The first deuterated drug has finally been approved by the FDA. It’s Austedo (deutetrabenazine), from Teva (NYSE:TEVA), and it targets Huntington’s chorea. This is an interesting development on several levels. The idea of adding deuteriums (instead of plain hydrogens) to drug structures had been kicking around for many years, but only in the last 8 or 10 years has serious development been underway on them.

Some readers outside the field may be wondering what the big deal is, so here’s a bit of background. Deuterium is the (fairly well known) “heavy hydrogen” isotope of regular hydrogen, which is heavy because it has another neutron in it. That basically doubles its weight (the single electron in the atom is a roundoff error in that regard), so these two are an isotope pair with a large percentage difference in weight indeed. (Hydrogen to tritium, the two-neutron isotope, is the single biggest weight percentage change, but tritium is radioactive and is thus out of the running for the use we’re discussing). The reason this weight difference makes a difference is when a bond breaks between the hydrogen (or deuterium) and another atom. The bond is actually harder to break with the heavier isotope, an effect that can be modeled surprisingly well with springs and fishing weights. This is the “primary kinetic isotope effect”, and if that bond-breaking is an important step in some process, you can slow the whole works down by just putting in a D where an H used to be. For drugs, the key is that many of them are metabolized and destroyed when they hit they liver, and this is often done through breaking a C-H bond. So a well placed deuterium (or two, or three) can actually have a significant effect on how long a drug will circulate in the bloodstream, by slowing down the liver’s clearance mechanism.

So Teva’s drug is a version of tetrabenazine, an older compound which has been used for several years as a treatment for movement disorders. The structure has two methoxy groups on its aryl ring, and that’s where one set of metabolizing enzymes hit – as is so often the case, the methoxys are demethylated to the phenol/catechol. Such structures are almost invariably cleared out with dispatch, generally through attaching some other group (like a glucuronic acid) on the phenolic OH, which is pretty much like slapping a red disposal tag on a molecule as far as the kidneys are concerned. Deutatetrabenazine switches both from OCH3 to OCD3, and that’s enough to slow the compound’s clearance down to a useful degree. Actually, both the plain and the deuterated forms of tetrabenazine first get metabolized through reduction of the carbonyl group. That gives you two isomers, only one of which is active, and these are the ones whose methoxy groups get chewed off – it’s the prolongation of the active metabolite’s lifetime that really gives the deuterated form a dosing advantage. Importantly, slowing down that step also give a lot less variability in blood levels, patient-to-patient.

At the site of action, the transporter VMAT-2, both drugs would appear to be basically identical, which is what you’d expect (tetrabenazine is not hugely effective, but it does help). Deuterium is the same size as hydrogen and has the same polarity (or lack of it); it’s just the weight that’s different, and that shows up only when a bond to it is being broken or formed. (Update: see the comments for testimony from analytical chemists that deuterated compounds can act a bit differently, though). That’s the reason that so many people have been looking at deuteration, actually. There’s an excellent chance that if you pick your cases carefully, that you will have a drug that does exactly what a nondeuterated form does, but just lasts longer. This does not always work – nothing always works – because a leader in this area (Concert Pharmaceuticals) had their lead deuterated drug (CTP-499) wipe out in clinical trials a couple of years ago.

In this instance, all that metabolic processing actually slowed down the drug’s path to the market, since last summer Teva was asked by the FDA for more data on the levels of the various metabolites. That didn’t need a new trial, fortunately – the samples and data were still there to be rooted through from the earlier work – but it did slow things down by nine months or so. There are several other deuterated drugs in various pipelines, and the idea itself is now so common that there are likely to be a small but steady number of them hitting the market in years to come.

Disclosure: None.



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