TriumphSpitSix wrote: Across NSAIDs as a class, liver toxicity is observed within 1 to 3 months of starting the medication.
For individual NSAIDS:
Diclofenac- 2-6 months
Ketoprophen- "within a few days"
Ibuprofen - "within a few days to 3 weeks"
Naproxen- 1-6 weeks
Antibe only has safety/efficacy data out to a max of 14 treatment days (and an additional 14 monitoring days, post dosing) for any of the trials completed to date. The recent Ph2 dose-rangong study and the 2017 GI safety trial were both 14 days. The 2016 efficacy trial was only 10 days.
Since we're using a derivative of Naproxen, that's the time-to-onset range we should be concerned about. We only have 2-weeks of dosing data as it relates to liver tox issues. In Ph3 we could still see liver tox issues that did not arise during any of the completed studies due to its 12 week dosing regime. That's 10 more weeks than we have data for where hepatotoxicity could present. We should be primarily concerned with those first additional 4 weeks given that Naproxen's typical time to onset is 6 weeks at the high end, although issues have been documented first arising as far out as 12 weeks after starting the drug. But, if we get to the 6-week point with no significant adverse events, we're "probably" good.
This is why I have mentioned in multiple of my other posts that the company should be laser-focused on plumbing the depths of the low end of the dosing range. The lower the dose, the less likely the Naproxen component will do its damage.
Even at the expense of some degree of efficacy... safety first, efficacy second.
Sub-100mg should do it!
Pragmatist wrote: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347500/
Two points of note from this recent paper which might be of interest:
6.4. Risk of hepatotoxicity
Clinically apparent liver injury caused by NSAIDs is rare, approximately 1–10 cases per 100,000 prescriptions. Consequently, hepatotoxicity mostly is encountered after a new drug has gone to market, when more data/observations become available.
Oten's elevated liver enzymes in past trials are comparable to other NSAIDs. Assuming this continues, then any liver issues will likey be revealed after FDA aprroval, and likely after ATE achieves its end-game.
7. Pharmacophore modification
"Since H2S has been linked to cardiovascular homeostasis and normal physiology of kidney, H2S prodrugs can be also effective against CVD and renal failure." This is good.
Perhaps thoses can read/understand this paper might have some thoughts?