Flibanserin

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Flibanserin
Flibanserin.svg
Flibanserin ball-and-stick model.png
Systematic (IUPAC) name
1-(2-{4-[3-(Trifluoromethyl)phenyl]piperazin-1-yl}ethyl)-1,3-dihydro-2H-benzimidazol-2-one
Clinical data
Trade names Girosa
Legal status
  • Investigational
Routes of
administration
Oral
Identifiers
CAS Registry Number 167933-07-5 YesY
ATC code None
PubChem CID: 6918248
IUPHAR/BPS 8182
ChemSpider 5293454 YesY
UNII 37JK4STR6Z YesY
KEGG D02577 YesY
ChEMBL CHEMBL231068 YesY
Chemical data
Formula C20H21F3N4O
Molecular mass 390.40 g/mol
 YesY (what is this?)  (verify)

Flibanserin (INN, USAN) (developmental code name BIMT-17; proposed trade names Girosa and Addyi) is a drug that is being studied as a non-hormonal treatment for pre-menopausal women with hypoactive sexual desire disorder (HSDD).[1][2] Development by Boehringer Ingelheim was halted in October 2010 following a negative evaluation by the U.S. Food and Drug Administration.[3] The rights to the drug were then transferred to Sprout Pharmaceuticals, which is continuing the drug development process.

The medication increases the number of satisfying sexual events per month by about one half to one over placebo from a starting point of about two to three.[4]

HSDD was recognized as a distinct sexual function disorder for more than 30 years, but was removed from the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders in 2013, and replaced with a new diagnosis called female sexual interest/arousal disorder (FSIAD).[5][6]

Effectiveness[edit]

The medication increases the number of satisfying sexual events per month by about one half to one over placebo from a starting point of about two to three.[4]

Trials involving more than 5,000 pre-menopausal women with generalized acquired hypoactive sexual desire disorder (HSDD) demonstrated that:[7][8]

Although the two North American trials that used the flibanserin 100 mg qhs dose showed a statistically significant difference between flibanserin and the placebo for the endpoint of [satisfying sexual events], they both failed to demonstrate a statistically significant improvement on the co-primary endpoint of sexual desire. Therefore, neither study met the agreed-upon criteria for success in establishing the efficacy of flibanserin for the treatment of [Hypoactive Sexual Desire Disorder].

The women receiving flibanserin reported that the average number of times they had “satisfying sexual events” rose from 2.8 to 4.5 times a month. However, women receiving placebo reported also an increase of “satisfying sexual events” from 2.7 to 3.7 times a month. Evaluation of the overall improvement of their condition and whether the benefit was meaningful to the women, showed a significantly higher rate of a meaningful benefit in the flibanserin-treated people versus the placebo group.[9] The onset of the flibanserin effect was seen from the first timepoint measured after 4 weeks of treatment and maintained throughout the treatment period.[10] The overall incidence of adverse events among women taking flibanserin was low, the majority of adverse events being mild to moderate and resolved during the treatment. The most commonly reported adverse events included dizziness, nausea, fatigue, somnolence and insomnia.[8]

Mechanism of action[edit]

The proposed mechanism of action refers to the Kinsey dual control model.[11] Several sex steroids, neurotransmitters, and hormones have important excitatory or inhibitory effects on the sexual response. Among the neurotransmitters, the excitatory activity is driven by dopamine and norepinephrine, while the inhibitory activity is driven by serotonin. The balance between these systems is relevant for a healthy sexual response. By modulating these neurotransmitters in selective brain areas, flibanserin, a 5-HT1A receptor agonist, D4 receptor very weak partial agonist/antagonist, and 5-HT2A receptor antagonist, may improve the balance between these neurotransmitter systems.[12][13]

Flibanserin is a 5-HT1A receptor agonist, D4 receptor very weak partial agonist/antagonist, and 5-HT2A receptor antagonist that had initially been investigated as an antidepressant.[14][15] Preclinical evidence suggested that flibanserin targets these receptors preferentially in selective brain areas and helps to improve the balance between these inhibitory and excitatory effects.[12]

FDA approval[edit]

On June 18, 2010, a federal advisory panel to the U.S. Food and Drug Administration (FDA) unanimously voted against recommending approval of flibanserin. Earlier in the week, a FDA staff report also recommended non-approval of the drug. While the FDA still could have approved flibanserin, usually negative panel votes tend to cause the FDA not to approve.[16] On October 8, 2010, Boehringer Ingelheim announced that it would discontinue its development of flibanserin in light of the FDA advisory panel's recommendation.[17]

On June 27, 2013, Sprout Pharmaceuticals confirmed they had resubmitted flibanserin for FDA approval.[18] In December 2013, a Formal Dispute Resolution was filed,[19] which contained the requirements of the FDA for further studies. These include two studies in healthy subjects to determine if flibanserin impairs their ability to drive, and to determine if it interferes with other biochemical pathways.[19][20][21] Sprout expected to resubmit the New Drug Application (NDA) in the 3rd quarter of 2014.[19][20]

