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August 10, 2005
Another Thing You'd Think Would Be Simple
A little while back, I wrote about combination therapies, and why they're sometimes not pursued. (That question, like so many that begin with "I wonder why they. . .?", has the answer "Money.")
But there are some areas where combinations make sense both medically and financially, and an outstanding one is in antiretroviral therapy. HIV dosing schedules are famously strenuous and complex, and patients (and their insurance companies) are certainly willing to pay for something better. Gilead, about one of whose drugs (Emtriva, emtricitabine) I wrote here, has already combined that one with another drug of theirs (Viread, tenofovir) to make a combination pill sold as Truvada. Now they've been trying to co-formulate that one with Sustiva (efavirenz), from Bristol-Meyers Squibb, to get three agents into one dose.
It's turned out to be harder than it looks. This is their second attempt at getting the combination to show equivalent blood levels to the individual drugs dosed separately, and they still can't get it to work. There are all kinds of reasons why this might be happening - formulation (galenics) is an esoteric science with about as mystic a component as you'll find in the drug industry. Unexpectedly different dissolution rates or effects on each other's solubility, formation of some sort of complex with something else in the gut, competition for the same transport mechanisms across the local area of the gut wall - you could fill up a big sheet of paper with possibilities, and I'm sure that many have been so filled. Gilead isn't saying what they think the problem is, since they have no mandate to satisfy the curiosity of onlookers.
They have said, though, that their next shot is going to be a "bi-layer" formulation, which is about the closest thing to separate dosing that you can do in one pill. Each ingredient will be formulated in the way that suits it best, and the two (completely different) mixtures will be layered one on top of the other and turned into one pill. This is one of the more expensive ways to do it, but it's clearly come to that. Gilead and BMS say that they're going to take three different shots at this technique, and I wish them luck, which is still the most efficacious ingredient in any formulation. Damn stuff is usually on back-order when you really need it, though.
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