Editorial pubs.acs.org/molecularpharmaceutics
Industry−Academic Collaboration in Oral Biopharmaceutics: The European IMI OrBiTo Project of drug absorption in WP4. This special edition of Molecular Pharmaceutics follows the structure and flow of the OrBiTo program and contains a number of manuscripts across the four work packages. WP1 seeks to improve the understanding of the physicochemical and biopharmaceutical properties which impact the in vivo performance of poorly soluble active pharmaceutical ingredients (APIs) (BCS class II and IV drugs). The data generated by the new models and characterization tests developed though WP1 will inform the selection of candidate molecules during preclinical testing and guide appropriate formulation selection for first in human studies. It is widely acknowledged that the absorption of poorly soluble drugs is strongly influenced by the GI fluid content and composition. In the study by Zhou et al., the solubility profile of seven low solubility drugs was investigated using a four component mixture design to understand the solubilization capacity and interactions of bile salts, lecithin, oleate and monglyceride. The ratio of components strongly affected solubility profiles and highlights the need to consider a more complete solubility profile beyond that typically performed with single point medium determinations so that the full extent of variability associated with in vivo solubility can be fully considered. Implementing a solubility screen to cover this full range can be challenging during the preclinical development phase due to limited availability of compound and the resources required for a comprehensive screen. A small-scale statistical approach was adopted by Ainousah et al. to investigate equilibrium solubility in simulated fasted and fed intestinal fluids. Results from this study indicated that a small format design of experiments approach could provide solubility ranges which were similar to published data with human and simulated fasted and fed fluids. The use of lipid formulations to improve bioavailability of poorly soluble drugs is a commonly used strategy for bioenhancement, but the internal molecular structure of lipid-based formulations is poorly understood. The study by Larsson et al. describes the use of a coarse-grained molecular dynamics simulation approach which could be used as an in silico screening tool to provide insights on the structures formed in complex lipid based formulations. This could also facilitate the understanding of the molecular interactions of lipidic formulation components when dispersed in aqueous media. Supersaturation delivery strategies are also often utilized to increase the bioavailability of drug candidates with low aqueous solubility. A thorough understanding of the supersaturation and precipitation behavior is required to optimize the delivery approach (e.g., identify the requirements and screen for effective precipitation inhibitors), and a novel characterization method using a video-microscopic technique
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he Innovative Medicines Initiative (IMI) OrBiTo project is a precompetitive collaboration between pharma, academia and specialist technology companies which aims to enhance our understanding of how orally administered drugs are absorbed from the gastrointestinal tract and to apply this knowledge to develop both new in vitro and in silico models that will better predict the performance of oral formulations in patients. The five year OrBiTo project, which started in October 2012, brings together more than 150 scientists spread across 13 industrial and 14 academic, regulatory and technology partners. To date, over 100 papers have been published from the combined efforts of this group to deliver more than 70 research tasks spread across four technical work packages. It is the objective of the OrBiTo program to effectively integrate both in vitro and in silico approaches to provide a biopharmaceutics toolkit, validated using clinical data, to accelerate drug development. The industrial need for tools which will predict formulation performance after oral administration is driven by several factors. First, it is widely recognized that drug discovery portfolios from innovative pharma companies have a large proportion of poorly soluble compounds which often require a complex formulation approach to achieve consistent and reliable oral delivery. Second, development paradigms are changing with accelerated projects, particularly in the oncology therapeutic area, progressing through the drug development process much more rapidly than traditional development timelines. The combined impact of technical and time pressures makes it essential that the tools and models used to characterize oral formulations provide an accurate prediction of their performance across the range of clinically relevant states including fasted and fed and the impact of concomitant medication such as proton pump inhibitors. Our understanding of the gastrointestinal (GI) environment and prediction of formulation performance has advanced significantly over