1.
Hens, Bart, et al.
(author)
Formulation predictive dissolution (fPD) testing to advance oral drug product development : An introduction to the US FDA funded '21st Century BA/BE' project
2018
In: International Journal of Pharmaceutics. - : Elsevier. - 0378-5173 .- 1873-3476. ; 548:1, s. 120-127
Research review (peer-reviewed) abstract
Over the past decade, formulation predictive dissolution (fPD) testing has gained increasing attention. Another mindset is pushed forward where scientists in our field are more confident to explore the in vivo behavior of an oral drug product by performing predictive in vitro dissolution studies. Similarly, there is an increasing interest in the application of modern computational fluid dynamics (CFD) frameworks and high-performance computing platforms to study the local processes underlying absorption within the gastrointestinal (GI) tract. In that way, CFD and computing platforms both can inform future PBPK-based in silico frameworks and determine the GI-motility-driven hydrodynamic impacts that should be incorporated into in vitro dissolution methods for in vivo relevance. Current compendial dissolution methods are not always reliable to predict the in vivo behavior, especially not for biopharmaceutics classification system (BCS) class 2/4 compounds suffering from a low aqueous solubility. Developing a predictive dissolution test will be more reliable, cost-effective and less time-consuming as long as the predictive power of the test is sufficiently strong. There is a need to develop a biorelevant, predictive dissolution method that can be applied by pharmaceutical drug companies to facilitate marketing access for generic and novel drug products. In 2014, Prof. Gordon L. Amidon and his team initiated a far-ranging research program designed to integrate (1) in vivo studies in humans in order to further improve the understanding of the intraluminal processing of oral dosage forms and dissolved drug along the gastrointestinal (GI) tract, (2) advancement of in vitro methodologies that incorporates higher levels of in vivo relevance and (3) computational experiments to study the local processes underlying dissolution, transport and absorption within the intestines performed with a new unique CFD based framework. Of particular importance is revealing the physiological variables determining the variability in in vivo dissolution and GI absorption from person to person in order to address (potential) in vivo BE failures. This paper provides an introduction to this multidisciplinary project, informs the reader about current achievements and outlines future directions.
2.
Ebeling Barbier, Charlotte, et al.
(author)
Limitations and Possibilities of Transarterial Chemotherapeutic Treatment of Hepatocellular Carcinoma
2021
In: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 22:23
Research review (peer-reviewed) abstract
Because diagnostic tools for discriminating between hepatocellular carcinoma (HCC) and advanced cirrhosis are poor, HCC is often detected in a stage where transarterial chemoembolization (TACE) is the best treatment option, even though it provides a poor survival gain. Despite having been used worldwide for several decades, TACE still has many limitations. First, there is a vast heterogeneity in the cellular composition and metabolism of HCCs as well as in the patient population, which renders it difficult to identify patients who would benefit from TACE. Often the delivered drug does not penetrate sufficiently selectively and deeply into the tumour and the drug delivery system is not releasing the drug at an optimal clinical rate. In addition, therapeutic effectiveness is limited by the crosstalk between the tumour cells and components of the cirrhotic tumour microenvironment. To improve this widely used treatment of one of our most common and deadly cancers, we need to better understand the complex interactions between drug delivery, local pharmacology, tumour targeting mechanisms, liver pathophysiology, patient and tumour heterogeneity, and resistance mechanisms. This review provides a novel and important overview of clinical data and discusses the role of the tumour microenvironment and lymphatic system in the cirrhotic liver, its potential response to TACE, and current and possible novel DDSs for locoregional treatment.
3.
Dahlgren, David, et al.
(author)
Intestinal absorption of BCS class II drugs administered as nanoparticles : A review based on in vivo data from intestinal perfusion models
2020
In: ADMET & DMPK. - : International Association of Physical Chemists (IAPC). - 1848-7718. ; 8:4, s. 375-390
Research review (peer-reviewed) abstract
An established pharmaceutical strategy to increase oral drug absorption of low solubility-high permeability drugs is to create nanoparticles of them. Reducing the size of the solid-state particles increases their dissolution and transport rate across the mucus barrier and the aqueous boundary layer. Suspensions of nanoparticles also sometimes behave differently than those of larger particles in the fed state. This review compares the absorption mechanisms of nano- and larger particles in the lumen at different prandial states, with an emphasis on data derived from in vivo models. Four BSC class II drugs-aprepitant, cyclosporine, danazol and fenofibrate-are discussed in detail based on information from preclinical intestinal perfusion models.
