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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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In the Pipeline

« Experimental Update | Main | Our Buddies at the FDA »

July 25, 2002

What to Do When the Rats Die on You

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Posted by Derek

I've had some e-mail asking if the diabetes drug I mentioned the other day is dead or not, and if not, why not. I don't have any direct contacts in the companies involved, not that they'd tell me all about it even if I did, but I can make some informed guesses. They'll illustrate what happens in these cases.

Readers in the industry will know that this situation (dramatically worse tox results in one species versus another) is a common one. You'd think that mice and rats, for example, would be pretty similar, but there are real differences at every level (from gross anatomy to molecular biology.)

To get off topic for a minute, that's one reason that I'm only partially impressed by figures showing how humans and (fill in the species) share (fill in some high percentage) of their DNA sequences. It's interesting, in one way, but the differences that do exist count for an awful lot.

Differences in toxicology between species, of course, are why the FDA (and drug companies themselves) want to see tox results from more than one species. The more, the better. Most of the time, it's rats and dogs, sometimes rats and monkeys, sometimes all three. Mice aren't considered quite as predictive a species - they're OK for rough-and-ready tox screening (and you need a lot less compound to do it that way,) but not for real decision making.

That's why I'm sure that Novo and Dr. Reddy's weren't thrilled at seeing bladder cancer in the rats, with much less of it in the mice. If it had been the other way around, the path forward might have been a little bit easier, but it'd be hard no matter what. Their compound isn't dead yet, I assume. But what it'll need to go forward is an idea of what the mechanism of the carcinogenesis might be.

Is is the parent compound causing trouble, or some metabolite? Which one? How much of it is in the urine, and how long does it stay there? As mentioned the other day, do rats make more of any of the metabolites, or are they just more sensitive to them? And, the big question once those have been answered: what do we know about how humans might behave?

If the companies have a backup compound waiting in the wings, then we can assume that it's already in intense tox trials. If it's clean, then the original drug is dead, of course, and the backup goes on, more or less as if nothing had happened. But the prudent course would be to do the work outlined above anyway, so you can use it to show why you got the clean tox results you did on the new compound. That's the only way to feel really sure.

I've had animal rights people make the argument to me that such differences in toxicity prove that animal models are worthless. Untrue, untrue. Without testing on animals, no one would have known that this compound could cause bladder cancer in any species at all. The known differences between humans and various animals can then be used to estimate the risks if the compounds proceeds.

If there were an in vitroway to determine the risk, we'd all be lining up to use it. It would, by definition, be much faster, much cheaper, and much easier to apply earlier in the project before all that time, money, and effort gets wasted. If PETA and their ilk would like to devote themselves to developing such tests, I'll cheer them on.

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