I haven't gotten
back to
the "selection of antidepressants" series. Mostly that is
because, alphabetically, the next one is supposed to be citalopram.
While citalopram
(Celexa™)
is a perfectly fine antidepressant, it is kind of boring.So to spice things up a little bit, I'm going to jump ahead to desvenlafaxine. This is a drug that is in development by Wyeth. They plan to market it with the brand name, Pristiq™. The FDA issued an "approvable" letter in January of 2007. While this is not a guarantee, it does mean that the product is highly likely to reach the market. Rumor has it that it will be on pharmacy shelves in a couple of months.
I have to study up on new products anyway, preferably before they hit the market. So I might as well get a blog post out of it.
Desvenlafaxine
is similar to venlafaxine (Effexor™,
Effexor XR™),
which has been on the market for
about 14 years. As the name suggests, it is the same as
venlafaxine except for the removal of a methyl group. The
structure on the right shows venlafaxine, with the methyl group
attached to the oxygen atom on the bottom. Desvenlafaxine is
an
active metabolite of venlafaxine. What this means is that
when
people take venlafaxine, it is broken down, in the liver, to
desvenlafaxine. Thus, all of the millions of persons who have
taken venlafaxine have been exposed to desvenlafaxine. This
attenuates, somewhat, any concerns we might have about unexpected
hazards.Naturally, this will lead to suspicion that desvenlafaxine is a "me-too drug." That is, there will be allegations that it is not a significant advance, being so similar to other products already on the market. I would say this: desipramine is the same as imipramine, except it is missing a methyl group. Yet the two drugs have distinct pharmacological profiles. More importantly, there are some people who respond to one, but not the other. In turn, imipramine is the same as clomipramine, except it is missing a chlorine atom. There are significant differences between the two drugs. So I would not be quick to dismiss desvenlafaxine as a minor change.
The argument about me-too drugs primarily concerns medical economics. The patent is about to run out on venlafaxine, so one could allege that Wyeth came up with a minor reformulation so they can have a patented product on the market. Likely, there is some truth to that. But there is another side to this argument. There still are a lot of people who do not have an entirely satisfactory outcome with any of the available drugs. Having another drug available is likely to expand the percentage of people who can have a satisfactory outcome, even if by only a few percentage points. If this turns out to be the case, it is worth a lot.
Yeah, the company will make billions from this. But the high price will only last a couple of decades. Presumably, humans will be around a lot longer than that. And it is safe to assume that will still will be dealing with depression for a long time.
So how does this stuff work? As it happens, like with any of these things, we know a lot about what it does to small groups of neurons. That do not really tell us how it works on the organ level (that is, with the entire brain), but it will be a while before we understand that (if we ever do).
Desvenlafaxine inhibits reuptake of both norepinephrine and serotonin. The current lingo for that is SNRI: serotonin-norepinephrine reuptake inhibitor. To that extent, it is like venlafaxine and duloxetine (Cymbalta™). It also has a weak effect on dopamine reuptake, although that is not thought to be a big part of its effect. (I would not dismiss this entirely, though.)
The detailed pharmacology is outlined in this article:
Desvenlafaxine Succinate: A New Serotonin and Norepinephrine Reuptake Inhibitor
Journal of Pharmacology And Experimental Therapeutics
First published on May 4, 2006;
DOI: 10.1124/jpet.106.103382
Darlene C. Deecher, Chad E. Beyer, Grace Johnston, Jenifer Bray, S. Shah, M. Abou-Gharbia, and Terrance H. Andree
The purpose of this study was to characterize a new chemical entity, desvenlafaxine succinate (DVS). DVS is a novel salt form of the isolated major active metabolite of venlafaxine. Competitive radioligand binding assays were performed using cells expressing either the human serotonin (5-HT) transporter (hSERT) or norepinephrine (NE) transporter (hNET) with Ki values for DVS of 40.2 ± 1.6 and 558.4 ± 121.6 nM, respectively. DVS showed weak binding affinity (62% inhibition at 100 µM) at the human dopamine (DA) transporter. Inhibition of [3H]5-HT or [3H]NE uptake by DVS for the hSERT or hNET produced IC50 values of 47.3 ± 19.4 and 531.3 ± 113.0 nM, respectively. DVS (10 µM), examined at a large number of nontransporter targets, showed no significant activity. DVS (30 mg/kg orally) rapidly penetrated the male rat brain and hypothalamus. DVS (30 mg/kg orally) significantly increased extracellular NE levels compared with baseline in the male rat hypothalamus but had no effect on DA levels using microdialysis. To mimic chronic selective serotonin reuptake inhibitor treatment and to block the inhibitory 5-HT1A autoreceptors, a 5-HT1A antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclo hexanecarboxamide maleate salt (WAY-100635) (0.3 mg/kg s.c.), was administered with DVS (30 mg/kg orally). 5-HT increased 78% compared with baseline with no additional increase in NE or DA levels. In conclusion, DVS is a new 5-HT and NE reuptake inhibitor in vitro and in vivo that demonstrates good brain-to-plasma ratios, suggesting utility in a variety of central nervous system-related disorders.
