This afternoon the FDA released a statement about the Celebrex news from this morning. This clears things up a bit, but it means that the agency (and Pfizer) have some very hard decisions to make.

There appears to have been a clear dose dependence in the elevated cardiovascular risks. At 400 mg b.i.d. (twice a day), the treatment group showed 3.4 times the risk of the placebo group. At 200 mg b.i.d., the risk was 2.5x. The average duration of treatment was 33 months - pretty substantial, but a lot of people take Celebrex for an extended period for pain relief.

Now, Pfizer has stated that another trial at a similar dose has shown no indication of cardiovascular trouble, and that's true as far as it goes - it's a 400 mg trial, but the drug is dosed q.d. (once a day). How can 400 mg act so differently, taken all at once versus split up? My industry colleagues are already nodding their heads at the probable answer. The difference is coverage.

Coverage, as in how high the blood levels are, for how long - what pharmacologists call AUC (area under the curve) in a blood-level versus time plot. A single 400 mg dose of a typical drug will spike right up as it gets absorbed and hits the bloodstream in a big initial wave, then the line will decay down over several hours, eventually back to uselessly low levels. Ideally, that still works out to decent coverage of the drug's target for a once-a-day dose.

Taking that same drug twice a day at half the dose means that you never hit that maximum level you would in the first dosing regime, but you cover the target longer at pharmacologically active levels. Some drugs work better one way, some the other. And some drugs work differently all by themselves when they're dosed in those two kinds of regimens. It would appear that Celebrex is more worrisome when it covers its targets for longer continuous periods, rather than hitting higher levels but then going away. Perhaps in the latter case things have a chance to get back to normal before the next dose hits, but not in the multiple-dosing protocol.

If this is the case, it's going to be tough figuring out what to do. The FDA is already saying:

"Physicians should consider this evolving information in evaluating the risks and benefits of Celebrex in individual patients. FDA advises evaluating alternative therapy. At this time, if physicians determine that continued use is appropriate for individual patients, FDA advises the use of the lowest effective dose of Celebrex."

I won't mince words: to me, this looks like the first step to pulling the drug. At the very least, I think its use is going to be severely restricted. The fallout? I'll be intensely surprised if Novartis goes ahead with their planned launch of their own COX-2 drug, for one. And Pfizer is looking at some severe trouble, because they're so huge that they need a constant infusion of billion-dollar drugs just to stay where they are. I've never been able to figure out where those were supposed to come from. And I sure can't figure out how they can afford to lose one.