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The absorption of oral drugs is frequently plagued by significant variability with potentially serious therapeutic consequences. The source of variability can be traced back to interindividual variability in physiology, differences in special populations (age- and disease-dependent), drug and formulation properties, or food-drug interactions. Clinical evidence for the impact of some of these factors on drug pharmacokinetic variability is mounting: e.g. gastric pH and emptying time, small intestinal fluid properties, differences in pediatrics and the elderly, and surgical changes in gastrointestinal anatomy. However, the link of colonic factors variability (transit time, fluid composition, microbiome), sex differences (male vs. female) and gut-related diseases (chronic constipation, anorexia and cachexia) to drug absorption variability has not been firmly established yet. At the same time, a way to decrease oral drug pharmacokinetic variability is provided by the pharmaceutical industry: clinical evidence suggests that formulation approaches employed during drug development can decrease the variability in oral exposure. This review outlines the main drivers of oral drug exposure variability and potential approaches to overcome them, while highlighting existing knowledge gaps and guiding future studies in this area.

Ниската разтворимост във вода е основен проблем при оралното доставяне на лекарствени вещества (ЛВ), поради тяхната ниска или силно варираща орална бионаличност. Обект на изследване в дисертацията е един от класическите методи за подобряване на разтворимостта на хидрофобни ЛВ: солюбилизацията в мицели на повърхностно-активни вещества (ПАВ). Целта на дисертацията е да изясни как молекулната структура на ПАВ и ЛВ определят солюбилизационния капацитет на мицелите (съответно и разтворимостта на ЛВ) и да даде физикохимична интерпретация на наблюдаваните ефекти. Изследвани бяха три хидрофобни ЛВ (прогестерон, даназол и фенофибрат) и широк набор от ПАВ (над 20 вида). Установено беше, че солюбилизацията на хидрофобни ЛВ нараства с увеличаване на дължината на хидрофобната опашка на ПАВ, без значение от заряда и вида на хидрофилната глава. Доказана беше ролята на йон-диполните взаимодействия за солюбилизацията на стероидни лекарствени вещества (прогестерон и даназол) в мицели на йонни повърхностно-активни вещества. Установено беше, че етоксилирането на натриев додецил сулфат намалява солюбилизацията на лекарствени вещества, поради затрудненото подреждане на молекулите в мицелите. Чрез ултравиолетова спектроскопия беше доказано, че солюбилизираният фенофибрат е локализиран в хидрофобното ядро на нейонните мицелите и в палисадния слой на йонните мицелите., Low aqueous solubility is one of the major problems in oral drug delivery, as it leads to very low or highly variable oral drug bioavailability. The dissertation provides a systematic study of one of the classical approaches for drug solubility enhancement: solubilization in micellar surfactant solutions. The aims of the dissertation are to clarify how the surfactant and drug molecular structures determine the micellar solubilization capacity and to provide mechanistic physicochemical interpretation of the observed effects. Three hydrophobic drugs (progesterone, danazol and fenofibrate) were studied, as well as a wide range of surfactants (more than 20 species). It was found that (1) the solubilization of hydrophobic drugs increases linearly with the increase of the surfactant hydrophobic chain length, regardless of the charge and type of the surfactant hydrophilic head group, (2) ion-dipole interactions contribute significantly to the solubilization of steroidal drugs in ionic surfactant micelles (3) the ethoxylation of sodium dodecyl sulfate decreases drug solubilization, most likely due to more difficult packing of the molecules in the micelles and (4) fenofibrate is solubilized in the hydrophobic core of nonionic surfactant micelles and in the palisade layer of ionic surfactant micelles, as determined via UV-spectroscopy.

Although oral drug delivery is the preferred administration route and has been used for centuries, modern drug discovery and development pipelines challenge conventional formulation approaches and highlight the insufficient mechanistic understanding of processes critical to oral drug absorption. This review presents the opinion of UNGAP scientists on four key themes across the oral absorption landscape: (1) specific patient populations, (2) regional differences in the gastrointestinal tract, (3) advanced formulations and (4) food-drug interactions. The differences of oral absorption in pediatric and geriatric populations, the specific issues in colonic absorption, the formulation approaches for poorly water-soluble (small molecules) and poorly permeable (peptides, RNA etc.) drugs, as well as the vast realm of food effects, are some of the topics discussed in detail. The identified controversies and gaps in the current understanding of gastrointestinal absorption-related processes are used to create a roadmap for the future of oral drug absorption research. European Cooperation in Science and Technology CA16205 National Centre for Research and Development POIR.01.02.00-00-0011/17 Ministry of Education, Youth and Sports of the Czech Republic TC19039, LTC18003 Czech Science Foundation 18-00132S