Desvenlafaxine

Desvenlafaxine

Systematic (IUPAC) name
4-[2-dimethylamino-1-(1-hydroxycyclohexyl) ethyl]phenol
Identifiers
CAS number	93413-62-8
ATC code	N06AX23
PubChem	125017
Chemical data
Formula	C16H25NO2
Mol. mass	263.375 g/mol
Pharmacokinetic data
Bioavailability	80%
Protein binding	Low (30%)
Metabolism	CYP3A4, (CYP2D6 is not involved)
Half life	11 h
Excretion	45% excreted unchanged in urine
Therapeutic considerations
Licence data	US FDA:link
Pregnancy cat.	C(US)
Legal status	℞-only(US)
Routes	Oral

Desvenlafaxine (Pristiq), also known as O-desmethylvenlafaxine, is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class developed and marketed by Wyeth. Desvenlafaxine is a synthetic form of the major active metabolite of venlafaxine (Effexor, Efexor). It is being targeted as the first non-hormonal based treatment for menopause.^[1]

Approval status

Wyeth announced on 23 January 2007 that it received an "approvable" letter from the Food and Drug Administration for desvenlafaxine. Final approval to sell the drug was contingent on a number of things, including:

• a satisfactory FDA inspection of Wyeth's Guayama, Puerto Rico facility, where the drug is to be manufactured;
• several post-marketing commitments;
• clarity by Wyeth around the company's product education plan for physicians and patients;
• approval of desvenlafaxine's proprietary name, Pristiq.^[2]

The FDA approved the drug for antidepressant use in February 2008, and was to be available in US pharmacies in May 2008.^[3]

On February 4, 2009, Health Canada approved use of desvenlafaxine for treatment of depression in Canada.^[4] Pristiq is now available in Canadian pharmacies.

Pharmacology

Desvenlafaxine is a synthetic form of the isolated major active metabolite of venlafaxine, and is categorized as a serotonin-norepinephrine reuptake inhibitor (SNRI). It works by blocking the transporter "reuptake" proteins for key neurotransmitters affecting mood, thereby leaving more active neurotransmitters in the synapse. The neurotransmitters affected are serotonin (5-hydroxytryptamine) and norepinephrine (noradrenaline). It is approximately 10-fold more potent at inhibiting serotonin uptake than norepinephrine uptake. ^[5] When most normal metabolizers take venlafaxine - 70% of the benefit comes from venlafaxine being metabolized into desvenlafaxine so the effects are very similar.^[6]

Side effects

Side-effect profiles were consistent for all three studies evaluated, with nausea being the most profound and prevalent. Although rates varied substantially from study to study, nausea was consistently the most common complaint (30-50% vs placebo 9-11%) and the most common reason for discontinuation.^[7][8][9] Suicidal ideation was monitored and was determined to be significant in 1-2 patients in each study.^[7][8][9] The most commonly observed adverse reactions in Pristiq-treated MDD patients in short-term fixed-dose studies (incidence >= 5% and at least twice the rate of placebo in the 50 or 100 mg dose groups) were nausea, dizziness, insomnia, hyperhidrosis, constipation, somnolence, decreased appetite, priapism, night terrors, anxiety, and delayed ejaculation.^[10] These side-effect patterns are consistent with those of other SNRIs venlafaxine (Effexor) and duloxetine (Cymbalta, Yentreve).^[11][12] Relative rates are not available, as there were no head-to-head studies.

Wyeth Pharmaceuticals also reports the following as potential side effects:^[13] headache, sweating, diarrhea, hypertension, abnormal bleeding and/or bruising, glaucoma, increased cholesterol and triglyceride levels, low sodium levels in the blood, and seizures. Pristiq has also been implicated with higher rates of discontinuation syndrome than are seen with other SSRI and SNRI antidepressant medications due to its short half-life. Discontinuation syndrome side effects can be so severe as to be described as "intolerable" by former users, with some individuals unable to cease use due to extremely long-term withdrawal symptoms following cessation of use.^[14]

Clinical efficacy

Pristiq tablets

Internal validity

In published phase III Trials, desvenlafaxine was compared only to placebo. In these trials, primary endpoints were powered to measure a reduction in depression (HAM-D17) scores^[7][8][9] and not the standard response measure of >=50% reduction in depression scores.^[15]

Response scores were secondary measures which the studies may or may not have been powered to address. These trials showed dose-erratic reductions in HAM-D17 scores, reductions which undermined the results. Response rates varied from 43-60%, lower than most current antidepressants, which have a 60-70% response rate.^[15] Remission rates of 23-37% for desvenlafaxine are also lower than those of other antidepressants, which have rates of 30-40%. Of course, generalizations of this nature cannot be made without careful statistical testing, and such testing was beyond the scope of this project.

Treatment duration for the three reviewed trials seemed inadequate, given the staging of Major Depressive Disorder (MDD). MDD acute phase lasts 12 weeks, while all three reviewed studies treated patients for only 8 weeks.^[15][16] Although it may not be practical or required to conduct a study of continuing therapy for an entire year, without the data that would result it is difficult to determine whether or not desvenlafaxine is an appropriate therapy.

External validity

There may be some differences in efficacy across ethnic backgrounds. One study, with three different dose strengths, showed efficacy in the 100mg and 400mg doses, but no efficacy in the 200mg dose. This group had a notably higher proportion of blacks and Hispanics than the other two active groups. The only other study which listed ethnic distributions had a notably higher proportion of blacks and Hispanics in the placebo group vs. the active group. Although kinetic studies have indicated there are no known active metabolites for desvenlafaxine, the possibility of ethnic variations in response cannot be ruled out.^[17]

References

External links

• Pristiq Official Site