OPUS 4 | Search

Measuring pH and buffer capacity in fluids aspirated from the fasted upper gastrointestinal tract of healthy adults (2019)

Chara Litou Dimitrios Psachoulias Maria Vertzoni Jennifer Dressman Christos Reppas

Purpose: The design of biorelevant conditions for in vitro evaluation of orally administered drug products is contingent on obtaining accurate values for physiologically relevant parameters such as pH, buffer capacity and bile salt concentrations in upper gastrointestinal fluids. Methods: The impact of sample handling on the measurement of pH and buffer capacity of aspirates from the upper gastrointestinal tract was evaluated, with a focus on centrifugation and freeze-thaw cycling as factors that can influence results. Since bicarbonate is a key buffer system in the fasted state and is used to represent conditions in the upper intestine in vitro, variations on sample handling were also investigated for bicarbonate-based buffers prepared in the laboratory. Results: Centrifugation and freezing significantly increase pH and decrease buffer capacity in samples obtained by aspiration from the upper gastrointestinal tract in the fasted state and in bicarbonate buffers prepared in vitro. Comparison of data suggested that the buffer system in the small intestine does not derive exclusively from bicarbonates. Conclusions: Measurement of both pH and buffer capacity immediately after aspiration are strongly recommended as “best practice” and should be adopted as the standard procedure for measuring pH and buffer capacity in aspirates from the gastrointestinal tract. Only data obtained in this way provide a valid basis for setting the physiological parameters in physiologically based pharmacokinetic models.

Combining biorelevant "in vitro" and "in silico" tools to simulate and better understand the "in vivo" performance of a nano-sized formulation of aprepitant in the fasted and fed states (2019)

Chara Litou Nikunjkumar Patel David B. Turner Edmund Kostewicz Martin Kuentz Karl J. Box Jennifer Dressman

Introduction: When developing bio-enabling formulations, innovative tools are required to understand and predict in vivo performance and may facilitate approval by regulatory authorities. EMEND® is an example of such a formulation, in which the active pharmaceutical ingredient, aprepitant, is nano-sized. The aims of this study were 1) to characterize the 80 mg and 125 mg EMEND® capsules in vitro using biorelevant tools, 2) to develop and parameterize a physiologically based pharmacokinetic (PBPK) model to simulate and better understand the in vivo performance of EMEND® capsules and 3) to assess which parameters primarily influence the in vivo performance of this formulation across the therapeutic dose range. Methods: Solubility, dissolution and transfer experiments were performed in various biorelevant media simulating the fasted and fed state environment in the gastrointestinal tract. An in silico PBPK model for healthy volunteers was developed in the Simcyp Simulator, informed by the in vitro results and data available from the literature. Results: In vitro experiments indicated a large effect of native surfactants on the solubility of aprepitant. Coupling the in vitro results with the PBPK model led to an appropriate simulation of aprepitant plasma concentrations after administration of 80 mg and 125 mg EMEND® capsules in both the fasted and fed states. Parameter Sensitivity Analysis (PSA) was conducted to investigate the effect of several parameters on the in vivo performance of EMEND®. While nano-sizing aprepitant improves its in vivo performance, intestinal solubility remains a barrier to its bioavailability and thus aprepitant should be classified as DCS IIb. Conclusions: The present study underlines the importance of combining in vitro and in silico biopharmaceutical tools to understand and predict the absorption of this poorly soluble compound from an enabling formulation. The approach can be applied to other poorly soluble compounds to support rational formulation design and to facilitate regulatory assessment of the bio-performance of enabling formulations.

Approaches to increase mechanistic understanding and aid in the selection of precipitation inhibitors for supersaturating formulations- A PEARRL Review (2018)

Daniel J. Price Felix Ditzinger Niklas J. Koehl Sandra Jankovic Georgia Tsakiridou Anita Nair René Holm Martin Kuentz Jennifer B. Dressman Christoph Saal

Objectives Supersaturating formulations hold great promise for delivery of poorly soluble active pharmaceutical ingredients (APIs). To profit from supersaturating formulations, precipitation is hindered with precipitation inhibitors (PIs), maintaining drug concentrations for as long as possible. This review provides a brief overview of supersaturation and precipitation, focusing on precipitation inhibition. Trial-and-error PI selection will be examined alongside established PI screening techniques. Primarily, however, this review will focus on recent advances that utilise advanced analytical techniques to increase mechanistic understanding of PI action and systematic PI selection. Key Findings. Advances in mechanistic understanding have been made possible by the use of analytical tools such as spectroscopy, microscopy and mathematical and molecular modelling, which have been reviewed herein. Using these techniques, PI selection can instead be guided by molecular rationale. However, more work is required to see wide-spread application of such an approach for PI selection. Conclusions PIs are becoming increasingly important in enabling formulations. Trial-and-error approaches have seen success thus far. However, it is essential to learn more about the mode of action of PIs if the most optimal formulations are to be realised. Robust analytical tools, and the knowledge of where and how they can be applied, will be essential in this endeavour.

