Innovation Pharmaceuticals Inc (IPIX)

[biodoc]

Got me thinking PlentyParanoid. My apologies in advance for my lengthy answer and some thoughts.

I'm using a conversion formula for mouse dose to human dose which gives me a very different human equivalent dose than the 800 mg used in your calculations. There is no perfect conversion formula but these forumlas give us a starting point.

animal dose conversion
Human equivalent dose (HED)= animal dose (mg/kg) x animal km/human km
= 10mg/kg x 3/37= 0.81mg/kg

For an 80 kg adult this would suggest about 65 mg/bid should be a good guesstimate for an appropriate human dose to match mouse results. 50 mg bid is more than 20% less than the effective mouse dose but was a reasonable dose for initial human testing. I think they were hoping to get another point distinct from placebo that might give a sense for the shape of the dose response curve. It's no shocker that the 50 mg or 50 mg bid doses were no different from placebo.

So Phase 2a tested:
50 mg qd(0.625mg/kg)- almost certainly subtherapeutic
50 mg bid (0.625 mg/kg)bid) - getting in range; I'm sure they were hoping this dose would trend higher than placebo.
and 100 mg (1.25 mg/kg) bid - encouraging trend

And comparable to mouse 10mg/kg bid would be about 65 mg bid (0.81mg/kg)

100 mg bid (1.25 mg/kg) is more than 50% higher than mouse 10 mg/kg (0.81 mg/kg).

Phase 2a revealed what I would consider a trend with 100 mg bid dosing which is really what the 2a was meant to do. It provided a rationale for two dosage arms in the powered 2b trial within the presumed therapeutic window. The interesting part to me is that they really don't know that these higher doses are well tolerated and within the therapeutic window but it appears they are basing the higher dosing on Ziagen dosing with abacavir as the major metabolite (as you suggested) and working with a therapeutic window comparable to Ziagen. It makes sense to me that 100 mg bid is on the dose response curve but it's not clear where and what even the rough shape of that curve looks like.

150 mg bid and 200 mg bid should be more effective than the maximum Phase 2a dose of 100 mg bid. We have no way of knowing how much more effective. We also don't know if these dosages will be well tolerated.

If 150 mg bid or 200 mg bid are effective but poorly tolerated, there are strategies to reduce some side effects with a short acting drug while maintaining the total daily dose and possibly improving efficacy. The most obvious strategy would be to maintain the total dose but spread it out over 3 doses (tid vs bid). In general, TID dosing is really difficult for patients. I don't know if this strategy would impact increased liver function tests (LFTs).

Prurisol's short half life (2 hrs) raises multiple dosing strategy questions but the simplest solution is to maximize the tolerated dose with as few doses as possible per day to maintain a higher average serum level through the day. Maximize bid dosing and see if it works.

We'll know soon enough.

Hoping for the best.
biodoc