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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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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

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May 19, 2004

The Dose Makes the Poison

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Posted by Derek

If you want to fake it and pass yourself off as a drug discovery scientist - which will cause the velvet ropes to just disintegrate at all the exclusive clubs - then one phrase you can drop is "TI". As in "We need to get the TI up for that", or "What's their TI?" It stands for "Therapeutic Index".

That's just the ratio between the toxic dose of a substance and the medically effective dose. Of course, those can be rather contentious terms, and some arguing goes on during drug development about where to draw the lines. But usually both of them are determined through testing a broad range of doses, and finding out what the dose is to get your desired response in 50% of the animals tested (the ED50) and, at the high end, doses that show the the corresponding onset of tox symptoms and your TD50. A ratio of the TD50 to the ED50 is the classic therapeutic index. More technical details (PDF) are here.

Things get hairy when the efficacy and toxicity start varying between animal models. Sometimes there's more than one kind of toxicity, with different effects that show up in different species, or sometimes it's just because one type of animal is just more sensitive. (Dogs, for example, are famously sensitive to cardiovascular side effects.) If one species shows a nasty TI, you'd better be able to explain it, and explain why you think it isn't relevant to human trials, or your development group isn't going to pick up the phone.

So what's a good TI? Depends on the disease. A value of 2 is cutting things very close, and you're probably going to only get that through when treating something bad. Better to have a minimum of 5 or 10 if you can get it, and the higher the better. No one will give you much trouble with a TI on up in the double digits, unless your toxic effect, when it finally shows up, is something especially heinous.

As you'd guess, the oncology field is famous for narrow TIs, thus all the careful clinical titrating of chemotherapies. Some other classic drugs with rather narrow windows are lithium carbonate for depression and coumadin (warfarin) for blood pressure. Interestingly, aspirin has a narrow TI for an over-the-counter medicine, what with all the gastric and platelet-inhibition effects. While it's a great drug, I really doubt that it would have been developed under current conditions, at least not as we use it now. Is that good (we're safer now!) or bad (how many good drugs are we missing!)

Comments (3) + TrackBacks (0) | Category: Toxicology


COMMENTS

1. Doug Sundseth on May 19, 2004 12:37 PM writes...

I'm sure that TD50 (ED50, LD50) is a useful concept, but how sharp do those bell curves tend to be? What sort of ratios would you expect to see between, say, TD50 and TD10 or TD1? Or ED or LD, for that matter.

Does the TI reflect (generally) the safe/toxic dose ratio in individual subjects, or is it a population average only?

IANAChemist, but I am interested, since these would seem to have implications for my (notionally 8-) continued health.

Permalink to Comment

2. Derek Lowe on May 19, 2004 1:20 PM writes...

Good questions. When the curves aren't sharp, then you do have to be cautious in interpreting the data. The PDF link above gives some details on alternate approaches.

For most of drug development, the TI is an animal-based determination. There's a lot of accumulated data on how to extrapolate it to humans, which technique works fairly well until it doesn't. In humans, the doses are only pushed until (at most) the very outer fringes of toxicity are skirted, compared to what's explored in animal studies.

So it's necessarily a population average, and the human data are only roughly there by the time you go through clinical trials. You can see if there are huge problems out there, and you can see if things are in line with what you saw in animal studies, but no clinical trial is ever going to match the breadth and depth of the data that accumulate once the drug makes it to market.

And even then, individual patients are unique. For some drugs, the average TI sits in the middle of a lot of variance, and both doctor and patient have to keep their eyes open. Toxicology is the very model of an inexact science. . .

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3. Roger Bigod on May 23, 2004 6:52 AM writes...

Pedantic points: lithium is for mania or the manic side of bipolar disorder. Coumadin is an anti-coagulant, not a treatment for hypertension. The background is that some clotting factor proteins are modified covalently after synthesis and this step is necessary for activity in the clotting cascade.

The clinical significance depends on the side effect. For lithiuum, the early side effects are tolerable (hypothyroidism, excessive production of dilute urine) but significant in a drug that's taken chronically. I've seen a TI of 2 quoted.

For coumadin, the clinical issue is that the end-point is significant bleeding, but the thing measured is the prothrombin time. So there's another level of analysis in what prolongation of pro time is effective versus dangerous. In real life, physicians just remember two values for pro time, the effective number and the danger flag number, and adjust doses accordingly. Obviously, there are non-linear relationships between dose/clotting factors, clotting factors/pro time, and pro time/risk. The TI may be something like 2 if you use easy bruising as the cut-off. Luckily, it's probably greater using hemorrhagic stroke, which is effectively the onlly irreversible complication.

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