Selection of Antidepressants: Desvenlafaxine (Pristiq)

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 href="http://en.wikipedia.org/wiki/Citalopram">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 href="http://en.wikipedia.org/wiki/Desvenlafaxine" rel="tag">desvenlafaxine.
 This is a drug that is in development by href="http://www.wyeth.com/" rel="tag">Wyeth.
 They plan to market it with the brand name, href="http://www.wyeth.com/news?nav=display&navTo=/wyeth_html/home/news/pressreleases/2007/1169585239706.html">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™ tabindex="0" accesskey="c" title="">,
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 " href="http://hcrenewal.blogspot.com/2005/10/most-drug-expenditures-for-me-too.html">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:

href="http://jpet.aspetjournals.org/cgi/content/full/318/2/657">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 href="http://www.nature.com/clpt/journal/v77/n2/abs/clpt2005111a.html">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 href="http://www.nature.com/clpt/journal/v79/n2/abs/clpt2006108a.html">not
significant.
 The drug can be used in persons with moderate to severe
hepatic
impairment, but the kinetics are different.  CYP 2D6
polymorphisms
href="http://www.cri-research.net/newsletter/NewsletterSpring07.pdf">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 " href="http://www.docguide.com/news/content.nsf/news/852571020057CCF6852573990062F634">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 href="http://psychiatricresourceforum.blogs.com/my_weblog/2007/05/desvenlafaxine.html">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 href="http://salesandmarketingnetwork.com/news_release.php?ID=2021151">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 href="http://www.docguide.com/news/content.nsf/news/852571020057CCF6852573990069E3B6">early
success,
that has href="http://www.pharmaceutical-business-review.com/article_feature.asp?guid=E05F6B48-41A4-4721-BCBF-E2139AE3C92D">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.