Calculation of drug-polymer mixing enthalpy as a new screening method of precipitation inhibitors for supersaturating pharmaceutical formulations (2019)

Daniel J. Price Anita Nair Martin Kuentz Jennifer Dressman Christoph Saal

Supersaturating formulations are widely used to improve the oral bioavailability of poorly soluble drugs. However, supersaturated solutions are thermodynamically unstable and such formulations often must include a precipitation inhibitor (PI) to sustain the increased concentrations to ensure that sufficient absorption will take place from the gastrointestinal tract. Recent advances in understanding the importance of drug-polymer interaction for successful precipitation inhibition have been encouraging. However, there still exists a gap in how this newfound understanding can be applied to improve the efficiency of PI screening and selection, which is still largely carried out with trial and error-based approaches. The aim of this study was to demonstrate how drug-polymer mixing enthalpy, calculated with the Conductor like Screening Model for Real Solvents (COSMO-RS), can be used as a parameter to select the most efficient precipitation inhibitors, and thus realise the most successful supersaturating formulations. This approach was tested for three different Biopharmaceutical Classification System (BCS) II compounds: dipyridamole, fenofibrate and glibenclamide, formulated with the supersaturating formulation, mesoporous silica. For all three compounds, precipitation was evident in mesoporous silica formulations without a precipitation inhibitor. Of the nine precipitation inhibitors studied, there was a strong positive correlation between the drug-polymer mixing enthalpy and the overall formulation performance, as measured by the area under the concentration-time curve in in vitro dissolution experiments. The data suggest that a rank-order based approach using calculated drug-polymer mixing enthalpy can be reliably used to select precipitation inhibitors for a more focused screening. Such an approach improves efficiency of precipitation inhibitor selection, whilst also improving the likelihood that the most optimal formulation will be realised.

Application of the relationship between pharmacokinetics and pharmacodynamics in drug development and therapeutic equivalence: a PEARRL review (2019)

Ioannis Loisios-Konstantinidis Rafael L.M. Paraiso Nikoletta Fotaki Mark McAllister Rodrigo Cristofoletti Jennifer Dressman

Objectives: The objective of this review is to provide an overview of PK/PD models, focusing on drug-specific PK/PD models and highlighting their value-added in drug development and regulatory decision-making. Key findings: Many PK/PD models, with varying degrees of complexity and physiological understanding, have been developed to evaluate the safety and efficacy of drug products. In special populations (e.g. pediatrics), in cases where there is genetic polymorphism and in other instances where therapeutic outcomes are not well described solely by PK metrics, the implementation of PK/PD models is crucial to assure the desired clinical outcome. Since dissociation between the pharmacokinetic and pharmacodynamic profiles is often observed, it is proposed that physiologically-based pharmacokinetic (PBPK) and PK/PD models be given more weight by regulatory authorities when assessing the therapeutic equivalence of drug products. Summary: Modeling and simulation approaches already play an important role in drug development. While slowly moving away from “one-size fits all” PK methodologies to assess therapeutic outcomes, further work is required to increase confidence in PK/PD models in translatability and prediction of various clinical scenarios to encourage more widespread implementation in regulatory decision-making.

Effects of medicines used to treat gastrointestinal diseases on the pharmacokinetics of co-administered drugs : a PEARRL review [Pharmacokinetic interactions with GI drugs] (2018)

Chara Litou Angela Effinger Edmund Kostewicz Karl Box Nikoletta Fotaki Jennifer Dressman

Background: Drugs used to treat gastrointestinal diseases (GI drugs) are widely used either as prescription or over23 the-counter (OTC) medications and belong to both the ten most prescribed and ten most sold OTC medications worldwide. Current clinical practice shows that in many cases, these drugs are administered concomitantly with other drug products. Due to their metabolic properties and mechanisms of action, the drugs used to treat gastrointestinal diseases can change the pharmacokinetics of some co27 administered drugs. In certain cases, these interactions can lead to failure of treatment or to the occurrence of serious adverse events. The mechanism of interaction depends highly on drug properties and differs among therapeutic categories. Understanding these interactions is essential to providing recommendations for optimal drug therapy. Objective: To discuss the most frequent interactions between GI and other drugs, including identification of the mechanisms behind these interactions, where possible. Conclusion: Interactions with GI drugs are numerous and can be highly significant clinically. Whilst alterations in bioavailability due to changes in solubility, dissolution rate and metabolic interactions can be (for the most part) easily identified, interactions that are mediated through other mechanisms, such as permeability or microbiota, are less well understood. Future work should focus on characterizing these aspects.

