Impact of gastrointestinal disease states on oral drug absorption – implications for formulation design – a PEARRL review

Abstract

Objectives Drug product performance in patients with gastrointestinal (GI) diseases can be altered compared to healthy subjects due to pathophysiological changes. In this review, relevant differences in patients with inflammatory bowel diseases, coeliac disease, irritable bowel syndrome and short bowel syndrome are discussed and possible in vitro and in silico tools to predict drug product performance in this patient population are assessed. Key findings Drug product performance was altered in patients with GI diseases compared to healthy subjects, as assessed in a limited number of studies for some drugs. Underlying causes can be observed pathophysiological alterations such as the differences in GI transit time, the composition of the GI fluids and GI permeability. Additionally, alterations in the abundance of metabolising enzymes and transporter systems were observed. The effect of the GI diseases on each parameter is not always evident as it may depend on the location and the state of the disease. The impact of the pathophysiological change on drug bioavailability depends on the physicochemical characteristics of the drug, the pharmaceutical formulation and drug metabolism. In vitro and in silico methods to predict drug product performance in patients with GI diseases are currently limited but could be a useful tool to improve drug therapy. Summary Development of suitable in vitro dissolution and in silico models for patients with GI diseases can improve their drug therapy. The likeliness of the models to provide accurate predictions depends on the knowledge of pathophysiological alterations, and thus, further assessment of physiological differences is essential.

The therapeutic importance of acid-base balance

“…Starting from a value of ∼1.5 in the stomach, it rises to ∼6.0 in the duodenum, reaches ∼7.4 in the terminal ileum, and falls again to ∼6.7 in the colon [438] . An additional consideration is that these values can vary with age, presence of food, diseases, and also by the co-administration of other drugs [439] , [440] , [441] , [442] . Finally, we note that the influence of pH on bioavailability could, in pH-disturbed states, result in underdose or overdose.…”

Dynamic Colon Model (DCM): A Cine-MRI Informed Biorelevant In Vitro Model of the Human Proximal Large Intestine Characterized by Positron Imaging Techniques

“…Furthermore, knowing/exploring this interplay between those factors, patients with specific profiles (i.e., motility patterns, fluid volumes, and so on) could be treated with the appropriate drug formulation, which will perform better under those patient-centric conditions. It has been shown that gastrointestinal transit times (GTT) are increased in patients with UC [24], whereas high variability in GTT has been observed in patients with severe UC [25]. In particular, the colonic transit times in healthy volunteers have a range of 7-20 h, whereas there is a much wider range (2-97.7 h) in patients with active UC [25].…”

Independent Tailoring of Dose and Drug Release via a Modularized Product Design Concept for Mass Customization

“…As target patient segments become progressively smaller, with each segment having unique needs from the pharmaceutical product, enabling simultaneous and independent individualization of multiple product features, i.e., multifunctional individualization, will demand a marked increase in the number of product variants. This encompasses, for example, simultaneous provision of individualized dosing [ 3 , 11 , 12 , 13 , 14 , 15 ] and individualized drug release [ 3 , 16 , 17 , 18 , 19 , 20 ], where required [ 3 ]. Individualized dosing demands an increased number of dose strengths within a pre-established dose range.…”