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Analytical Research In ADME profiling (ARIADME)

Final Report Summary - ARIADME (Analytical Research In ADME profiling (ARIADME))

* Background and objectives
The integration of absorption, distribution, metabolism and excretion (ADME) profiling into early drug discovery has been put forward as a strategy to reduce drug candidate attrition. The pharmaceutical sector in Europe and worldwide is challenged to develop novel ADME screening methodologies with increased efficiency and predictive power to profile the multitude of lead compounds currently being generated. The principal objective of this programme was to train a new generation of ADME scientists, equipped to tackle this challenge.
To this end, a structured, interdisciplinary training programme was set up. The programme enrolled 13 early-stage researchers (ESRs) in a training consortium consisting of four academic (KU Leuven, University of Copenhagen, VU University Amsterdam and Uppsala University) and two industrial full partners (Janssen Pharmaceutica and Unilever R&D). Seven non-academic associate partners further supported the consortium. The scientific aim of the programme was to improve and expand the current ADME profiling armamentarium by introducing innovative ADME tools (work package (WP) 1), novel analytical methodologies (WP 2) and computational approaches (WP 3).

* Project implementation, results and impact
The 1st of October 2013 was the official starting date of the ARIADME project. The consortium launched the project website www.ariadme.eu in January 2014 to collect and provide information on the individual research projects (IRPs), the scientific output and network-wide events. The recruitment of the ESRs was completed after approximately 6 months, just in time for the Kick-off meeting and open symposium in Leuven, Belgium (09-12/03/2014). Over the course of the next 36 months, the ESRs were able to achieve results that substantially progressed the field beyond the state of the art.
Danny Riethorst performed an in-depth compositional and structural characterization of human duodenal fluids in fed and fasted state (Riethorst et al. J Pharm Sci. 2015, Riethorst et al. Mol Pharmaceut. 2016). The results of these studies can be used as a reference data set for physiologically based pharmacokinetic modelling and to guide the development of new biorelevant media used to assess solubility and dissolution of candidate drugs. Two non-vertebrate animal models were established: the locust for drug metabolism studies and zebrafish for whole body drug uptake (Kislyuk et al. Talanata. 2017) and for drug-induced liver toxicity (Nguyen et al. Int J Mol Sci. 2017). In addition, a novel human cell line model was able to shed light on the effects of clinically-relevant genetic polymorphisms on drug metabolism (Lazarska et al. Toxicol Lett. Accepted for publication).
Over the course of the project, several novel analytical approaches were developed. David Fuchs developed an electromembrane extraction probe for real-time monitoring of drug metabolism (Fuchs et al. Anal Chem. 2015) which was later on coupled to LC-MS (Fuchs et al. Anal Chem. 2016) and implemented in an automated workflow for high-throughput applications (Fuchs et al. Anal Chim Acta. 2016). Other results include the development of a nanofractionation platform with parallel mass spectrometry for the identification of metabolic enzyme inhibitors by Barbara Zietek (Zietek et al. SLAS Discov. Accepted for publication) and the development of a fast and easy method using chemical derivatization to study metabolism by Arnaud Lubin (Lubin et al. J Mass Spectrom. 2015). Clément Chalet developed a suitable method for identification of secondary metabolites from flavonoids (Chalet et al. Anal Bioanal Chem. 2017), while Theodosia Vallianatou studied penetration and distribution of drugs in the brain, and Pranov Ramana explored the use of capillary electrophoresis for in-line studies of drug metabolism (Ramana et al. Electrophoresis. 2017; Ramana et al. Talanta. 2017).
Another notable result is the introduction of intracellular drug bioavailability as a predictor of system dependent drug disposition by Andrea Treyer. This concept can be applied in predictive pharmacokinetics as well as for compound profiling during drug discovery (Mateus et al. Sci Reports. 2017). Ahmed Adeyemi used computational models for the design of antibiotics with optimised ADME properties. He also developed a cheap, easy-to-build, and effective resistively heated reactor for continuous flow synthesis together with colleagues from Uppsala University and secondment partner AstraZeneca (Adeyemi et al. Org Process Res Dev. 2017). Finally, Marco Montefiori was able to elucidate the reaction mechanism of aldehyde oxidase, an important enzyme in drug metabolism (Montefiori et al. ACS Omega. 2017).
Overall, the work performed by the ESRs in the ARIADME project has led to more than 30 peer-reviewed publications, either as first author or as co-author, and featured in over 70 presentations at various conferences including high-level, international conferences such as the AAPS Annual Meeting, the International Symposium on Microscale Separations and Bioanalysis, the ASMS conference on Mass Spectrometry, the World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology and the Pharmaceutical Sciences World Congress.
The ARIADME fellows also communicated their results and significance of the project to a non-scientific audience through a project video on YouTube, by participating in Science Events and other local outreach activities, by visiting secondary schools in the host or the home country of the ESRs and through press releases and contributions to online blogs and magazines.
Training in scientific, soft, and transferable skills as well as career development has been a red line throughout this project. All ESRs were enrolled in doctoral training programmes, participated in the ULLA Summer School and received training in transferable skills such as research integrity, scientific writing, networking and project management during workshops organised by the consortium. David Fuchs and Marco Montefiori have already obtained their PhD and the others are expected to obtain their PhD in the near future. Some fellows are already working in their new job as postdoc or will start a new job in academia or the private sector shortly after their PhD defence. We are confident that eventually all ESRs will establish successful career paths.

* Conclusion
The ARIADME Initial Training Network has completed the objectives originally set out in the work plan. ARIADME has led to significant scientific progress in the field, as illustrated by the large number of publications, and has trained 13 early-stage researchers to become experts in pharmaceutical sciences. The tools, methods and models developed over the course of the project will impact on drug development by reducing costs and the time it takes to bring a drug from target to market.

* Contact information
Project coordinator prof. Patrick Augustijns
Drug Delivery and Disposition, O&N II Herestraat 49 - box 921, 3000 Leuven
tel. +32 16 33 03 01 or +32 16 33 03 00; patrick.augustijns@kuleuven.be

Project manager dr. Tim Thijs
Drug Delivery and Disposition, O&N II Herestraat 49 - box 921, 3000 Leuven
tel. +32 16 32 22 70; tim.thijs@kuleuven.be

* Project logo in attachment
* project website www.ARIADME.eu