Assessment of the Performance of Non-systemic Locally-Acting Drugs in the Gastrointestinal Tract

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmacokinetics and Pharmacodynamics".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 2234

Special Issue Editors


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Guest Editor
Biopharmaceutics, Pharmaceutical Development. PDS, MST, RD Platform Technology & Science, GlaxoSmithKline Building 5, First Floor—Red Zone, David Jack Centre, Park Road, Ware, Hertfordshire SG12 0DP, UK
Interests: biopharmaceutics; food–drug interactions; IVIVE; IVIVC; IVIVR; PBPK/PBBM modelling; PBPK/PD modelling

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Guest Editor
Department of Pharmacy and Pharmacology, Centre for Therapeutic Innovation (CTI), University of Bath, Claverton Down, Bath BA2 7AY, UK
Interests: physiologically based pharmacokinetic (PBPK) modeling; physiologically based biopharmaceutics modeling (PBBM); in vitro–in vivo correlations (IVIVC); drug absorption; biopharmaceutics; precision medicines; in vitro dissolution biorelevant/compendial methods; dissolution imaging; biowaivers; pharmacometrics; animal models; formulation development; poor solubility
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Special Issue Information

Dear Colleagues,

It is our pleasure to invite you to submit an original manuscript to the Special Issue “Assessment of the performance of non-systemic locally acting drugs in the gastrointestinal tract”.

Non-systemic drugs are a unique subset of orally administered agents that exert their therapeutic effects locally in the GI tract. Unlike traditional drugs, the plasma concentration cannot be used as a surrogate for the PK/PD performance of non-systemic APIs. Moreover, in terms of locally acting drug products, administered to exert local action in the gastrointestinal (GI) tract, it is often not feasible/easy to quantify the rate at which, and extent to which, a drug becomes available at the site of action.

Understanding and predicting regional drug concentrations in the lumen, mucosal layer, epithelia and lamina propria, as well as the mechanism of action, and intra- and inter-subject variability, is of great importance for the discovery and product development of non-systemic drugs.

This Special Issue will highlight the advances, challenges and opportunities in an assessment of the performance of non-systemic locally acting drugs in the gastrointestinal tract.

Currently available, or novel, in vivo, in vitro and ex vivo methodologies to quantify/assess regional drug concentrations in the GI tract, as well as strategies to develop, verify and validate PBPK/PD models, describing the regional dissolution, absorption and disposition of drug substances along the GI tract, are strongly encouraged for submission to this Special Issue. Original research papers and review articles are both welcome.

In addition, original research and/or reviews pertaining to in vitro and PBPK-PBBM/PD models for locally acting drugs with systemic exposure would be relevant, provided that these models are used to support the development and validation of models for non-systemic locally acting drug in the GI tract.

Dr. Konstantinos Stamatopoulos
Dr. Nikoletta Fotaki
Guest Editors

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Keywords

  • non-systemic drugs
  • non-absorbable drugs
  • loally acting drugs
  • biopharmaceutics
  • controlled drug delivery
  • non-absorbable markers
  • PBPK/PD modeling
  • PBBM modeling
  • PBPK/QSP modeling

Published Papers (1 paper)

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Research

16 pages, 2435 KiB  
Article
Physiologically Based Biopharmaceutics Model (PBBM) of Minimally Absorbed Locally Acting Drugs in the Gastrointestinal Tract—Case Study: Tenapanor
by Konstantinos Stamatopoulos, Nena Mistry, Nikoletta Fotaki, David B. Turner and Brandon Swift
Pharmaceutics 2023, 15(12), 2726; https://doi.org/10.3390/pharmaceutics15122726 - 04 Dec 2023
Viewed by 1360
Abstract
A physiologically based biopharmaceutics model (PBBM) was developed to predict stool and urine sodium content in response to tenapanor administration in healthy subjects. Tenapanor is a minimally absorbed small molecule that inhibits the sodium/hydrogen isoform 3 exchanger (NHE3). It is used to treat [...] Read more.
A physiologically based biopharmaceutics model (PBBM) was developed to predict stool and urine sodium content in response to tenapanor administration in healthy subjects. Tenapanor is a minimally absorbed small molecule that inhibits the sodium/hydrogen isoform 3 exchanger (NHE3). It is used to treat irritable bowel syndrome with constipation (IBS-C). Its mode of action in the gastrointestinal tract reduces the uptake of sodium, resulting in an increase in water secretion in the intestinal lumen and accelerating intestinal transit time. The strategy employed was to perform drug–drug interaction (DDI) modelling between sodium and tenapanor, with sodium as the “victim” administered as part of daily food intake and tenapanor as the “perpetrator” altering sodium absorption. Food effect was modelled, including meal-induced NHE3 activity using sodium as an inducer by normalising the induction kinetics of butyrate to sodium equivalents. The presented model successfully predicted both urine and stool sodium content in response to tenapanor dosed in healthy subjects (within 1.25-fold error) and provided insight into the clinical observations of tenapanor dosing time relative to meal ingestion. The PBBM model was applied retrospectively to assess the impact of different forms of tenapanor (free base vs. HCl salt) on its pharmacodynamic (PD) effect. The developed modelling strategy can be effectively adopted to increase confidence in using PBBM models for the prediction of the in vivo behaviour of minimally absorbed, locally acting drugs in the gastrointestinal tract, when other approaches (e.g., biomarkers or PD data) are not available. Full article
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