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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: derekb.lowe@gmail.com Twitter: Dereklowe

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January 29, 2008

The Animal Testing Hierarchy

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Posted by Derek

I've had some questions about animal models and testing, so I thought I'd go over the general picture. As far as I can tell, my experience has been pretty representative.

There are plenty of animal models used in my line of work, but some of them you see more than others. Mice and rats are, of course, the front line. I’ve always been glad to have a reliable mouse model, personally, because that means the smallest amount of compound is used to get an in vivo readout. Rats burn up more hard-won material. That's not just because they're uglier, since we don’t dose based on per cent ugly, but rather because they're much larger and heavier. The worst were some elderly rodents I came across years ago that were being groomed for a possible Alzheimer’s assay – you don’t see many old rats in the normal course of things, but I can tell you that they do not age gracefully. They were big, they were mean, and they were, well, as ratty as an animal can get. (They were useless for Alzheimer's, too, which must have been their final revenge).

You can’t get away from the rats, though, because they’re the usual species for toxicity testing. So if your pharmacokinetics are bad in the rat, you’re looking at trouble later on – the whole point of tox screens is to run the compound at much higher than usual blood levels, which in the worst cases you may not be able to reach. Every toxicologist I’ve known has groaned, though, when asked if there isn’t some other species that can be used – just this time! – for tox evaluation. They’d much rather not do that, since they have such a baseline of data for the rat, and I can’t blame them. Toxicology is an inexact enough science already.

It’s been a while since I’ve personally seen the rodents at all, though, not that I miss them. The trend over the years has been for animal facilities to become more and more separated from the other parts of a research site – separate electronic access, etc. That’s partly for security, because of people like this, and partly because the fewer disturbances among the critters, the better the data. One bozo flipping on the wrong set of lights at the wrong time can ruin a huge amount of effort. The people authorized to work in the animal labs have enough on their hands keeping order – I recall a run of assay data that had an asterisk put next to it when it was realized that a male mouse had somehow been introduced into an all-female area. This proved disruptive, as you’d imagine, although he seemed to weather it OK.

Beyond the mouse and rat, things branch out. That’s often where the mechanistic models stop, though – there aren’t as many disease models in the larger animals, although I know that some cardiovascular disease studies are (or have been) run in pigs, the smallest pigs that could be found. And I was once in on an osteoporosis compound that went into macaque monkeys for efficacy. More commonly, the larger animals are used for pharmacokinetics: blood levels, distribution, half-life, etc. The next step for most compounds after the rat is blood levels in dogs – that’s if there’s a next step at all, because the huge majority of compounds don’t get anywhere near a dog.

That’s a big step in terms of the seriousness of the model, because we don’t use dogs lightly. If you’re getting dog PK, you have a compound that you’re seriously considering could be a drug. Similarly, when a compound is finally picked to go on toward human trials, it first goes through a more thorough rat tox screen (several weeks), then goes into two-week dog tox, which is probably the most severe test most drug candidates face. The old (and cold-hearted) saying is that “drugs kill dogs and dogs kill drugs”. I’ve only rarely seen the former happen (twice, I think, in 19 years), but I’ve seen the second half of that saying come true over and over. Dogs are quite sensitive – their cardiovascular systems, especially – and if you have trouble there, you’re very likely done. There’s always monkey data – but monkey blood levels are precious, and a monkey tox screen is extremely rare these days. I’ve never seen one, at any rate. And if you have trouble in the dog, how do you justify going into monkeys at all? No, if you get through dog tox, you're probably going into man, and if you don't, you almost certainly aren't.

Comments (8) + TrackBacks (0) | Category: Animal Testing | Drug Assays | Drug Development | Pharmacokinetics | Toxicology


COMMENTS

1. milkshake on January 29, 2008 9:07 AM writes...

we have been working on compounds that act on cell-level stress signaling. Turns out the levels of the phosphorylated proteins in brain depend on enviroment and mice are nervous creatures: very easy-to-frighten animals. The bioassay numbers got more consistent only after the mice were aclimatised to their surroundings, trained to be hand-handled. They had to bed kept in the minimal-possible stress environment (no lound noises, bright lights, location isolated from smells and sounds of other rodents etc)

At our previous company they made elementary error when going to the clinic: the cancer compound candidate was efficacious in rodents and worked well in dog models but failed in humans because it was strongly plasma protein bound (it had carbpxylic acid) and it was even more so in human plasma - so much so that the effective concentration of unbound drug could not be achieved in humans.

