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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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February 7, 2007

There's Toxicity and There's Toxicity

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Posted by Derek

When a drug candidate runs into toxicity trouble, the first question that comes to everyone's mind in the lab is: mechanism-based or not? If the project is a follow-on compound to something that's already made it to the market, the answer is probably already clear - after all, if the first one was clean, why shouldn't the second one be?

But if you're working on a new target, this is a major headache, with major implications either way. If the tox is related to the compound's mechanism of action, you're probably going to have to abandon the compound, and perhaps abandon any hope of a follow-up while you're at it. A really solid link to trouble can kill a target for you and for everyone else in the industry. That sound like bad news, and in the short run it probably is - but in the long run, it's better to know these things. There are enough things to waste time on already, so getting rid of one isn't such a catastrophe, unless it's your own drug.

On the other hand, if the toxicity isn't mechanism-based, then it's likely due to something odd about the particular compound, some off-target effect that it has. Chasing these things down can be extremely difficult, and often there's no way to really tell what went wrong. You just have to move along another compound, from a different structural series if possible, and hold your breath. At least you know what to look for first. But there's always the horrible possibility that the follow-up compound will show an equally ugly but completely different tox profile, which brings on thoughts of truck-driving school, where you at least would know what the hell is going on.

Of course, the usual reservations apply here (toxicology is full of these). For example, it's always possible that the compound is toxic in one species, but not in another. Happens all the time, actually. But in that case, you'd better have a really, really plausible reason why humans are on the safe side of the line, and convincing ones can be hard to find. Maybe all the problems are caused by a metabolite, and not by the original drug (that one's far from unknown, too). Back to the lab you'll go for that one, too, because you don't know how human will react to the metabolite, and you can't be quite sure how much of it they'll produce relative to the animals, anyway.

Barring these, though, either the compound is dead, or the whole structural class of compounds is dead along with it, or the whole universe of compounds that work the same way is dead. None of those are necessarily appealing, but those are the main choices, and there's nothing written down - anywhere - that says that you have to get one that you like.

Comments (7) + TrackBacks (0) | Category: Drug Development | Toxicology


1. tom bartlett on February 8, 2007 9:08 AM writes...

"it's always possible that the compound is toxic in one species, but not in another."

I've seen this a few times.

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2. Jim Hu on February 8, 2007 1:05 PM writes...

I'm missing something...why does the fact that a drug has made it to market mean that the follow-on won't be clean? I suspect I'm not grasping the technical definitions of "follow-on" and/or "clean" and I'm reacting to the vernacular usages.

As it happens, I'm posting this from the Grace Auditorium at Cold Spring Harbor where Todd Golub from the Broad Institute just gave a drug discovery in academia talk. I love wifi in seminars...

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3. Derek Lowe on February 8, 2007 1:53 PM writes...

What I'm trying to say is that if there's a marketed drug, the mechanism-based toxicity question has probably already been settled, or at least had some clear boundaries placed on it. A follow-up drug's problems, if they occur, have a better chance of being non-mechanism-based.

One exception would be when the attempt at a next generation drug cranks up the effect of the original one to where trouble sets in (for example, like some of the PPAR gamma compounds for diabetes that GSK tried a few years back).

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4. Antibody researcher on February 8, 2007 3:07 PM writes...

Dear Derek & visitors

I am a newcomer to the industry and your blog site and learning a lot about reality from the posts. I would like to have an opinion from the industry veterans like you guys. I did my postdoc in U.S and decided to join biotech industry. I got attracted to biologics, specifically to therapeutic antibodies. Started applying to the US companies and everywhere they turned me down because i didn't have INDUSTRY experience. As a stop gap, i joined an Indian biotech doing antibody stuff. However, i don't get much chance to do real discovery stuff , as the financial shock absorber is pretty thin.too much derisking i guess. Now with one year INDUSTRY experience i am back applying heavily..Funnily now their logic has changed, since i need H1B visa sponsorship to work..i am not welcome. Could you guys let me know whether there is any future for me applying to US companies. Are they all same like i encountered or do they process visa at times.
Thanks, sorry if i bored you guys. Good luck in you job search.

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5. curiousGeorge on February 8, 2007 4:12 PM writes...


I would say that the fact you are here is a very positive sign. I would continue to visit this and related blogs and to apply. In the meantime look at Singapore.

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6. Joseph on February 8, 2007 11:30 PM writes...


The US has reduced the number of visas recently. It used to never be problem when recruiting but this past year we actually considered visa status when looking at candidates. HR had informed us that we would have difficulty obtaining the necessary visas (I work at a major pharma company).

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7. Chrispy on February 9, 2007 3:23 PM writes...


Good luck in your search! This is a very difficult time to find a job in the U.S. due to all the recent layoffs (Pfizer and Bayer mostly). In a year or so, after this bolus of people has been absorbed, things should be a little easier.

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