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- Heimbach, Tycho, et al.
(författare)
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Dissolution and Translational Modeling Strategies Toward Establishing an In Vitro-In Vivo Link : a Workshop Summary Report
- 2019
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Ingår i: AAPS Journal. - : SPRINGER. - 1550-7416. ; 21:2
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Tidskriftsartikel (refereegranskat)abstract
- This publication summarizes the proceedings of day 2 of a 3-day workshop on Dissolution and Translational Modeling Strategies Enabling Patient-Centric Product Development. Patient-centric drug product development from a drug product quality perspective necessitates the establishment of clinically relevant drug product specifications via an in vitro-in vivo link. Modeling and simulation offer a path to establish this link; in this regard, physiologically based modeling has been implemented successfully to support regulatory decision-making and drug product labeling. In this manuscript, case studies of physiologically based biopharmaceutics modeling (PBBM) applied to drug product quality are presented and summarized. These case studies exemplify a possible path to achieve an in vitro-in vivo link and encompass (a) development of biopredictive dissolution methods to support biowaivers, (b) model-informed formulation selection, (c) predicting clinical formulation performance, and (d) defining a safe space for regulatory flexibility via virtual bioequivalence (BE). Workflows for the development and verification of absorption models/PBBM and for the establishment of a safe space using dissolution as an input are described with examples. Breakout session discussions on topics, such as current challenges and some best practices in model development and verification, are included as part of the Supplementary material.
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- Olivares-Morales, Andres, et al.
(författare)
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Translating Human Effective Jejunal Intestinal Permeability to Surface-Dependent Intrinsic Permeability : a Pragmatic Method for a More Mechanistic Prediction of Regional Oral Drug Absorption
- 2015
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Ingår i: AAPS Journal. - : Springer Science and Business Media LLC. - 1550-7416. ; 17:5, s. 1177-1192
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Tidskriftsartikel (refereegranskat)abstract
- Regional intestinal effective permeability (P-eff) values are key for the understanding of drug absorption along the whole length of the human gastrointestinal (GI) tract. The distal regions of the GI tract (i.e. ileum, ascending-transverse colon) represent the main sites for GI absorption when there is incomplete absorption in the upper GI tract, e.g. for modified release formulations. In this work, a new and pragmatic method for the estimation of (passive) intestinal permeability in the different intestinal regions is being proposed, by translating the observed differences in the available mucosal surface area along the human GI tract into corrections of the historical determined jejunal P-eff values. These new intestinal Peff values or "intrinsic" P-eff(P-eff,P-int) were subsequently employed for the prediction of the ileal absorption clearance (CLabs,ileum) for a set of structurally diverse compounds. Additionally, the method was combined with a semi-mechanistic absorption PBPK model for the prediction of the fraction absorbed (f(abs)). The results showed that Peff, int can successfully be employed for the prediction of the ileal CLabs and the f(abs). P-eff,P-int also showed to be a robust predictor of the f(abs) when the colonic absorption was allowed in the PBPK model, reducing the overprediction of f(abs) observed for lowly permeable compounds when using the historical P-eff values. Due to its simplicity, this approach provides a useful alternative for the bottom-up prediction of GI drug absorption, especially when the distal GI tract plays a crucial role for a drug's GI absorption.
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- Yau, Estelle, et al.
(författare)
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Global Sensitivity Analysis of the Rodgers and Rowland Model for Prediction of Tissue: Plasma Partitioning Coefficients: Assessment of the Key Physiological and Physicochemical Factors That Determine Small-Molecule Tissue Distribution
- 2020
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Ingår i: AAPS Journal. - : Springer Nature. - 1550-7416. ; 22:2, s. 1-13
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Tidskriftsartikel (refereegranskat)abstract
- In physiologically based pharmacokinetic (PBPK) modelling, the large number of input parameters, limited amount of available data and the structural model complexity generally hinder simultaneous estimation of uncertain and/or unknown parameters. These parameters are generally subject to estimation. However, the approaches taken for parameter estimation vary widely. Global sensitivity analyses are proposed as a method to systematically determine the most influential parameters that can be subject to estimation. Herein, a global sensitivity analysis was conducted to identify the key drug and physiological parameters influencing drug disposition in PBPK models and to potentially reduce the PBPK model dimensionality. The impact of these parameters was evaluated on the tissue-to-unbound plasma partition coefficients (Kpus) predicted by the Rodgers and Rowland model using Latin hypercube sampling combined to partial rank correlation coefficients (PRCC). For most drug classes, PRCC showed that LogP and fraction unbound in plasma (fup) were generally the most influential parameters for Kpu predictions. For strong bases, blood:plasma partitioning was one of the most influential parameter. Uncertainty in tissue composition parameters had a large impact on Kpu and Vss predictions for all classes. Among tissue composition parameters, changes in Kpu outputs were especially attributed to changes in tissue acidic phospholipid concentrations and extracellular protein tissue:plasma ratio values. In conclusion, this work demonstrates that for parameter estimation involving PBPK models and dimensionality reduction purposes, less influential parameters might be assigned fixed values depending on the parameter space, while influential parameters could be subject to parameters estimation.
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