The challenge: getting to grips with the impacts of medicines on the environment
The active ingredients in medicines (known as the active pharmaceutical ingredient, or API) can be released into the environment in a variety of ways. The most common route is via the sewage system, when patients excrete them. APIs can also escape into the environment when people dispose of medicines incorrectly, and during the manufacturing process. APIs are, by definition, biologically active, and although their concentration in the environment is generally extremely low, there are concerns about the effect of these chemicals on wildlife and ecosystems in general.
Since 2006, new medicines have had to undergo an environmental risk assessment before they are approved for use. However, current testing strategies need to be optimised to accurately predict harmful impacts on wildlife.
Furthermore, there are many APIs that were already in use before the new rules came into force, and just a small number of these (around a tenth) have been subjected to environmental risk assessments. As testing all of these will be a mammoth task, guidance is needed to help identify which of these ‘legacy’ APIs are most likely to pose a risk to the environment and so should be prioritised for testing. This guidance is also needed to ensure environmental impacts are fully considered during the development of new APIs.
The goal of iPiE was to develop frameworks and tools to help determine which legacy APIs should be prioritised for environmental testing, and to support the smarter environmental testing of new APIs under development.
A unique database on the environmental impacts of APIs
Underlying most of iPiE’s outputs is the iPiE database, which brings together in one place extensive information on the environmental aspects of over 350 APIs. Much of this information was provided by 13 pharmaceutical companies, and has never been published, making the iPiE database a unique resource.
New models to predict levels and activity of APIs in the environment
When carrying out environmental risk assessments, one key question is what level of the API organisms are actually exposed to. To answer this, iPiE created the ePiE tool (the ‘e’ stands for exposure), which models the path of an API from the moment it is taken by a patient, via the toilet and sewage pipes to waste water treatment plants, to the moment it is released into a river. The tool draws on national consumption data of different APIs and their chemical properties, and delivers a prediction of the concentration that would be found in certain key European river basins.
iPiE has also created computer algorithms called QSPRs (quantitative structure property relationships), which analyse the chemical properties of APIs to predict what will happen to them and how they will behave in the environment, e.g. whether they are likely to break down in a waste water treatment plant, or attach themselves to soil particles…
Using evolution to assess risks
Another key question in environmental risk assessment is knowing which APIs are most likely to cause harm to wildlife. After all, they are designed to be biologically active, and although millions of years of evolution separate us from fish, for example, we do still share a number of proteins in common. This means that if a freshwater fish has a protein that is also a target of a human drug, it is likely that the drug could harm fish if it gets into our rivers and lakes. To help scientists quickly find out which human drug targets are also found in wildlife, iPiE created the ECOdrug database. The publicly available tool draws on data from multiple sources and has information on over 600 species, including other primates, rodents, birds, fish, microscopic animals, fungi, and plants.
Focus on fish
In freshwater environments, fish are one of the most closely related groups to humans, and so have more shared drug targets than e.g. insects and plants. This makes fish particularly vulnerable to pharmaceuticals in the environment. iPiE took an existing model that assesses the ‘safe’ level of an API for fish and improved it by adding additional information and data.
Comprehensive resources for assessing the impacts of medicines in the environment
The project’s databases, tools and models are brought together in two comprehensive tools: iPiE*SYS and iPiE*SUM.
iPiE*SYS is accessible to all the project partners and provides seamless, one-stop access to the iPiE database, the iPiE models and tools, and extensive data on the environmental impacts of all 350+ APIs in the iPiE database.
iPiE*SUM is a publicly available tool that provides a high-level information on most of the APIs in the iPiE database. Via a simple user interface, users can search for compounds and related studies in the iPiE database.
Making a difference
The iPiE project has created an impressive legacy. On the scientific front, it has achieved its goal of delivering tools that help to prioritise the environmental testing of legacy APIs, and incorporate environmental questions into the development of new APIs. These tools are also described in the scientific literature.
Crucially, the pharmaceutical industry is using the iPiE database to avoid the duplication of tests, something that will reduce animal testing and costs. They are also using the tools, for example to assess the risk of an API for surface waters.
Thanks to the project, and in particular its advisory board, the project partners have forged strong links with key stakeholders involved in discussions on pharmaceuticals in the environment, including national agencies, the water industry, business associations, and more.
Finally, and perhaps most significantly, the growing interest among politicians at EU and national levels in the subject mean that iPiE’s tools, knowledge and expertise could help to shape policy in this important area.
Meanwhile, a new IMI project, PREMIER, builds on many of the iPiE outputs.
Achievements & News
Scientists from IMI’s iPiE and PREMIER projects used ePiE to predict levels of ibuprofen in four major European river basins.
