Exploring gastrointestinal variables affecting drug and formulation behavior: Methodologies, challenges and opportunities

Abstract

(2017) Exploring gastrointestinal variables affecting drug and formulation behavior: methodologies, challenges and opportunities. International Journal of Pharmaceutics, 519 (1-2). pp. 79-97. ISSN 1873-3476Access from the University of Nottingham repository: http://eprints.nottingham.ac.uk/39960/1/FinalVersion-Revised-FOR_EPRINTS_1_YEAR_EMBARGO_ELSEVIER.pdf Copyright and reuse:The Nottingham ePrints service makes this work by researchers of the University of Nottingham available open access under the following conditions. This article is made available under the Creative Commons Attribution Non-commercial No Derivatives licence and may be reused according to the conditions of the licence. For more details see: http://creativecommons.org/licenses/by-nc-nd/2.5/ A note on versions:The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the repository url above for details on accessing the published version and note that access may require a subscription. After oral intake, a drug formulation is challenged by several gastrointestinal (GI) barriers. Complex variables such as pH, GI secretions and GI transit/motility along the GI tract can affect drug release and absorption in a positive or negative way depending on the physicochemical properties of the drug compound (e.g. pH/pKa interplay for ionizable drugs) and/or the formulation characteristics (e.g. pHsensitive coating). In addition, inter-subject variability in characteristics of the GI environment may cause variable drug absorption and systemic drug availability (Riethorst et al., 2015). Determining the median and range for specific GI variables, and understanding how they influence oral drug behavior along the GI tract, will be helpful in the field of drug development. 2The present review provides an overview of different methodologies that can be applied to study physiological variables of the human GI tract and their impact on oral drug absorption in healthy and patient populations. The methodologies have been subdivided into two groups: (i) noninvasive and (ii) invasive methodologies. Although some of the methodologies are more historical than operational, they have been of paramount importance for innovations in drug and formulation development; in addition, they have created the basis for several novel methodologies, leading to an in-depth comprehension of different GI variables: gastric emptying (magnetic resonance imaging (MRI), scintigraphy, acetaminophen absorption technique, ultrasonography, breath test, intraluminal sampling and telemetry), motility (MRI, small intestinal/colonic manometry and telemetry), GI volume changes (MRI and ultrasonography), temperature (telemetry) and GI pH (intraluminal sampling and telemetry). Noninvasive methodologiesa. Scintigraphy Disturbances in the normal movement of food along the GI tract can be associated with abdominal pain, early satiety and nausea. Measurement of GI transit, es...

Ribociclib Bioavailability Is Not Affected by Gastric pH Changes or Food Intake: In Silico and Clinical Evaluations

“…The in vitro solubility data also provided a foundation for the hypothesis that food may not affect ribociclib absorption, further supported by PBPK models for ribociclib, which were constructed and validated with clinical data from healthy volunteers and patients with cancer. Sensitivity analyses based on PBPK models of ribociclib absorption built into both the GastroPlus and Simcyp software packages showed that exposure was independent of gastric pH over the physiologic range (pH range, 1.0–8.0), consistent with the lack of impact of pH on the in vitro solubility of ribociclib in the biorelevant media. This hypothesis was then tested and confirmed by the food effect study in healthy volunteers, which showed that ribociclib PK parameters were similar in the fed or fasted state.…”

Segmental-Dependent Intestinal Drug Permeability: Development and Model Validation of In Silico Predictions Guided by In Vivo Permeability Values

“…2,3 However, intestinal permeability is more complex than generally recognized; for example, drug permeability is location dependent and may vary in each point throughout the GIT. 4,5 The mechanisms behind this segmental-dependent permeability phenomenon include variations in the expression level of different transporters (e.g., P-glycoprotein [P-gp]), pH changes along the GIT, varying water content in different intestinal segments, 6,7 different morphologies and mucosal cell differentiation along the GIT, and so forth. 1,[8][9][10][11][12][13] For instance, upward expression pattern was shown for P-gp along the small intestine (SI), while the opposite trend was shown for MRP2, resulting in segmentaldependent drug permeability.…”

Innovation for Generic Drugs: Science and Research Under the Generic Drug User Fee Amendments of 2012

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