Statistical alignment based on fragment insertion and deletion models (2002)

Dirk Metzler

Motivation: The topic of this paper is the estimation of alignments and mutation rates based on stochastic sequence-evolution models that allow insertions and deletions of subsequences ("fragments") and not just single bases. The model we propose is a variant of a model introduced by Thorne, Kishino, and Felsenstein (1992). The computational tractability of the model depends on certain restrictions in the insertion/deletion process; possible effects we discuss. Results: The process of fragment insertion and deletion in the sequence-evolution model induces a hidden Markov structure at the level of alignments and thus makes possible efficient statistical alignment algorithms. As an example we apply a sampling procedure to assess the variability in alignment and mutation parameter estimates for HVR1 sequences of human and orangutan, improving results of previous work. Simulation studies give evidence that estimation methods based on the proposed model also give satisfactory results when applied to data for which the restrictions in the insertion/deletion process do not hold. Availability: The source code of the software for sampling alignments and mutation rates for a pair of DNA sequences according to the fragment insertion and deletion model is freely available from www.math.uni-frankfurt.de/~stoch/software/mcmcsalut under the terms of the GNU public license (GPL, 2000).

The politics of embarrassment (2017)

Frieder M. Paulus Laura Müller-Pinzler Dar Meshi Tai-Quan Peng Marina Martinez Mateo Sören Krach

Within the last year, expressions of second-hand embarrassment on Twitter significantly increased. We show how this relates to the current situation in U.S. politics under Trump and provide two explanations for why people feel this way in response to his actions. First, compared to former politicians, Trump’s norm violations seem intentional. Second, intentional norm violations specifically threaten the social integrity of in-group members—in this case, U.S citizens. We theorize that these strong, frequent and widespread feelings of second-hand embarrassment motivate political actions to prevent further harm to individuals’ self-concept and protect their social integrity.

Welt der Werte – die Auflösung des Dualismus von Wert und Natur (2014)

Titus Stahl

Die Bedeutung des philosophischen Programms John McDowells, das schon in der theoretischen Philosophie eine revolutionäre Neuausrichtung vornimmt, kann erst voll erkannt werden, wenn man auch seine Konsequenzen für die praktische Philosophie in den Blick nimmt. Zwar geht Geist und Welt primär von Dilemmata der Erkenntnistheorie aus. Aus McDowells Vorschlag, die Gleichsetzung der äußeren Natur mit dem bedeutungsfreien Raum der Naturgesetze zugunsten einer Konzeption von Gründen in der Welt aufzugeben, ergibt sich aber die Möglichkeit einer so neuartigen Perspektive auf die Natur moralischer Urteile, dass es fast so scheint, als sei McDowells theoretisches Programm auf diesen Gewinn für die praktische Philosophie hin angelegt worden.

Habermas and the Project of Immanent Critique (2013)

Titus Stahl

According to his own understanding, Jürgen Habermas’ Theory of Communicative Action offers a new account of the normative foundations of critical theory. 1 Habermas’ motivating insight is that neither a transcendental or metaphysical solution to the problem of normativity, nor a merely hermeneutic reconstruction of historically given norms, is sufficient to clarify the normative foundations of critical theory. In response to this insight, Habermas develops a novel account of normativity which locates the normative demands upon which critical theory draws within the socially instituted practice of communicative understanding. Although Habermas has claimed otherwise, this new foundation for critical theory constitutes a novel and innovative form of “immanent critique”. To argue for and to clarify this claim, I offer, in section 1, a formal account of immanent critique and distinguish between two different ways of carrying out such a critique. In section 2, I examine Habermas’ rejection of the first, hermeneutic option. Against this background, I then show, in section 3, that the Theory of Communicative Action attempts to formulate an immanent critique of contemporary societies according to a second, “practice-based” model. However, because Habermas, as I will argue in section 4, commits himself to an implausibly narrow view in regard to one central element of such a model – in regard to the social ontology of immanent normativity – his normative critique cannot develop its full potential (section 5).

Refine

Author

Year of publication

Document Type

Language

Has Fulltext

Is part of the Bibliography

Keywords

Institute

565 search hits