4.
Dahlgren, David, et al.
(author)
Intestinal Permeability and Drug Absorption : Predictive Experimental, Computational and In Vivo Approaches
2019
In: Pharmaceutics. - : MDPI. - 1999-4923 .- 1999-4923. ; 11:8
Research review (peer-reviewed) abstract
The main objective of this review is to discuss recent advancements in the overall investigation and in vivo prediction of drug absorption. The intestinal permeability of an orally administered drug (given the value P-eff) has been widely used to determine the rate and extent of the drug's intestinal absorption (F-abs) in humans. Preclinical gastrointestinal (GI) absorption models are currently in demand for the pharmaceutical development of novel dosage forms and new drug products. However, there is a strong need to improve our understanding of the interplay between pharmaceutical, biopharmaceutical, biochemical, and physiological factors when predicting F-abs and bioavailability. Currently, our knowledge of GI secretion, GI motility, and regional intestinal permeability, in both healthy subjects and patients with GI diseases, is limited by the relative inaccessibility of some intestinal segments of the human GI tract. In particular, our understanding of the complex and highly dynamic physiology of the region from the mid-jejunum to the sigmoid colon could be significantly improved. One approach to the assessment of intestinal permeability is to use animal models that allow these intestinal regions to be investigated in detail and then to compare the results with those from simple human permeability models such as cell cultures. Investigation of intestinal drug permeation processes is a crucial biopharmaceutical step in the development of oral pharmaceutical products. The determination of the intestinal P-eff for a specific drug is dependent on the technique, model, and conditions applied, and is influenced by multiple interactions between the drug molecule and the biological membranes.
5.
Di, Li, et al.
(author)
The Critical Role of Passive Permeability in Designing Successful Drugs
2020
In: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 15:20, s. 1862-1874
Research review (peer-reviewed) abstract
Passive permeability is a key property in drug disposition and delivery. It is critical for gastrointestinal absorption, brain penetration, renal reabsorption, defining clearance mechanisms and drug-drug interactions. Passive diffusion rate is translatable across tissues and animal species, while the extent of absorption is dependent on drug properties, as well as in vivo physiology/pathophysiology. Design principles have been developed to guide medicinal chemistry to enhance absorption, which combine the balance of aqueous solubility, permeability and the sometimes unfavorable compound characteristic demanded by the target. Permeability assays have been implemented that enable rapid development of structure-permeability relationships for absorption improvement. Future advances in assay development to reduce nonspecific binding and improve mass balance will enable more accurately measurement of passive permeability. Design principles that integrate potency, selectivity, passive permeability and other ADMET properties facilitate rapid advancement of successful drug candidates to patients.
6.
Hens, Bart, et al.
(author)
Leveraging Oral Drug Development to a Next Level : Impact of the IMI-Funded OrBiTo Project on Patient Healthcare
2021
In: Frontiers in Medicine. - : Frontiers Media S.A.. - 2296-858X. ; 8
Research review (peer-reviewed) abstract
A thorough understanding of the behavior of drug formulations in the human gastrointestinal (GI) tract is essential when working in the field of oral drug development in a pharmaceutical company. For orally administered drug products, various GI processes, including disintegration of the drug formulation, drugrelease, dissolution, precipitation, degradation, dosage form transit and permeation, dictate absorption into the systemic circulation. These processes are not always fully captured in predictive in vitro and in silico tools, as commonly applied in the pre-clinical stage of formulation drug development. A collaborative initiative focused on the science of oral biopharmaceutics was established in 2012 between academic institutions and industrial companies to innovate, optimize and validate these in vitro and in silico biopharmaceutical tools. From that perspective, the predictive power of these models can be revised and, if necessary, optimized to improve the accuracy toward predictions of the in vivo performance of orally administered drug products in patients. The IMI/EFPIA-funded “Oral Bioavailability Tools (OrBiTo)” project aimed to improve our fundamental understanding of the GI absorption process. The gathered information was integrated into the development of new (or already existing) laboratory tests and computer-based methods in order to deliver more accurate predictions of drug product behavior in a real-life setting. These methods were validated with the use of industrial data. Crucially, the ultimate goal of the project was to set up a scientific framework (i.e., decision trees) to guide the use of these new tools in drug development. The project aimed to facilitate and accelerate the formulation development process and to significantly reduce the need for animal experiments in this area as well as for human clinical studies in the future. With respect to the positive outcome for patients, high-quality oral medicines will be developed where the required dose is well-calculated and consistently provides an optimal clinical effect. In a first step, this manuscript summarizes the setup of the project and how data were collected across the different work packages. In a second step, case studies of how this project contributed to improved knowledge of oral drug delivery which can be used to develop improved products for patients will be illustrated.
