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FOOD AND DRUG ADMINISTRATION - page 204 / 263

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it changes.  It's a moving target.

And the other thing that was mentioned, TSH changes exponentially with small changes in T4, and in fact, you can have a doubling in TSH for only a 12.5 percent change in T4.

Now, consider the biostudies.  Consider normal volunteers.  T4 is a very, very unusual drug.  Unlike other drugs, if there's too much of it on board, then its clearance increases.  If there's not enough of it, then its clearance decreases.  Think about that in context of a biostudy when you're administering two non-equivalent doses.  The body is going to try very hard to get rid of both of them, but it's going to try harder to get rid of the larger dose.

In the briefing document, I've shown you a graph of what happens to TSH.  I'm going to show you a little bit of a different orientation about TSH response.  We're going to express T4 and TSH as a fold change from baseline in our biostudy.  We're going to invert the TSH ratio because TSH and T4 are reciprocally related.

So these are the results for those three doses.  The thing that you can notice with the high dose,

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