Gastrointestinal Safety Pharmacology in Drug Discovery and Development

Abstract

Although the basic structure of the gastrointestinal tract (GIT) is similar across species, there are significant differences in the anatomy, physiology, and biochemistry between humans and laboratory animals, which should be taken into account when conducting a gastrointestinal (GI) assessment. Historically, the percentage of cases of drug attrition associated with GI-related adverse effects is small; however, this incidence has increased over the last few years. Drug-related GI effects are very diverse, usually functional in nature, and not limited to a single pharmacological class. The most common GI signs are nausea and vomiting, diarrhea, constipation, and gastric ulceration. Despite being generally not life-threatening, they can greatly affect patient compliance and quality of life. There is therefore a real need for improved and/or more extensive GI screening of candidate drugs in preclinical development, which may help to better predict clinical effects. Models to identify drug effects on GI function cover GI motility, nausea and emesis liability, secretory function (mainly gastric secretion), and absorption aspects. Both in vitro and in vivo assessments are described in this chapter. Drug-induced effects on GI function can be assessed in stand-alone safety pharmacology studies or as endpoints integrated into toxicology studies. In silico approaches are also being developed, such as the gut-on-a-chip model, but await further optimization and validation before routine use in drug development. GI injuries are still in their infancy with regard to biomarkers, probably due to their greater diversity. Nevertheless, several potential blood, stool, and breath biomarkers have been investigated. However, additional validation studies are necessary to assess the relevance of these biomarkers and their predictive value for GI injuries.

Physical Properties and Effect in a Battery of Safety Pharmacology Models for Three Structurally Distinct Enteric Polymers Employed as Spray-Dried Dispersion Carriers

“…While an enteric polymer, such as those tested in the present study, would not be absorbed into the blood, it is well established that within the digestive system, GI reflexes can be modulated through both systemic as well as complex local and regional effects processed entirely within the digestive system itself (e.g., to control secretion and local motility via gastro-colic, entero-gastric, and colono-ilial reflexes) ultimately affecting GI function (Furness et al, 2014 ; Al-Saffar et al, 2015 ). The importance of proper formulation excipient characterization has also been noted specifically in support of small-animal telemetry profiling for cardiovascular safety (Guth, 2007 ) to enable detection of the low-magnitude yet physiologically-relevant effects, and where volume, dose rate, and physicochemical characteristics of the excipient are critical factors impacting hemodynamic responses (Authier et al, 2015 ).…”

“…Moreover, to protect the Phase I volunteer, in vivo studies are mandated by regulatory authorities in key organ systems, including testing in models to investigate effects on CNS, respiratory, and cardiovascular function (USDHHS, 2001 ). Effects on other organ systems (e.g., gastrointestinal and renal function) are also commonly assessed as part of a comprehensive battery of in vivo safety profiling (Al-Saffar et al, 2015 ; Benjamin et al, 2015 ).…”

Developingin vitroassays to transform gastrointestinal safety assessment: potential for microphysiological systems

“…Second, Valentin and colleagues observed that most GI AEs are functional toxicities thereby indicating that functional screening assays should be prioritized. 4 Third, strategies for managing GIT in the clinic have exploited dose scheduling, thereby suggesting that kinetic data should be generated, if possible, to inform mathematical modelling and guide discovery of optimized clinical schedules (discussed in Enabling PK-PD and mechanistic mathematical modelling). Selecting assay endpoints that measure GI-specific functions in a non-destructive, re-readable manner will likely enhance predictivity and expand utility.…”

“…Since GITs are generally nonlife-threatening, the medical response tends to focus on dose reduction and/or palliative co-therapies (e.g., anti-diarrheal). 4,5 Whilst such clinical management strategies avoid drug attrition, symptomatic relief is transient, and the underlying issues are not addressed. Hence, the existing safety assessment paradigm results in (i) drugs advancing into the clinic with GI liabilities, (ii) GI-related limitations on dosing/efficacy persisting throughout the drug life cycle, and (iii) patients bearing the burden of reduced quality of life, reduced drug compliance, and compromised efficacy.…”

“…Hence, the existing safety assessment paradigm results in (i) drugs advancing into the clinic with GI liabilities, (ii) GI-related limitations on dosing/efficacy persisting throughout the drug life cycle, and (iii) patients bearing the burden of reduced quality of life, reduced drug compliance, and compromised efficacy. 4 In an ideal scenario, DI-GIT would be identified early with assays suitable for screening out the liability during preclinical drug discovery. One recent review evaluated toxicity-related drug attrition by target organs during the preclinical and clinical phases.…”