7.
Lennernäs, Hans
(author)
Animal data : The contributions of the Ussing Chamber and perfusion systems to predicting human oral drug delivery in vivo
2007
In: Advanced Drug Delivery Reviews. - : Elsevier BV. - 0169-409X .- 1872-8294. ; 59:11, s. 1103-1120
Research review (peer-reviewed) abstract
Oral administration dominates contemporary drug therapy and will most likely continue to do so as it is considered to be safe, efficient and easily accessible with minimal discomfort to the patient compared to other routes of administration such as intramuscular, subcutaneous, rectal and pulmonary delivery. However, despite these advantages, many of the mechanisms of drug uptake following oral administration remain to be fully characterized. In drug discovery and preclinical development there is a strong demand for the accurate and rapid characterization of processes such as absorption, distribution, metabolism and excretion. These biopharmaceutical/pharmacokinetic variables should also be related to pharmacodynamic and toxicological variables such potency and duration of effect. Although these processes are highly dynamic and complex, they are not yet fully characterized in vivo. Various in vitro pharmacokinetic screening methodologies have significantly increased the amount of experimental data generated in this part of the drug discovery process. In addition to these techniques, there is a strong need for in silico methods that may be used to accurately predict pharmacokinetic properties from molecular structure. For instance, pharmacokinetic filters that can sort out compounds with undesirable pharmacokinetic properties can be applied to virtual screening or compound design to reduce attrition rates. The aim of this review is to summarize reported human permeability values and to evaluate how they correlate to corresponding rat intestinal permeability data obtained in single-pass perfusion and Ussing Chamber experiments. The human permeability data are based on direct in vivo determinations in the human gastrointestinal tract with a single-pass perfusion system. The focus of this attention is particularly justified as the availability of directly determined in vivo permeability data in the literature is limited. In addition, there is a shortage of intestinal permeability studies in other mammals.
8.
Lennernäs, Hans
(author)
Modeling gastrointestinal drug absorption requires more in vivo biopharmaceutical data : experience from in vivo dissolution and permeability studies in humans
2007
In: Current drug metabolism. - 1389-2002 .- 1875-5453. ; 8:7, s. 645-657
Research review (peer-reviewed) abstract
The majority (84%) of the 50 most-sold pharmaceutical products in the US and European markets are given orally. The dominating role of this route in drug therapy is a consequence of it being safe, efficient and easily accessible with minimal discomfort to the patient in comparison with other routes of drug administration. A successful drug discovery and development of oral pharmaceutical products require an in-depth understanding of multiple biochemical and physiological processes that determine the dissolution rate, intestinal permeability, gastrointestinal transit, first-pass extraction and systemic exposure-time profiles of drugs. It is crucial to realize that these basic biopharmaceutic and pharmacokinetic properties are crucial to focus on to allow successful drug development. Identification of the rate-limiting step(s) in order to overcome these barriers and understanding of the sources of variability are important in the selection of suitable candidate molecules in drug development. Several reports based on in vitro investigations in various cell models have suggested that carrier-mediated intestinal efflux may be a major reason for incomplete absorption and variable bioavailability of drugs, as well being a site for drug-drug and specific food-drug interactions. However, many drugs which were initially suggested to undergo significant efflux in vitro were later shown to be completely absorbed in vivo. This apparent discrepancy between in vitro and in vivo results may be due to several factors that will be discussed in this review. Novel data on solubility and dissolution in human gastrointestinal derived fluids will be reviewed. The effect of food intake on solubility and dissolution rate of a range of drugs including felodipine, danazol, griseofulvin, cyclosporine, probucol and ubiquinone in simulated and real intestinal fluids is discussed. The biopharmaceutic and physicochemical data discussed here can potentially be used as a benchmark set for validation of new experimental techniques or in silico models in future. Factors such as structural diversity, commercial availability, price and a suitable analytical technique for quantification were considered in the selection of a specific drug set. Using the compiled data set lipophilicity as determined by reverse phase HPLC and permeability across Caco-2 cell monolayers were determined; means to overcome the experimental difficulties due to the diversity of the data are also discussed.
