30 June 2007

drug + drug = better drug

Old Drugs In, New Ones Out -- from today's New York Times.

A field known as combinatorial chemistry has recently emerged. Many molecules have similar "backbones" to each other and only differ in, say, a few groups of atoms hanging off of the end; the canonical example are proteins, which are built up from just twenty different amino acids. The amino acids all look like the image at the left, differing only in the group called "R". The actual protein is made up by sticking these molecules together via peptide bond formation, which eliminates the -OH group at the right end and one of the hydrogen atoms at the left end, bonding the carbon and nitrogen in adjacent amino acids together directly.

In drug design, it seems that what's often considered is the pharmacophore -- basically, the "business end" of a molecule. If you synthesize a bunch of molecules that are the same at one end but different at the other end, well, that means that the "business end" won't be exactly the same in each instance, and some might be better than others.

But what they're doing now takes this to a new level. Drugs that have already been created are now being combined with other drugs -- not chemically, just being put in the same pill. (Although sometimes more subtly than just throwing them both in, which means that you can't just take the two pills separately.) And of course, there are a lot of combinations you can get this way. What's more, the combinations aren't what a mathematician would call "linear" -- if you take a drug that does A, and a drug that does B, and stick them together, you don't always get a drug that does A-and-B. For example, one drug mentioned by the article -- Avanir's Zenvia -- takes a cough suppressant and a drug used to treat heart rhythm disturbances, and gets out a drug to stop uncontrolled laughing and crying. Predicting which combinations of drugs will have effects like this is tricky, and a lot of the work is in screening the combinations. But synthesizing all those combinations is also hard. Here's a patent for robotic synthesis.

One company, CombinatoRx, got my attention because their name is pronounced like the word "combinatorics". The article states that their current research program is to take two thousand generic drugs, make all possible pairs, and screen them to see if they do anything interesting; then develop the interesting drugs. There are two million possible pairs of drugs. They test "several thousand pairs of medicines a day". How long can this last? Well, if you assume "several thousand" means "two thousand", then it can last a thousand days. (Presumably they could expand their library of generic drugs, though.)

The next step would then be to try three-part drugs -- with the same library, you'd have about 1.3 billion of them. At 2000 combinations tested a day, that would take about two thousand years to test.

For a triple combination, the F.D.A. might want evidence that the trio is better than not only the individual parts but also better than any of the possible pairs. Showing that would require huge and costly clinical trials.

One wonders if it would be as huge and costly as implied here. My instinct is that combinations of three, four, or more drugs would come from adding a single drug to an already existing combination -- or, in the case of four-part drugs, taking two two-part drugs and putting them together. So some of the testing would already be done. From what I've heard about the FDA, though, they're likely not to care.

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