IMI’s iPiE project on the impacts of pharmaceuticals in the environment will hold its final conference on 24-25 June in York, UK. ###Since its launch over four years ago, the iPiE project has worked to develop frameworks that utilise information from toxicological studies, pharmacological mode of action and computational tools to support intelligence-based environmental testing of pharmaceuticals in drug development and to prioritise legacy pharmaceuticals (those authorised prior to the 2006 enactment of Medicines Agency requirements) for targeted environmental risk assessment and/or environmental (bio) monitoring. The project’s closing event will act as a forum to disseminate the results of the project while also providing opportunity to others working on the prioritisation and intelligent assessment of pharmaceuticals, to present their work.
IMI’s iPiE project has released an online tool that summarises the properties, environmental toxicity and characteristics of active pharmaceutical ingredients (APIs). Dubbed, iPiE*SUM (‘iPiE Summary Database Search’), the tool is designed to allow public and regulatory bodies to obtain a high-level overview of what studies were collected during the iPiE project and what eco-toxicity data and studies are available.### APIs can be released to the natural environment during the manufacturing process, following use by patients, or when unused medicines are disposed of inappropriately. The goal of iPiE is to develop a framework that will provide methodologies to prioritise new and existing medicinal compounds for a comprehensive environmental risk assessment. As such it will support and inform regulatory activities designed to assess and reduce the environmental impact of medicines.
IMI’s iPie project has released ECOdrug, a new database that connects drugs to their protein targets across different species. The team hopes the tool, which is freely accessible at www.ecodrug.org, will help industrial, academic and regulatory scientists to assess and manage the risks associated with pharmaceuticals in the environment. ###Medicines are designed to interact with specific targets (e.g. proteins) in the human body. Very often, these targets have equivalents in other species, especially those that are closely related to humans.
The ECOdrug database draws on data from multiple sources and has information on over 600 species, including other primates, rodents, birds, fish, microscopic animals, fungi, and plants. The user-friendly interface has two tabs – one for drug-related information and one for drug targets. A search of a drug name brings up a table showing the targets of the drug and how well they are conserved across different species. Similarly, a search by drug target uncovers links to all drugs that target that protein, and the interface shows an evolutionary tree showing the numbers of species in different groups that have an equivalent to the drug target.
Looking to the future, the project plans to improve ECOdrug further by integrating it with other platforms. The tool is described in detail in a paper in the journal Nucleic Acids Research. The authors conclude: ‘Through integration with the systems outlined above, the addition of new features and regular updating we aim to ensure ECOdrug is maintained as a valuable and contemporary research tool for the communities in drug discovery, comparative and evolutionary biology and (eco)toxicology.’
ParticipantsShow participants on map
- Astrazeneca AB, Södertälje, Sweden
- Bayer Aktiengesellschaft, Leverkusen, Germany
- Boehringer Ingelheim Internationalgmbh, Ingelheim, Germany
- Bristol-Myers Squibb Company Corp, Princeton, NJ, United States
- Eli Lilly And Company LTD, Basingstoke, United Kingdom
- F. Hoffmann-La Roche AG, Basel, Switzerland
- Glaxosmithkline Research And Development LTD., Brentford, Middlesex, United Kingdom
- Janssen Pharmaceutica Nv, Beerse, Belgium
- Merck Sharp & Dohme Corp, Whitehouse Station, New Jersey, United States
- Novartis Pharma AG, Basel, Switzerland
- Pfizer Limited, Sandwich, Kent , United Kingdom
- Sanofi-Aventis Recherche & Developpement, Chilly Mazarin, France
- Teva Pharmaceuticals Europe B.V., Amsterdam, Netherlands
Universities, research organisations, public bodies, non-profit groups
- Fundacio Institut Hospital Del Mar D Investigacions Mediques, Barcelona, Spain
- Helmholtz-Zentrum Fur Umweltforschung GMBH - Ufz, Leipzig, Germany
- Lhasa Limited, Leeds, United Kingdom
- Liverpool John Moores University, Liverpool, United Kingdom
- Stichting Radboud Universiteit, Nijmegen, Netherlands
- The University Of Exeter, Exeter, United Kingdom
- Universidad Pompeu Fabra, Barcelona, Spain
- University Of York, York, United Kingdom
Small and medium-sized enterprises (SMEs)
- Ect Oekotoxikologie GMBH, Flörsheim a.M., Germany
- Molecular Networks GMBH Computerchemie, Erlangen, Germany
- Synapse Research Management Partners SL, Barcelona, Spain
Non EFPIA companies
- Umweltbundesamt, Dessau-Roßlau, Germany
|Name||IHI funding in €|
|Ect Oekotoxikologie GMBH||332 459|
|Fundacio Institut Hospital Del Mar D Investigacions Mediques||150 157|
|Helmholtz-Zentrum Fur Umweltforschung GMBH - Ufz||262 862|
|Lhasa Limited||288 640|
|Liverpool John Moores University||157 060|
|Molecular Networks GMBH Computerchemie||258 475|
|Stichting Radboud Universiteit||360 400|
|Synapse Research Management Partners SL||224 866|
|The University Of Exeter||258 566|
|Universidad Pompeu Fabra||125 583|
|University Of York||394 255|
|Total Cost||3 000 000|