9.
Lennernäs, Hans, et al.
(author)
Oral biopharmaceutics tools - Time for a new initiative - An introduction to the IMI project OrBiTo
2014
In: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 57:SI, s. 292-299
Research review (peer-reviewed) abstract
OrBiTo is a new European project within the IMI programme in the area of oral biopharmaceutics tools that includes world leading scientists from nine European universities, one regulatory agency, one non-profit research organization, four SMEs together with scientists from twelve pharmaceutical companies. The OrBiTo project will address key gaps in our knowledge of gastrointestinal (GI) drug absorption and deliver a framework for rational application of predictive biopharmaceutics tools for oral drug delivery. This will be achieved through novel prospective investigations to define new methodologies as well as refinement of existing tools. Extensive validation of novel and existing biopharmaceutics tools will be performed using active pharmaceutical ingredient (API), formulations and supporting datasets from industry partners. A combination of high quality in vitro or in silico characterizations of API and formulations will be integrated into physiologically based in silica biopharmaceutics models capturing the full complexity of GI drug absorption. This approach gives an unparalleled opportunity to initiate a transformational change in industrial research and development to achieve model-based pharmaceutical product development in accordance with the Quality by Design concept. Benefits include an accelerated and more efficient drug candidate selection, formulation development process, particularly for challenging projects such as low solubility molecules (BCS II and IV), enhanced and modified-release formulations, as well as allowing optimization of clinical product performance for patient benefit. In addition, the tools emerging from OrBiTo are expected to significantly reduce demand for animal experiments in the future as well as reducing the number of human bioequivalence studies required to bridge formulations after manufacturing or composition changes.
10.
Lennernäs, Hans, et al.
(author)
Oral drug absorption and the biopharmaceutics classification system
2007
In: Journal of drug delivery science and technology. - 1773-2247. ; 17:4, s. 237-244
Research review (peer-reviewed) abstract
Bioavailability (BA) and bioequivalence (BE) play a central role in pharmaceutical product development and BE studies are presently being conducted for New Drug Application (NDAs) of new compounds, in supplementary NDAsfor new medical indications and product line extensions, in Abbreviated New Drug Applications (ANDAs) of generic products and in applications for scale-up and post-approval changes. The Biopharmaceutics Classification System (BCS) has been developed to provide a scientific approach for classifying drug compounds based on solubility as related to dose and intestinal permeability in combination with the dissolution properties of the oral immediate release (IR) dosage form. The aim of BCS is to provide a regulatory tool for replacing certain BE studies by accurate in vitro dissolution tests. The aim of the present review is to present the status of BCS and discuss its future application in pharmaceutical product development. This will be discussed in relation to novel findings in human intestinal absorption, permeability and solubility. The future application of BCS is likely to be increasingly important if the BCS borders for certain Class II and III drugs are extended. The BCS is also a simple tool in early drug development to determine the rate-limiting step in the oral absorption process, which has facilitated the information between different experts involved in the overall drug development process. In the future, this increased awareness of a proper biopharmaceutical characterization of new drugs may result in drug molecules with a sufficiently high permeability, solubility and dissolution rate that will automatically increase the importance of BCS as a regulatory tool over time.
