucidated. A PBPK model of buprenorphine and norbuprenorphine in adults has been developed and scaled to children and preterm neonates, accounting for age-related changes. One-hundred-percent of the predicted AUClast values in adults (geometric mean fold error (GMFE): 1.22), 90% of individual AUClast predictions in children (GMFE: 1.54) and 75% in preterm neonates (GMFE: 1.57) met the 2-fold acceptance criterion. Moreover, the adult model was used to simulate DDI scenarios with clarithromycin, itraconazole and rifampicin. We demonstrate the applicability of scaling adult PBPK models to pediatrics for the prediction of individual plasma profiles. The novel PBPK models could be helpful to further investigate buprenorphine pharmacokinetics in various populations, particularly pediatric subgroups

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) 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

In Vitro–In Silico Modeling of Caffeine and Diclofenac Permeation in Static and Fluidic Systems with a 16HBE Lung Cell Barrier

Static in vitro permeation experiments are commonly used to gain insights into the permeation properties of drug substances but exhibit limitations due to missing physiologic cell stimuli. Thus, fluidic systems integrating stimuli, such as physicochemical fluxes, have been developed. However, as fluidic in vitro studies display higher complexity compared to static systems, analysis of experimental readouts is challenging. Here, the integration of in silico tools holds the potential to evaluate fluidic experiments and to investigate specific simulation scenarios. This study aimed to develop in silico models that describe and predict the permeation and disposition of two model substances in a static and fluidic in vitro system. For this, in vitro permeation studies with a 16HBE cellular barrier under both static and fluidic conditions were performed over 72 h. In silico models were implemented and employed to describe and predict concentration–time profiles of caffeine and diclofenac in various experimental setups. For both substances, in silico modeling identified reduced apparent permeabilities in the fluidic compared to the static cellular setting. The developed in vitro–in silico modeling framework can be expanded further, integrating additional cell tissues in the fluidic system, and can be employed in future studies to model pharmacokinetic and pharmacodynamic drug behavior