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2. no one of significance on January 30, 2008 12:36 PM writes...

There's a typo in the post title.

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3. srp on January 30, 2008 7:56 PM writes...

Is there any actual evidence--controlled studies or opportunity samples--that show that things that don't work in rats or mice likely won't work in humans? At a more primitive level, what are the mouse/rat, rat/dog, etc. conditional probabilities in each direction? I'm willing to grant that animal analogues are more believable for safety than for efficacy issues, but even there I'm skeptical.

We know, per Derek, that aspirin is a great drug in humans that couldn't get through the various animal screens today. Isn't that a big, clanging alarm bell? How many other good drugs get flushed (and bad drugs get pushed on to clinical trials) with very little evidentiary basis?

Sorry for all the questions, but they're not entirely rhetorical. It may be that there is some trove of evidence that we outsiders are unaware of. It just bugs me that we have this sophisticated double-blind testing regime for efficacy at the human stage and what seems like a very crude and untested protocol before getting to the human stage.

And please, don't tell me about the institutional realities of lawsuits and the risk-averse FDA; if the scientific basis for these things could be proven false, then we could set about changing those institutional realities. On the other hand, if we really believe that the animal screens are good science--not just customary and comfortable, but well-supported good science--then we could go on with the status quo in good conscience.

Permalink to Comment

4. srp on January 30, 2008 8:00 PM writes...

Is there any actual evidence--controlled studies or opportunity samples--that show that things that don't work in rats or mice likely won't work in humans? At a more primitive level, what are the mouse/rat, rat/dog, etc. conditional probabilities in each direction? I'm willing to grant that animal analogues are more believable for safety than for efficacy issues, but even there I'm skeptical.

We know, per Derek, that aspirin is a great drug in humans that couldn't get through the various animal screens today. Isn't that a big, clanging alarm bell? How many other good drugs get flushed (and bad drugs get pushed on to clinical trials) with very little evidentiary basis?

Sorry for all the questions, but they're not entirely rhetorical. It may be that there is some trove of evidence that we outsiders are unaware of. It just bugs me that we have this sophisticated double-blind testing regime for efficacy at the human stage and what seems like a very crude and untested protocol before getting to the human stage.

And please, don't tell me about the institutional realities of lawsuits and the risk-averse FDA; if the scientific basis for these things could be proven false, then we could set about changing those institutional realities. On the other hand, if we really believe that the animal screens are good science--not just customary and comfortable, but well-supported good science--then we could go on with the status quo in good conscience.

(BTW, check spelling on "hierarchy" in the post title. Although I kind of like what you have--"Rule by the inheritors" would probably be the translation.)

Permalink to Comment

5. srp on January 30, 2008 8:02 PM writes...

(Minor typo in title: it's "hierarchy.")

Is there any actual evidence--controlled studies or opportunity samples--that show that things that don't work in rats or mice likely won't work in humans? At a more primitive level, what are the mouse/rat, rat/dog, etc. conditional probabilities in each direction? I'm willing to grant that animal analogues are more believable for safety than for efficacy issues, but even there I'm skeptical.

We know, per Derek, that aspirin is a great drug in humans that couldn't get through the various animal screens today. Isn't that a big, clanging alarm bell? How many other good drugs get flushed (and bad drugs get pushed on to clinical trials) with very little evidentiary basis?

Sorry for all the questions, but they're not entirely rhetorical. It may be that there is some trove of evidence that we outsiders are unaware of. It just bugs me that we have this sophisticated double-blind testing regime for efficacy at the human stage and what seems like a very crude and untested protocol before getting to the human stage.

And please, don't tell me about the institutional realities of lawsuits and the risk-averse FDA; if the scientific basis for these things could be proven false, then we could set about changing those institutional realities. On the other hand, if we really believe that the animal screens are good science--not just customary and comfortable, but well-supported good science--then we could go on with the status quo in good conscience.

Permalink to Comment

6. Rachel on June 10, 2008 9:30 AM writes...

Animal testing is worng

Permalink to Comment

7. Anonymous on March 22, 2009 10:19 AM writes...

animal testing will be obsolete in a few years...drug development is gearing up by using stem cells. stem cell innovations SCLL. www.activtox.com.

Permalink to Comment

8. Chemjobber on March 22, 2009 11:56 AM writes...

Really, anonymous? How much should I buy? Will I be rich today or tomorrow?

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