On June 4, 2015, the panel to the FDA recommended approval of the drug by 18–6.[22]

See also[edit]

References[edit]

  1. ^ Borsini F, Evans K, Jason K, Rohde F, Alexander B, Pollentier S (Summer 2002). "Pharmacology of flibanserin". CNS Drug Rev. 8 (2): 117–142. doi:10.1111/j.1527-3458.2002.tb00219.x. PMID 12177684. 
  2. ^ Jolly E, Clayton A, Thorp J, Lewis-D’Agostino D, Wunderlich G, Lesko L (April 2008). "Design of Phase III pivotal trials of flibanserin in female Hypoactive Sexual Desire Disorder (HSDD)". Sexologies 17 (Suppl 1): S133–4. doi:10.1016/S1158-1360(08)72886-X. 
  3. ^ Spiegel online: Pharmakonzern stoppt Lustpille für die Frau, 8 October 2010 (in German)
  4. ^ a b "Joint Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee (BRUDAC) and the Drug Safety and Risk Management (DSaRM) Advisory Committee" (PDF). June 4, 2015. Retrieved 5 June 2015. 
  5. ^ American Psychiatric Association. Sexual and gender identity disorders. In: American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 2000:493–538.
  6. ^ http://www.nytimes.com/2015/02/27/opinion/nothing-is-wrong-with-your-sex-drive.html?_r=0
  7. ^ "Proposed Indication: Flibanserin is indicated for the treatment of hypoactive sexual desire disorder in premenopausal women" (PDF). May 20, 2010. p. 38. Retrieved June 17, 2010. 
  8. ^ a b "Proposed Indication: Flibanserin is indicated for the treatment of hypoactive sexual desire disorder in premenopausal women" (PDF). May 20, 2010. Retrieved June 16, 2010. 
  9. ^ Jolly E, Thorp J, Clayton AH, et al. Patients’ Perspective of Efficacy of Flibanserin in Premenopausal Women with HSDD. Oral presentation at the 58th Annual Clinical Meeting of The American College of Obstetricians and Gynecologists, May 2010.
  10. ^ Simon JA, Thorp J, Katz M et al. Onset of Efficacy of Flibanserin in Premenopausal Women with Hypoactive Sexual Desire Disorder. Abstract presented at the 58th Annual Clinical Meeting of The American College of Obstetricians and Gynecologists, May 2010.
  11. ^ Janssen, E, Bancroft J. The dual control model: The role of sexual inhibition & excitation in sexual arousal and behavior In Janssen, E. (Ed). (2006). The Psychophysiology of Sex. Bloomington, IN:Indiana University press.
  12. ^ a b Pfaus JG (June 2009). "Pathways of sexual desire". J Sex Med 6 (6): 1506–33. doi:10.1111/j.1743-6109.2009.01309.x. PMID 19453889. 
  13. ^ Allers K, Dremencov E, Ceci A et al. (May 2010). "Acute and repeated flibanserin administration in female rats modulates monoamines differentially across brain areas: a microdialysis study". J Sex Med 7 (5): 1757–67. doi:10.1111/j.1743-6109.2010.01763.x. PMID 20163532. 
  14. ^ D'Aquila P, Monleon S, Borsini F, Brain P, Willner P (December 1997). "Anti-anhedonic actions of the novel serotonergic agent flibanserin, a potential rapidly-acting antidepressant". European Journal of Pharmacology 340 (2–3): 121–32. doi:10.1016/S0014-2999(97)01412-X. PMID 9537806. 
  15. ^ Invernizzi RW, Sacchetti G, Parini S, Acconcia S, Samanin R (August 2003). "Flibanserin, a potential antidepressant drug, lowers 5-HT and raises dopamine and noradrenaline in the rat prefrontal cortex dialysate: role of 5-HT1A receptors". Br J Pharmacol. 139 (7): 1281–8. doi:10.1038/sj.bjp.0705341. PMC 1573953. PMID 12890707. 
  16. ^ "Drug for sexual desire disorder opposed by panel". New York Times. 18 June 2010. 
  17. ^ Burger, Ludwig (8 October 2010). "Boehringer pulls the plug on "pink Viagra"". Reuters. 
  18. ^ "Sprout Pharmaceuticals resubmits flibanserin NDA for treating HSDD in pre-menopausal women". 27 June 2013. 
  19. ^ a b c http://sproutpharma.com/sprout-pharmaceuticals-receives-clear-guidance-from-fda-on-path-forward-to-resubmit-new-drug-application-for-flibanserin-the-first-potential-medical-treatment-for-hypoactive-sexual-desire-disorder-in/
  20. ^ a b FDA seeks more tests on a female Viagra, by Matthew Perrone, The Detroit Free Press, page 2A Wednesday, Feb. 12, 2014
  21. ^ http://www.cnn.com/2014/02/11/health/female-sex-drive-drug/index.html?hpt=hp_t2
  22. ^ Stein, Rob (June 4, 2015). "Advisers To FDA Recommend Agency Approve Drug To Boost Female Libido". NPR. Retrieved June 4, 2015. 

External links[edit]