David Elder on In Silico Modelling and Genotoxic Impurities

David Elder, Externalisation Director, GlaxSmithKline joins Pharma IQ to discuss navigating the hurdles of drug discovery and development and the challenges of poorly soluble drugs.

Pharma IQ: Please could you outline your current role?

D Elder:  I work for GlaxoSmithKline within a group called Synova which is in preclinical discovery, and the idea behind Synova was to help our partners, particularly small bio-pharms to navigate through the hurdles of drug discovery and development. 

Pharma IQ:
What percentage

I think the answer to that question is probably in the high 80s or 90% and the reason for it is high throughput in combinatorial chemistry.  We’re effectively producing drugs in the non-drugable space most of them now are high molecular weight, high lipophilicity and the consequence of that is poor solubility.

Pharma IQ: What role does in silico modelling play in early discovery?

I think in silico modelling plays a really useful role in, as a screen in early discovery.  We can use it, if you like to deselect candidates which would have poor solubility.  So there’s a lot of activity going on across the industry in drug discovery to try and make more drugable molecules, molecules with better solubility characteristics, and by being able to accurately predict and that’s the rope, it’s the accurate prediction of aqueous solubility that would go a long way towards improving and increasing our chances of overcoming early phase attrition.
I think as a part of a screening cascade and as a key decision maker about taking pre-candidates forward.  So if the, if all the candidates looked equally good from a specificity and efficacy perspective then, you could screen out those that had poor solubility using in silico modelling.

I think by predicting ahead of time the absorption fraction of molecules we will save considerable time and money.  We have some statistics within GSK and I think it will be equally Germaine and the other big pharmas that suggest that if you compare the development times of compounds with good solubility, good permeability versus those with poor solubility and even good permeability, you find sort of probably of the order of about 12 months difference if not longer, in terms of absolute development times.  We tend to hit many more problems when we’ve got sort of poor absorption and it, as I say it takes a lot of time and effort to resolve those problems.

Certainly speaking personally the regulation that has given me the most challenges in the last 12 months is genotoxic impurities.  I think right across the industry we’re realising that it is a huge challenge.  So it’s not just the issue of impurities but also degradance and metabolites are coming to the fore now, and because of their toxicity we have to control these impurities to very, very low levels, particle million levels, so that one’s going to be really challenging.

I think some of the other challenges would be centred around delivery.  It may not be specifically in the regulatory field, but I think the regulators will catch up in this area delivering things such as stem cells and all [unclear] and these agents have their activity within the cell so classic means of delivery which get into the systemic system, but don’t necessarily get into the cell can be quite tricky.  So I think that would be a significant challenge as well.

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