The half-life of a sustained-release preparation of desvenlafaxine is 9 to 11 hours. The time to maximum concentration (Tmax) in blood occurs 6 to 8 hours after a dose. Note that this study was done with only 79 male persons. Different people may have different results. Absorption is about 80%. The Tmax is delayed by two hours if the preparation is taken with food, but the extent of absorption is not affected by food. Mild hepatic impairment is not significant. The drug can be used in persons with moderate to severe hepatic impairment, but the kinetics are different. CYP 2D6 polymorphisms do not affect [PDF link] the pharmacokinetics of desvenlafaxine. Furthermore, it is not highly protein-bound. It appears that the potential for drug-drug interactions is low.
Adverse effects? Yeah, especially nausea, headache, etc. Nothing surprising. Dropout rates are the bottom-line indication of the likely adverse effect burden, and the dropout rate is said to be comparable to other SNRIs. Weight gain? One study indicates "no major weight gain" over 9 months of treatment.
Premarketing efficacy studies indicate that desvenlafaxine works about as well as any other antidepressant, in a population of depressed patients. Of course, once in is on the market, Wyeth will conduct trials to see if they can demonstrate superior efficacy. Some of the premarketing studies are summarized briefly here.
Is there anything interesting about this drug, something that distinguishes it from others in a clear manner? Nothing dramatic, at this point. What I notice is that Wyeth has adapted a new marketing strategy. In the past, a company typically would get the drug on the market for only only indication. After some years, they would add another, then another, and perhaps more. Partly, this would be done to better position themselves in the market. Also, it could extend the period of exclusive marketing.
The marketplace is very different now. There are many good generic antidepressants. If a drug does not have something distinctive at the outset, it will be hard for it to get a place on an insurance formulary.
Wyeth has already done investigations to show that desvenlafaxine can be helpful for perimenopausal or postmenopausal hot flashes. They are trying to position the drug as the first nonhormonal treatment for such vasomotor symptoms. In July 2007, they were given an approvable letter for this indication.
Never mind that its predecessor, venlafaxine, is already used for this purpose. There is no FDA indication for use of venlafaxine for hot flashes.
As it happens, depressed, middle-age women are a large part of the antidepressant market. So having both indications for one drug could be just what they need to gain a spot on insurance formularies.
Wyeth also went after the pain market, doing studies intended to show that desvenlafaxine is good for fibromyalgia. Despite some early success, that has not panned out. At least, is does not look as though the data will be good enough to get an FDA indication right out of the gate.
Overall, it appears that desvenlafaxine will be a useful addition to the collection of existing antidepressants. Not revolutionary, but good to have around.
Comments
Since the drug is similar to Effexor, is it likely to have the same "withdrawal" issues when a patient goes off of it? Missing a dose of Effexor creates lousy side affects for a significant portion of patients. Going off it, one has to go through the same side affects. Dizziness, wooziness, wierd electric shock sensations to the back of the neck/base of the skull, confusion and "fuzzy headed" feelings are some of the complaints.
If this new drug does *not* have these affects, that will create a HUGE market edge.
Posted by: Kelly | December 12, 2007 10:20 AM