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Ergebnisse nach Hochschule und Institut
Publikation Investigating oral absorption of carbamazepine in paediatric populations(2017) Kohlmann, Philip; Stillhart, Cordula; Parrot, Neil; Kuentz, MartinPrediction of the pharmacokinetics of orally administered drugs in children is of importance to optimize the efficacy and safety of pediatric medicines. Physiologically based pharmacokinetic (PBPK) models can be helpful for this purpose. However, application of these tools is limited by significant knowledge gaps regarding the physiological and anatomical changes which occur with age. This study aimed at investigating the age-dependent differences in oral absorption of a poorly soluble model compound, carbamazepine (CBZ) in children, infants, and neonates. We developed an oral absorption model in GastroPlus® and, after evaluation of the PBPK model for adults, extrapolation to younger ages was verified with clinical data and sensitivity analyses were applied for uncertain model parameters. We found that age-based scaling of physiological parameters, with clearance in particular, was important to obtain adequate simulation results. The sensitivity analysis revealed that CBZ absorption was influenced by solubility, particle radius, and small intestinal transit time depending on the pediatric age group and CBZ dose. However, in vitro dissolution testing using proposed pediatric biorelevant media suggested no major age dependency of dissolution kinetics. Such better understanding of oral absorption in pediatric patients is required to improve the prediction of exposure in children and the confidence in oral biopharmaceutical tools.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Trends in the Assessment of Drug Supersaturation and Precipitation In Vitro Using Lipid-Based Delivery Systems(Elsevier, 2016) Stillhart, Cordula; Kuentz, MartinThe generation of drug supersaturation close to the absorptive site is an important mechanism of how several formulation technologies enhance oral absorption and bioavailability. Lipid-based formulations belong to the supersaturating drug delivery systems although this is not the only mechanism of how drug absorption is promoted in vivo. Different methods to determine drug supersaturation and precipitation from lipid-based formulations are described in the literature. Experimental in vitro setups vary according to their complexity and proximity to the in vivo conditions and, therefore, some tests are used for early formulation screening, while others better qualify for a later stage of development. The present commentary discusses this rapidly evolving field of in vitro testing with a special focus on the advancements in analytical techniques and new approaches of mechanistic modeling. The importance of considering a drug absorption sink is particularly emphasized. This commentary should help formulators in the pharmaceutical industry as well as in academia to make informed decisions on how to conduct in vitro tests for lipid-based delivery systems and to decide on the implications of experimental results.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Using physiologically based pharmacokinetic (PBPK) Modelling to Gain insights into the effect of physiological factors on oral absorption in paediatric populations(08.07.2016) Villiger, Angela; Stillhart, Cordula; Parrot, Neil; Kuentz, MartinPaediatric pharmaceutics has become an important topic, but currently, there is an incomplete knowledge of paediatric gastrointestinal physiology and adequate biopharmaceutical tools still have to be developed. The present study aimed to increase the understanding of oral drug absorption in paediatric populations by using physiologically based pharmacokinetic (PBPK) modelling and in vitro dissolution testing. The oral absorption of two model compounds, sotalol and paracetamol, was studied by collection of reported pharmacokinetic profiles from adult and paediatric subjects. A PBPK model based on input parameters collected from the literature was first developed and validated in adults before being extrapolated to paediatric age groups. The accuracy of the model simulations was assessed by comparison to the observed pharmacokinetic profiles, and in the case of discrepancy, further investigations were made via parameter sensitivity analysis and in vitro dissolution testing. The PBPK models accurately predicted sotalol and paracetamol exposure in adult populations. An accurate simulation was also obtained after model extrapolation to children older than 2 years of age. However, the simulation in infants and newborns resulted in a discrepancy, which was further analysed. Dissolution testing suggested no significant difference in the drug release rate between paediatric and adult age groups. In contrast, mean gastric emptying time seemed to be underestimated in infants and newborns, and optimisation of this input parameter improved the prediction of the model. Considering age-specific differences in gastrointestinal tract physiology should improve prediction of drug absorption in paediatric patients.01A - Beitrag in wissenschaftlicher Zeitschrift