A mechanism-Based Approach for Absorption Modeling: The Gastro-Intestinal Transit Time (GITT) Model

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• 作者：Emilie Hénin (1)
  Martin Bergstrand (1)
  Joseph F. Standing (1)
  Mats O. Karlsson (1)
  
• 关键词：absorption ; model ; non ; linear mixed effect ; semi ; mechanistic
• 刊名：The AAPS Journal
• 出版年：2012
• 出版时间：June 2012
• 年：2012
• 卷：14
• 期：2
• 页码：155-163
• 全文大小：470KB
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• 作者单位：Emilie Hénin (1)
  Martin Bergstrand (1)
  Joseph F. Standing (1)
  Mats O. Karlsson (1)
  
  1. Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
  
• ISSN：1550-7416

文摘

Absorption models used in the estimation of pharmacokinetic drug characteristics from plasma concentration data are generally empirical and simple, utilizing no prior information on gastro-intestinal (GI) transit patterns. Our aim was to develop and evaluate an estimation strategy based on a mechanism-based model for drug absorption, which takes into account the tablet movement through the GI transit. This work is an extension of a previous model utilizing tablet movement characteristics derived from magnetic marker monitoring (MMM) and pharmacokinetic data. The new approach, which replaces MMM data with a GI transit model, was evaluated in data sets where MMM data were available (felodipine) or not available (diclofenac). Pharmacokinetic profiles in both datasets were well described by the model according to goodness-of-fit plots. Visual predictive checks showed the model to give superior simulation properties compared with a standard empirical approach (first-order absorption rate-?lag-time). This model represents a step towards an integrated mechanism-based NLME model, where the use of physiological knowledge and in vitro-em class="a-plus-plus">in vivo correlation helps fully characterize PK and generate hypotheses for new formulations or specific populations.