Project Planning

Published by ndt228 on 4 July 2010 - 1:39pm
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Chiral Switch Project Outline.pdf19.58 KB

Based on past experience with "Chiral Switch" projects in a commercial environment, I have drafted the attached document as a summary of my understanding of the aims of the PZQ project in the context of what would be needed (technically) to get (R)-PZQ to market in the western world.  This does not examine manufacture per se, but rather the many necessary steps to obtain permission to market.  I am sure there are some which I may have missed, but the point is that there would (in my past experience) be far more going on than focussing as at present on "manufacture" and "cost of goods", however important these will be in the long-run. 
It is necessary to prove both safety & effectiveness.  Now this may already be in place, but it is not yet evident on this site, and the expected standards change over time.  This is why I suggest a critical review of the existing data, to identify any gaps in 21st-Century terms.  If these are found to exist, then they can only presently be addressed through re-supply of (R)-PZQ by chromatographic means, which is a project in itself.  Commercially, this would be pursued in parallel with the efforts to identify a viable manufacturing route to the single enantiomer.
This is intended as a discussion document, and I am receptive to amendments or additions.  Some of the points made by "guest" under the PZQ Manufacturing Capacity thread are quite relevant.

Comments

Having read your document, I think that it addresses all of the main issues.

The key to taking the project forward is to have a "champion" to carry it forward. In most drug development projects this would clearly be a pharmaceutical company whose motivation is profit. The only way this project could be carried forward is by the intervention of some NGO, probably WHO, who are concerned about potential resistance to praziquantel (forget taste- this is easily addressed by formulation).

As you rightly say, what really needs to be done currently, is to isolate the desired isomer by chiral chromatography and to perform some initial ADME studies in order to determine the profile of the single isomer against the racemate in humans. Hopefully things will be a lot better than with chiral mefloquine!(http://www.treague.com/).

Unfortunately, this all requires substantial funding with the question of where it is coming from.

ndt228's picture

Thanks for your review/comments.  Indeed the WHO mention resistance as a concern.  Somehow I doubt that a chiral switch would have any effect on that issue; rather they are looking at a joint chemotherapy approach with another API.
Another debate is this:  If there is limited money available to buy and distribute treatment, what right do we have to spend any of it on activities/luxuries that detract from the amount of treatment that happens ?  Its fine to have high principles about racemate vs single enantiomer, but if the cost goes up that will mean less people get treated on a finite budget.  There does not seem to be sufficient "bad press" about the racemate to justify stopping its use. From what I have read it is typically a single-dose treatment, so I don't think compliance is likely to be a big issue, despite the taste.  It seems from some WHO documents that there is a 150mg tablet as well as 600mg so even the size aspect is perhaps already covered.
If there were a Western market, I'd be looking to resolve the PZQ Amine, initially by SMB to buy time, and also trying to realise the hypothetical racemisation of off-isomer.  This would for sure deliver material for trials, but however atom-efficient the ultimate process, it could never reach the price of racemate.  So, although it looked odd to me to concentrate on the chemistry and apparently ignore all the other activities, perhaps its the right way after all in these circumstances ?