Periodic Reporting for period 1 - InPharma (A fully integrated, animal-free, end-to-end modelling approach to oral drug product development)
Reporting period: 2021-01-01 to 2022-12-31
Oral medicines are preferred by patients worldwide due to ease of self-administration and overall higher patient compliance. Yet, the challenges around formulating molecules into medicines for oral administration have increased substantially over the last 30 years, mainly because most drugs coming through the drug discovery pipeline are too poorly soluble to be dissolved and efficiently absorbed from the gastrointestinal tract. Furthermore, due to the considerable challenges in formulating poorly soluble drugs for oral delivery, the number of animals used to screen oral absorption of formulation prototypes is increasing, despite the EU’s commitment to reducing animals in research.
In order to ensure a rich pipeline of new oral medicines for European patients and to avoid unnecessary animal testing in oral drug product development, a quantum leap is needed in identifying the optimal formulation design for a new drug candidate. The InPharma consortium aims to solve these important challenges through pioneering research focused on advancing an integrated, end-to-end, animal-free approach to formulating poorly soluble drugs for oral administration.
InPharma is the first European Industrial Doctorate (EID) that aims to eliminate animals from the development of oral drug formulations. The InPharma consortium brings together leading pharmaceutical scientists from six multi-national pharmaceutical companies, five world-class research institutions and eight partner organisations, from complementary technology and service providers (SMEs) to additional pharma and regulatory representatives to create a research network involving nine European countries.
The main research objectives in InPharma are to develop a fully integrated, end-to-end model-based approach to oral drug development, linking ‘big data’ available from drug profiling repositories with computational tools to predict oral formulation design, generating innovative physiologically relevant in vitro tools and adapting computational models to predict drug absorption from ‘enabling’ oral drug formulations in clinically relevant scenarios.
In order to ensure a rich pipeline of new oral medicines for European patients and to avoid unnecessary animal testing in oral drug product development, a quantum leap is needed in identifying the optimal formulation design for a new drug candidate. The InPharma consortium aims to solve these important challenges through pioneering research focused on advancing an integrated, end-to-end, animal-free approach to formulating poorly soluble drugs for oral administration.
InPharma is the first European Industrial Doctorate (EID) that aims to eliminate animals from the development of oral drug formulations. The InPharma consortium brings together leading pharmaceutical scientists from six multi-national pharmaceutical companies, five world-class research institutions and eight partner organisations, from complementary technology and service providers (SMEs) to additional pharma and regulatory representatives to create a research network involving nine European countries.
The main research objectives in InPharma are to develop a fully integrated, end-to-end model-based approach to oral drug development, linking ‘big data’ available from drug profiling repositories with computational tools to predict oral formulation design, generating innovative physiologically relevant in vitro tools and adapting computational models to predict drug absorption from ‘enabling’ oral drug formulations in clinically relevant scenarios.
13 Early Stage Researchers (ESRs) have been recruited in InPharma, to focus their research endeavours on developing a fully integrated, animal-free, end-to-end modelling approach to oral drug product development. A unique intersectoral training plan that allows ESRs to gain experience in both industry and academia has been designed and all 13 ESRs are approximately halfway through their personalised intersectoral training programme. All ESRs have received training on computational formulation design, bio-predictive in vitro testing and physiologically based pharmacokinetic modelling, with specific training provided depending on the individual needs of each ESR project. All ESRs have also undergone a transferable skills training programme to build proficiency in essential research and industry disciplines, while training in professional skills and entrepreneurship to inspire them to become trailblazers in industrial drug product development.
This research strategy is reflected in two research work packages (WPs), and a summary of the key achievements in these WPs during this reporting period are detailed as follows:
• WP1 is focused on advancing computational tools to develop oral drug formulations. There are two main research objectives of WP1, namely (1) Investigate novel mechanistic and data-driven algorithms for their ability to support formulation design of poorly soluble drugs and (2) Use the algorithms to select drug-excipient mixtures which can be used to optimally select the right excipient for a given drug. Highlights of WP1 within this reporting period are the successes in formulation innovation (ESR1, ESR2 and ESR5), new data-driven computational tools for the prediction of formulation design (ESR3, ESR4) and novel mechanistic modelling approaches for understanding drug-excipient interactions (ESR6).