the past two decades with the widespread adoption of tools such as biorelevant dissolution media, in vitro permeability models, the biopharmaceutical classification scheme and computational tools such as physiology-basedpharmacokinetic (PBPK) models for the prediction of GI drug absorption. However, significant gaps in our understanding of GI physiology and its relevance to oral biopharmaceutics still exist and constrain our ability to consistently predict formulation performance. The OrBiTo vision is to transform our ability to predict the in vivo performance of oral drug products across all stages of drug development. A fundamental design principle of the OrBiTo program was to effectively leverage the data assets held by the industrial partners to provide a unique resource for the development and validation of new tools and models. OrBiTo is structured in four research work packages (WPs) focusing on physicochemical tools (WP1), in vitro tools (WP2) and in vivo understanding and tools (WP3), with the integration of results and data across all WPs being achieved through the application of in silico models © 2017 American Chemical Society
Special Issue: Industry-Academic Collaboration in Oral Biopharmaceutics: The European IMI OrBiTo Project Published: December 4, 2017 4129
DOI: 10.1021/acs.molpharmaceut.7b00940 Mol. Pharmaceutics 2017, 14, 4129−4131
Molecular Pharmaceutics
Editorial
ethanol concentrations measured in this study may serve as reference data set for the further development of biorelevant in vitro models to assess ethanol effects on formulation performance. Research efforts within WP3 have focused on addressing key gaps in our knowledge of the GI tract relevant to the behavior of compounds and formulations, e.g., GI transit properties, regional absorption data and human GI fluid distribution data. Efforts within WP3 are intended to develop a more detailed knowledgebase on how the in vivo gastrointestinal environment impacts the GI processing of orally administered dosage forms. Finally, the aims of WP3 are to define how animal models can be used as tools to enrich the predictability of human oral absorption and systemic availability. The WP3 manuscripts submitted to this theme issue include an assessment of methods to determine regional intestinal permeability in rats and the use of the rat intestinal transport model to evaluate the effect of absorption modifying excipients on transport of five model compounds. An additional manuscript from WP3 describes the use of the rat single-pass intestinal perfusion model to determine the mechanisms controlling intestinal absorption from aprepitant nanoformulations. In addition to the assessment of the utility of preclinical animal models to predict the performance of oral drug delivery systems, WP3 also focused on the human in vivo performance of dosage forms and how data from investigative studies could be used to improve our in vitro systems. In the study by Al-Gousous et al., the erratic performance of enteric coated dosage forms is reviewed and the limitations of current in vitro systems to predict performance are critiqued. The authors conclude that an appropriate simulation of pH and the buffer molarity gradient along the length of the human intestine, simulation of the mechanical stresses and utilization of in vivo relevant fluid volumes are all critical to the development of biopredictive in vitro methods. Our knowledge of fluid volumes and the dynamics associated with transit, absorption and reabsorption in the GI tract has expanded considerably over the past decade, and a WP3 clinical study on gastric water emptying under fed state clinical trial conditions provides further insights on the potential for rapid emptying in the fed state via the Magenstrasse or stomach road. Two manuscripts are included from WP 4. The focus of this work package is to improve existing computational models by making changes to the way key parameters are calculated or through changes in the systems biology (e.g., lymphatic route, mucosal compartment, bile salt concentration) for better predictions of in vivo performance of oral dosage forms. In essence the objectives of WP4 are intimately linked with the outputs from WPs 1−3. By iterative approaches, and the testing of several inputs to the models coupled to model refinements, the ultimate aim is to progress in terms of quality of bioavailability prediction. Finally, we have included two manuscripts submitted from authors located outside the main OrBiTo consortium but which align perfectly with the research objectives described above. The first of these papers, by Hens et al., provides data to characterize the buffer capacity and motility profiles along the GI tract and assesses the implications for in vivo dissolution and absorption of ionizable drugs. Additionally, the in vivo dissolution and systemic absorption of ibuprofen delivered as an immediate-release tablet under fed and fasted conditions is described in the manuscript by Sun et al. In summary, we would like to thank all the authors for their contributions to this theme issue of Molecular Pharmaceutics.
