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May 19, 2004
The Dose Makes the Poison
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!)
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