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August 10, 2005
Another Thing You'd Think Would Be Simple
Posted by Derek
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.
Comments (9)
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1. daen on August 11, 2005 6:54 AM writes...
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.
Permalink to CommentAha! Is that what you've been trying to make in the lab all these months, Derek? :-)
2. SP on August 11, 2005 8:42 AM writes...
Combination therapy has come up several times at the MedChem GRC over the last couple days. Some people are even suggesting that maybe drugs should lack complete specificity so that they hit multiple receptors and have the same effect as combination therapy. Blasphemy!
Permalink to Comment3. Matt Schiller on August 11, 2005 10:14 AM writes...
I think I should point out that the largest selling asthma drug is GSK's Advair (US sales were $3.6B in 2003). It is a combo of fluticasone and salmeterol.
Permalink to Comment4. Ian Ameline on August 11, 2005 11:10 AM writes...
I bet luck is not soluble in water either :-)
Permalink to Comment5. ex-chemguy on August 11, 2005 11:57 AM writes...
For me the problem was that it was never soluble in THF or toluene or methylene chloride or ...
Beginning to remember why I abandoned the bench, i.e. "the scenic detour", for a biopharm marketing gig.
Permalink to Comment6. qetzal on August 11, 2005 11:58 AM writes...
The real problem with pharmaceutical-grade luck is that it's incredibly unstable. Even on those rare occasions when you can get some, it never lasts!
;-)
Permalink to Comment7. PsychicChemist on August 11, 2005 12:15 PM writes...
How about some people always seem to have more luck than others or is that merely a co-incidence.
Permalink to Comment8. SP on August 11, 2005 1:40 PM writes...
I believe the quote is, "Chance favors the well prepared mind." (Louis Pasteur)
Permalink to Comment9. Lou Wainwright on August 11, 2005 1:42 PM writes...
I've always assumed that Advair was pretty easy from a chemistry standpoint. After all, both drugs were previously available in inhaled form, taken one right after each other, and I figured it wasn't too difficult to mix the powders. Was I wrong?
Permalink to CommentThe key to Advair's success (as an early adopter and enthuisast) is the drug delivery model which is near flawless. From the user standpoint it achieves the primary goal of avoiding a seperate mixing chamber, it eliminates an extra inhaler, it is an elegent and easy to cary design, and it is self sealing (preventing you from inhaling lint).
From GSK's perspective it's daily dosing counter forces another refill every 30 days of both drugs. Previously I would have probably stretched the separate inhalers out to an average of 35-40 days. So that's an increase of 20% in refill rate. Plus, I assume that the two drugs don't go into the public domain at the same time, but as long as one of them is GSK IP I'll continue to buy Advair for the convienence. Finally, even once both drugs are public, GSK might be able to keep me buying from them if they've got the drug delivery device well patented.