applied to the poorly soluble drug tadalafil is described in the study by Christfort et al. WP1 efforts to establish effective in vitro tools to characterize the critical biopharmaceutics properties of API have focused on delivering standardized assays which can be used when just a few milligrams of API are available. The small-scale supersaturation and precipitation method proposed by Plum et al. describes the methodology and the intra- and interlaboratory reproducibility of this method for three model compunds studied across seven OrBiTo partners. The focus of WP2 is on the development and validation of in vitro dissolution methodology which can provide accurate biorelevant characterization of products for late-stage formulation development. This special edition includes four manuscripts from WP2. The interlaboratory reproducibility of biorelevant dissolution testing (across 16 OrBiTo partners), using the paddle apparatus (USP 2), is described by Mann et al. This study evaluated the reproducibility of single stage biorelevant testing using FaSSGF and FaSSIF media and a two-stage protocol to simulate the gastric to intestinal transfer which occurs on gastric emptying. Interlaboratory reproducibility with the two-stage test was found to be acceptable, although the variability was somewhat greater than with the single medium tests. Dissolution in the lower intestine is important not only for modified-release dosage forms and colonically targeted systems but also for high dose low solubility drugs delivered as immediate-release dosage forms. Historically, dissolution method development has neglected this area, but efforts within WP2 have focused on the optimization of methodology (particularly with regard to hydrodynamics and fluid composition) to adequately simulate the environment in the distal ileum and proximal colon as described in the study by Georgaka et al. The use of physiological data which more accurately define the GI lumenal environment to improve dissolution methodologies was a key goal at the outset of the OrBiTo program. Several clinical studies have been conducted as part of OrBiTo and have yielded novel data which have been used to design or optimize dissolution conditions to accurately simulate different prandial states. Two studies from the KU Leuven research group using intubation techniques to sample gastric and intestinal contents are included in this special edition. The first study, by Augustijns et al., on the gastrointestinal and systemic disposition of diclofenac under fasted and fed state conditions aimed to gain further insight into the gastrointestinal disposition of this weakly acidic BCS class II drug and the implications for systemic drug exposure. The in vivo data was used as a reference for the evaluation of in vitro tools with different levels of complexity, i.e., a conventional USP II dissolution apparatus, a modified version of the dynamic open flow through test apparatus and the TNO gastrointestinal model-1 (TIM-1). A similar approach was taken to understand the effective ethanol concentration to which formulations could be exposed if dosed with alcoholic beverages. The regulatory requirements for dissolution testing with media containing high levels of ethanol postulated to simulate in vivo gastric and intestinal conditions after ingestion of alcoholic beverages has been an area of much debate within the dissolution community. The study by Rubbens et al. determined intraluminal ethanol concentrations (stomach and duodenum) in fed healthy volunteers after the consumption of common alcoholic beverages and compared results to a previous study in fasted volunteers. The authors concluded that the intraluminal 4130
DOI: 10.1021/acs.molpharmaceut.7b00940 Mol. Pharmaceutics 2017, 14, 4129−4131
Molecular Pharmaceutics
Editorial
This issue has highlighted recent status, achievements and challenges in our understanding of the mechanisms of GI absorption and the prediction of human bioavailability. In conclusion, over the five year duration of the OrBiTo project, the collaborative efforts of industrial biopharmaceutics scientists, specialist technology providers and academic centers have advanced our understanding of the GI tract and developed the models and technologies which will deliver a new generation of predictive tools for oral biopharmaceutics.
Mark McAllister,* Guest Editor
Drug Product Design, Pfizer, Sandwich CT13 9NJ, United Kingdom
Patricia Zane, Guest Editor
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Sanofi, Bridgewater, New Jersey 08807, United States
AUTHOR INFORMATION
Corresponding Author
*E-mail: mark.mcallister@pfizer.com. Notes
Views expressed in this editorial are those of the authors and not necessarily the views of the ACS.
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DOI: 10.1021/acs.molpharmaceut.7b00940 Mol. Pharmaceutics 2017, 14, 4129−4131
