Introduction

In October 2012, the IMI/EFPIA-funded initiative “Oral Bioavailability Tools (OrBiTo)” project was launched and established a 5 year ongoing collaboration (extended with one extra year) between academic institutions and pharmaceutical companies with one major goal: refining and accelerating the formulation drug development process in order to serve better drug products to patients. A total of 13 pharmaceutical companies, 9 universities, research organizations, public bodies, one regulatory body, one non-profit research organization and three small/medium enterprises (SMEs) participated in this project. The project was initiated by defining the state-of-art knowledge at the start of each work package. As traditional formulation development typically relies on an empirical approach requiring testing to determine the impact of changes during the development cycle, this project aimed to create a more rational and scientific framework to assist formulation scientists in developing better formulations customized to the patient’s needs. The mission statement of the project was: “Through partnership, collaboration and data sharing, we will develop our fundamental knowledge of the gastrointestinal (GI) environment to deliver innovative biopharmaceutics tools which will accurately predict product performance over a range of clinically relevant conditions. The integration of in vitro and in silico approaches will provide a biopharmaceutics toolkit, validated using clinical data, to accelerate drug development.” After oral administration, a drug product will have different transit times throughout multiple regions in the GI tract. In order to understand how much drug will reach the systemic circulation and which plasma-concentration profile is achieved, it is of utmost importance to understand the anatomy and ongoing physiology that regulate the householding of the human GI tract. By gathering in-depth knowledge about how the GI tract functions, scientists will better understand how differences in systemic plasma concentration-time profiles may occur between and within patients after intake of an approved oral drug product. This has previously been achieved in specially designed oral formulations for patients with Addison’s and/or Parkinson’s disease.

After intake, the dosage form needs to disintegrate in order to release the drug compound. Subsequently, the drug needs to dissolve in order to generate a driving force for intestinal absorption. Only then, can drug molecules permeate through the intestinal wall, reach the systemic circulation, and find their way to the site of action. Depending on the physicochemical characteristics of the compound and the formulation properties, some physiological processes (e.g., motility, gastric emptying, pH, biliary secretion) can become critical parameters for dictating drug absorption into the systemic circulation. When implementing these physiological variables into predictive in vitro and in silico computational biopharmaceutical tools, predictions can be made taking into account the most extreme situations (i.e., in terms of minimal and maximal systemic exposure of the drug) toward a patient population. Defining these physiological GI variables and using them as covariates in in silico simulation tools together with population based pharmacokinetic-pharmacodynamic modeling and quantitative systemic pharmacological predictions, it becomes a useful approach to predict the optimal dose for each patient suffering from a chronic/acute disease (i.e., personalized medicine).

Within “OrBiTo,” five discrete work packages (WP) were constructedto assure the successful completion of all pre-defined goals. Based on the outcomes from each work package, an intensive data analysis was performed and a decision tree was developed for different kinds of formulations and compounds of interest (e.g., immediate-release formulation for a weakly basic compound). The decision tree will assist formulation scientists in selecting the most appropriate in vitro dissolution test (eventually coupled with computational modeling) to better understand what can be expected from this formulation (in terms of systemic exposure) if it would be given to patients in the later stage of drug development. The decision tree can be downloaded from the following website: www.orbito-dissolution.eu. In the following paragraphs, a more detailed description of each work package will be discussed including the pre-defined goals. In addition, two specific case studies of how this project could contribute to improved patient healthcare will be demonstrated for an optimized drug formulation of the poorly soluble compound posaconazole (i.e., antifungal agent) and a second example will demonstrate how different intake conditions (sparkling vs. still water) were tested for paracetamol (i.e., pain-reliever) and resulted in unexpected differences with respect to the systemic concentrations.

By Bart Hens, Patrick Augustijns, Hans Lennernas, Mark McAllister and Bertil Abrahamsson