This is often the first question a new customer asks us when they engage with Drug Discovery Solutions (DDS). It is ultimately the most important question for a Biotech and their investors. Afterall, getting a new drug to market to serve an unmet medical need is the key goal. Therefore, the answer to this question can add tremendous value by helping project teams understand how close they are to having a candidate to nominate.
Whilst we work with clients at various stages of the drug discovery and development process, clients often engage with DDS once they have identified a promising or advanced compound, with good target pharmacology potency and acceptable selectivity, and often they already have some, or a significant amount of, in vitro and in vivo DMPK data. That often leads to the question: can this compound become a drug?
Potency and selectivity data are essential to any drug discovery program, but they only tell part of the story. A compound will only work if the required free drug concentration reaches the target for long enough to drive efficacy, and for that, it is essential that the teams understand the compound’s clearance and distribution alongside its bioavailability and calculated fraction absorbed (Fa) for an oral drug. The combination of the target unbound plasma requirement and the predicted human pharmacokinetics allows prediction of an efficacious dose that can then be contextualised: a promising 50 mg once daily or an impractical 1500 mg three times a day, for example. Without integrating all parts of the story, teams risk generating further expensive in vivo pharmacology/disease model data that lacks context or where the experiment has been designed sub-optimally to answer the pertinent questions.
By understanding the possible compound clearance mechanism using the Extended Clearance Classification System1, and providing clients with the correlation between their in vitro and in vivo CLint/clearance data, as well as doing an early human dose prediction, we can rapidly answer questions such as: is the compound exposure-limited, potency-limited or both? Is high clearance an issue? Is permeability, solubility and/or poor dissolution holding you back? To finally answer the question of – what should we focus on first?
We often work with clients who have invested heavily in DMPK studies, but the data has not been integrated into the project fully to further understanding of a compound’s key liabilities. By applying a more structured approach, we can give teams a direction to fully understand their compound and focus on the main areas of concern with a view to drive towards a nominated candidate
So… does your compound have potential to become a drug? The honest answer is, it depends… but maybe the more important question is: do you know what stands between your lead compound and a feasible human dose?
And that is where we can advise. If you think we may be able to help your project, please get in touch at info@drugdiscoverysolutions.co.uk. We’d be happy to have a no obligation introductory call or share our flyer on our fixed price human PK and dose prediction package.
(1) Varma MV 2015, Predicting Clearance Mechanism in Drug Discovery: Extended Clearance Classification System (ECCS), Pharm Res, vol. 32, pp. 3785–3802, DOI: 10.1007/s11095-015-1749-4