• Research in WP2 is focused on developing animal-free assessment methods for predicting formulation performance in patients. This is achieved by developing in vitro methodologies that are bio-predictive of enabling formulations under clinically relevant conditions, as well as the development of in silico models for predicting the drug concentration profile in patients after oral administration. Highlights of WP2 within this reporting period are progress made in advancing the animal-free ‘rDCS approach’ to predicting formulation strategy (ESR7), novel in vitro methods explored for evaluating bio-enabled formulations (ESR8, ESR9, ESR11, ESR12 & ESR13) and advancing in silico approaches to replace allometric scaling from animal studies with virtual trials (ESR8, ESR10, ESR11 & ESR12).
This research strategy is reflected in two research work packages (WPs), and a summary of the key achievements in these WPs during this reporting period are detailed as follows:
• WP1 is focused on advancing computational tools to develop oral drug formulations. There are two main research objectives of WP1, namely (1) Investigate novel mechanistic and data-driven algorithms for their ability to support formulation design of poorly soluble drugs and (2) Use the algorithms to select drug-excipient mixtures which can be used to optimally select the right excipient for a given drug. Highlights of WP1 within this reporting period are the successes in formulation innovation (ESR1, ESR2 and ESR5), new data-driven computational tools for the prediction of formulation design (ESR3, ESR4) and novel mechanistic modelling approaches for understanding drug-excipient interactions (ESR6).
• Research in WP2 is focused on developing animal-free assessment methods for predicting formulation performance in patients. This is achieved by developing in vitro methodologies that are bio-predictive of enabling formulations under clinically relevant conditions, as well as the development of in silico models for predicting the drug concentration profile in patients after oral administration. Highlights of WP2 within this reporting period are progress made in advancing the animal-free ‘rDCS approach’ to predicting formulation strategy (ESR7), novel in vitro methods explored for evaluating bio-enabled formulations (ESR8, ESR9, ESR11, ESR12 & ESR13) and advancing in silico approaches to replace allometric scaling from animal studies with virtual trials (ESR8, ESR10, ESR11 & ESR12).
To maximise the impact of InPharma related research, the consortium have arranged for a special ‘InPharma’ themed issue in European Journal of Pharmaceutical Sciences (Elsevier) to be published https://www.sciencedirect.com/journal/european-journal-of-pharmaceutical-sciences/special-issue/103ZHMQR6V6. Two scientific papers have already been published in this special issue and over 12 more articles are planned within this InPharma themed issue, which will include contributions from each ESR. ESRs have also published several conference abstracts and posters which are expected to lead to research manuscripts over the next number of months.
The results achieved in the first reporting period have already led to innovations in computational pharmaceutics tools and in animal-free approaches for predicting oral formulation performance in patients. The research and training programmes are on track and the ESRs have also been engaged in the outreach, dissemination and management activities. We anticipate to further maximise InPharma’s impact as the research projects develop throughout the second reporting period.
Collectively, these new technologies and tools will address the needs of the pharmaceutical industry for accelerating ‘molecule to market’ timelines for oral medicines. The outcomes from InPharma also align with societal obligations towards reducing animal testing in drug development. Finally, a key impact of InPharma will be that new medicines will be brought to the market more efficiently, with lower overall costs and crucially also with fewer ethical challenges associated with the conduct of testing in animals.
The results achieved in the first reporting period have already led to innovations in computational pharmaceutics tools and in animal-free approaches for predicting oral formulation performance in patients. The research and training programmes are on track and the ESRs have also been engaged in the outreach, dissemination and management activities. We anticipate to further maximise InPharma’s impact as the research projects develop throughout the second reporting period.
Collectively, these new technologies and tools will address the needs of the pharmaceutical industry for accelerating ‘molecule to market’ timelines for oral medicines. The outcomes from InPharma also align with societal obligations towards reducing animal testing in drug development. Finally, a key impact of InPharma will be that new medicines will be brought to the market more efficiently, with lower overall costs and crucially also with fewer ethical challenges associated with the conduct of testing in animals.