HOW MUCH FLUCIDE IS NEEDED FOR THE TOXICOLOGY STUDY?
The problem with this question is they have to do the PK/PD and toxicity studies across 3 species, one of which is usually a large animal, such as a dog. Mice, rats or ferrets and dogs are most common, although mice rats and ferrets have recently been accepted for the 3. Hybridized mice do a great job of estimating human equivalent, as do ferrets while the other two are often used to establish a safe starting dose for the human escalation study since both dogs and rats are usually more sensitive to injected drugs than mice and ferrets, so are considered better indicators for the starting dose in human escalation studies.
Though it would require an enormous amount of material and the maximum amount of time, it would be very cool if all 3 species showed dose equivalents to the earlier tox where mice finally started dying because of blood displacement and rupturing, dose way beyond the maximum feasible dose. On the other hand, because the LD10 for mice was so much higher than the maximum feasible dose, 100 times more material, it's likely that the FDA will only be looking for that or perhaps double that. The most important number would be the safe starting dose rather than the onset of adverse events (no observed adverse events level or NOAEL) divided 10. Across 3 species, that could be near the effective dose range, maybe even above.
What becomes the safe starting dose if the worst performing animal showed conversion equivalent doses that simply plugged arteries, displaced red blood cells, or ruptured organs due to volume? If a safe, but effective, dose in humans is 25 grams, then the dog equivalent would be:
average person = 60kg/25gm = 2.4gm/kg = 1.2gm/kg dog
So, if the 10LD for mice is 10 times the effective dose estimated in human equivalent as 25gm then converting to dogs yields a 10LD of 12gm/kg or 72gm for an 8kg dog. So, 4 animals per dose per sex means 8 animals per dose in the escalation to MTD yields almost a kilogram of material total material in the final dose. Each dose is then repeated 3 times, so ~2.5 kg of material might be needed just for the MTD in dogs. What they might do instead, and there is no way to know without the study protocol, is make the high dose the maximum feasible dose, and then establish that as safe with NOAEL.
Still the entire study of 3 species (mouse, rat, dog), each receiving 3 dose levels (low, medium, and high) for 8 animals per species might require more than 6kg of material produced in 1kg batches.
That's a lot of material, but at the current kilogram production scale, sufficient material could be produced in less than 12 weeks.
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