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Wednesday, 10 August 2011

Drug Repurposing: Screening of known drugs against malaria


Just a quick (but surprisingly wordy) follow up on the previous post on the drug profiling against malaria. Drug repurposing/reuse/rescue offers great potential for the enhancement of patient lives and also is a quick way of pushing new therapies through the clinic. It is often see as low cost and low risk, is highly translational in terms of the research, and there are some stunning success stories. It is therefore very sensible to screen known drugs in assays of interest, which is exactly what was done in the recent, excellent, Science paper.

The compounds in Table 1 of the paper are reported at the highly active set (and these exclude already known established antimalarial drugs which all pass the selection criteria used for compounds in this table, this seems a pretty good and pragmatic place to set cutoffs). For use as an widely-used and developing world-applicable antimalarial (co)-therapy I would have imagined that ideally you would want established well tolerated daily dosing, since existing malaria therapies are oral and have (generally) good tolerability.

So, for this list of 32 drugs, a quick internet-based classification was done - factors analysed included:
  1. whether the drugs were already approved for human use 
  2. the dosage/absorption route
  3. any special monitoring requirements (there is probably no option for dose titration/liver monitoring for the vast majority of malaria victims). 
The results are interesting, and a little sobering.

Of the 32, I could find (using a flaky internet connection from the my holiday sun-chair) data that looked OK on 30 (the ones I couldn't easily find things on were suberoylanilide and Alazanine triclofenate - if others know anything, post something in the comments). Of these 30, five (20%) are currently animal use only, nine (30%) are IV use only, one (3%) is not currently approved in humans or animals (Lestautinib), and eight (27%) are topical/inhaled use only. This leaves six (20%) that have the desired profile of being orally dosed and currently approved for human usage. Of these, four have restrictive use/or appear to be poorly tolerated (for example, fumagilin is hospital use only and requires careful monitoring). So this leaves two reasonable candidates for first pass consideration as real 'drug-repurposing' candidates - Dextroamphetamine saccharate and orlistat.

Dextroamphetamine will clearly have regulatory and huge misuse potential, so is also probably a non-starter, regardless of any PK/exposure concerns; so Orlistat then? Orlistat is used as an over-the-counter (in some territories) and prescription drug to assist with weight loss. If works by reducing the absorption of fat from the diet, leading to a variety of side effects - there is much discussion on the safety and side effects (google will find a lot of comment), so in populations that are in malaria endemic regions, a drug that could be dosed to underweight malnourished patients and that reduce the absorption of a key food group (and also most fatty essential vitamins) may not be optimal. A larger issue though is that orlistat works in the lumen of the stomach and intestine, where the target human enzyme is secreted, so for obesity treatment, orlistat does not need to be absorbed into the rest of the body, and it isn't. So, ignoring the side effects for a moment, the negligible systemic exposure of orlistat again probably precludes its use as an antimalarial.

It will be interesting to me if this sort of pattern of results, and the importance of considering in vitro to in vivo translation for 'known drug' screening is typical. Sorry for the long post - thoughts, comments and discussion most welcome.

Update: Looking at the supplementary material for the paper - it seems likely that suberoylanilide from table 1 is actually suberoylanilide hydroxamic acid (aka Vorinostat, or Zolinza). This is an oral drug for the treatment of certain refractory cancers, it can give rise to a wide range of serious side effects that would almost certainly preclude widespread non-supervised use (at least at the doses used for current indications).

Update 2: Thanks to the authors for confirming that the suberoylanilide should be SAHA, and also for confirming that Alazanide triclofenate is an unusual compound with not a lot of current published literature.

1 comment:

Chris Southan said...

No need to apologise. IMCO long technical posts are better than short ones. Lets 'ave more of 'em