Title: Characterization of intraluminal drug and formulation behavior in humans supporting the development of predictive tools
Other Titles: Ontwikkeling van biorelevante in vitro modellen voor de evaluatie van supersaturatie - inducerende formuleringen op basis van in vivo karakterisering bij de mens
Authors: Hens, Bart
Issue Date: 28-Oct-2016
Table of Contents: After oral intake, a drug needs to pass several barriers prior to reaching its site of action. As long as we are dealing with highly soluble and permeable drug compounds, the rate of intestinal absorption will be determined by the rate of gastric emptying (GE), and intestinal absorption will not be compromised. Unfortunately, drug discovery nowadays has to deal with an immense pipeline of new chemical entities (NCE) that exhibit insufficient aqueous solubility. Unless focusing on a formulation strategy to overcome this problem, these compounds would drop out in an early stage of drug development. Estimates are that approximately 70% of the new drug candidates exhibit a poor aqueous solubility in recent years (Kawabata et al., 2011). Increasing intestinal concentrations through a formulation approach may enhance the driving force for intestinal absorption, leading to sufficient systemic concentrations of the active drug compound. For decades, academics and industrial scientists expand their knowledge on how these enabling formulations behave after oral administration based on in vitro/in silico studies. Depending on the formulation, various hypotheses have been stated that may explain the underlying mechanisms of improved oral absorption after oral intake: some formulations will enhance intestinal concentrations by solubilizing-strategies, whereas others will create supersaturated concentrations of the drug along the gastrointestinal (GI) tract. Supersaturation can be created through formulation strategies (supersaturating drug delivery systems; e.g. solid dispersions, lipid based formulations, prodrugs), but, for basic compounds, also upon transit from the acidic environment in the stomach to the neutral environment in the intestine in terms of pH.
Whilst enabling formulations attract a lot of interest, it is still questionable how these formulations behave in the GI tract in terms of measured concentrations and, more importantly, how the GI tract may affect the life course of the drug and its corresponding formulation. The degree of intestinal supersaturation and, consequently, the tendency for absorption and/or precipitation, can be significantly affected by several gastrointestinal variables along the gastrointestinal tract (e.g. GE, dilutions, transit times, pH, etc.).
Information about intraluminal and systemic drug concentrations after oral intake of these enabling formulations may serve as unique reference data to optimize predictive models, frequently applied in an early stage of drug development. Therefore, clinical studies where drug concentrations along the GI tract are profiled in parallel with systemic concentrations, are indispensable and of paramount importance to help pharmaceutical companies in a time- and cost saving manner. This mindset was the basis for the research performed during my PhD, which will be described in detail in this doctoral dissertation.
To provide an overview of the different techniques mentioned in literature to explore gastrointestinal variables affecting drug delivery and disposition, the first chapter will give you an in-depth overview of the different methodologies, including their challenges and opportunities. The subsequent chapters will give you an overview of the results obtained by the intraluminal sampling technology.
Publication status: published
KU Leuven publication type: TH
Appears in Collections:Drug Delivery and Disposition

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