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Echo4/sandbox
Clinical data
ATC code
Identifiers
  • (2S,4S)-4-(4-Acetyl-1-piperazinyl)-N-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4-fluoro-2-methylphenyl)-N-methyl-1-piperidinecarboxamide
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC30H35F7N4O2
Molar mass616.26 g/mol g·mol−1
3D model (JSmol)
  • CC1=C(C=CC(=C1)F)[C@@H]2C[C@H] (CCN2C(=O)N(C)[C@H](C)C3=CC(=CC(=C3) C(F)(F)F)C(F)(F)F)N4CCN(CC4)C(=O)C
  • InChI=1S/C30H35F7N4O2/c1-18-13-24(31)5-6-26(18)27-17-25(40-11-9-39(10-12-40)20(3)42)7-8-41(27)28(43)38(4)19(2)21-14-22(29(32,33)34)16-23(15-21)30(35,36)37/h5-6,13-16,19,25,27H,7-12,17H2,1-4H3/t19-,25-,27+/m1/s1
  • Key:XGGTZCKQRWXCHW-JRLVAEJTSA-N
  (verify)

Casopitant (trade names Rezonic (US), Zunrisa (EU)) is an neurokinin 1 (NK1) receptor antagonist derived from piperazine developed for the treatment of chemotherapy-induced nausea and vomiting (CINV).[1] It was originally under development by GlaxoSmithKline (GSK).

Casopitant was developed after the commercially available aprepitant to be a more effective antiemetic medication for CINV patients.[2] The novel NK1 receptor antagonist appears to be as effective as its forerunner in suppression of nausea and vomiting symptoms, passing through phase III trials.[3] In July 2008, the company filed a marketing authorization application with the European Medicines Agency. The application was withdrawn in September 2009 because GSK decided that further safety assessment was necessary.[4]

Treatment

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Results of two phase III trials found that casopitant significantly reduced chemotherapy-induced nausea and vomiting.[5] Furthermore, when used with other drugs used to treat CINV, the drugs worked together to achieve an even more superior effect than when casopitant was not present, without causing toxicity. These drugs include ondansetron, dexamethasone, warfarin, cyclophosphamide, docetaxel, dolasetron, and granisetron.[3][6] However, like the already approved aprepitant the drug showed far inferior effects for nausea control in comparison to its use as an antiemetic.[2] Due to lacking data on safety of the drug, it could not be approved for release on the market, so GSK decided to discontinue regulatory filings on casopitant.[7]

Side Effects

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Side effects[3] of this drug include:

Pharmacodynamics

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Casopitant is a selective competitive antagonist at the NK1 receptor that is able to achieve a greater degree of receptor occupancy (RO) than other previously tested drugs, where a plasma concentration of 20 ng/ml can achieve RO of above 95%.[8] The exact pharmacodynamics of casopitant is not well understood, but in a study on ferrets, it was found to have a high affinity for the NK1 receptor (Ki < 1 nM).[9] As a NK1 receptor antagonist, casopitant works by blocking the binding of the endogenous substance P (SP), which has been known to regulate emesis. It is believed that casopitant works by blocking SP in the central vomiting center (VC) in the brain. The higher RO that casopitant is able to achieve may account for the greater effects, because it is more successful at blocking SP occupancy. Casopitant is able to reduce nausea and retching as hoped, but it has much more of an effect as an antiemetic than as a nausea suppressor, suggesting that the target NK1 receptor is not the only thing controlling nausea.

Pharmacokinetics

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In order for the NK 1 receptor antagonist to work, it must be able to bypass the blood-brain barrier (BBB), something impossible for peptide-based NK 1 receptor antagonists. However, as a non-peptide antagonist, casopitant is able to go through the BBB to act as an antiemetic. Clinical trials showed that a single 150 mg oral dose of casopitant was as effective as a three-day regimen.[3] Casopitant may also be administered intravenously. Peak plasma concentration in humans is achieved after about 1 hour, and the half-life of the drug is about 17 hours.[8] After administration, about 93% of the casopitant is quickly absorbed, and after the first pass effect, the bioavailability is about 57%.[10] Casopitant is broken down by CYP3A4, an enzyme that is also involved in the breakdown of several other antiemetic drugs, as well as a weak inhibitor.[3] After metabolism the drug is mainly excreted by way of feces.[10][11]

Interactions with other drugs

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  • ondansetron and dexamethasone- Phase II and phase III trials had already demonstrated the efficacy of administering casopitant with ondansetron and dexamethasone.[12] However, ondansetron, dexamethasone, and casopitant all share the same metabolic pathway, as they are all broken down by enzymes from the CYP3A family. A pharmacokinetic study in healthy subjects found that in a repeat-dose oral dexamethasone regimen with the coadministration of oral casopitant, there should be a decrease in dose of dexamethasone. Use of ondansetron was not affected by coadministration of casopitant.[13]
  • warfarin – Warfarin is metabolized by the enzymes CYP3A and CYP2C9, both of which are affected by casopitant, a moderate inhibitor and a moderate inducer respectively. A study found that after coadministration, no pharmacokinetic or pharmacodynamics interaction was observed, so there is no need to alter dosage. However, for participants that had bleeding-related adverse events, coadministration resulted in a higher bleeding risk.[14]
  • cyclophosphamide – Cyclophosphamide is a chemotherapeutic agent that often has emetogenic effects. Because it is a prodrug, cyclophosphamide needs to be metabolically converted by CYP enzymes before it can have any effect. Research on the administration of casopitant with cyclophosphamide found that casopitant did not impact safety of the treatment regimen, possibly because casopitant is only a moderate inhibitor of CYP3A4.[15]

See also

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References

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  1. ^ Lohr L (2008). "Chemotherapy-induced nausea and vomiting". Cancer J. 14 (2): 85–93. doi:10.1097/PPO.0b013e31816a0f07. PMID 18391612. S2CID 43224257.
  2. ^ a b Khojasteh, A; Khojasteh, A; Thornburg, BG; Maher, KR (June 2009). "Casopitant: a new warrior in the antiemetic crusade". Expert Opinion on Pharmacotherapy. 10 (8): 1367–76. doi:10.1517/14656560902953746. PMID 19445564. S2CID 25040559.
  3. ^ a b c d e Ruhlmann, C; Herrstedt, J (April 2009). "Casopitant: a novel NK(1)-receptor antagonist in the prevention of chemotherapy-induced nausea and vomiting". Therapeutics and Clinical Risk Management. 5 (2): 375–84. doi:10.2147/tcrm.s4026. PMC 2697542. PMID 19536319.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  4. ^ "GlaxoSmithKline withdraws its marketing authorisation application for Zunrisa" (PDF). London: EMEA. 13 October 2009. Retrieved 21 December 2009.
  5. ^ "New Drugs Online Report for casopitant". Uk Medicines Information.
  6. ^ Roila, F; Rolski, J; Ramlau, R; Dediu, M; Russo, MW; Bandekar, RR; Grunberg, SM (November 2009). "Randomized, double-blind, dose-ranging trial of the oral neurokinin-1 receptor antagonist casopitant mesylate for the prevention of cisplatin-induced nausea and vomiting". Annals of Oncology : Official Journal of the European Society for Medical Oncology / ESMO. 20 (11): 1867–73. doi:10.1093/annonc/mdp194. PMID 19541792.
  7. ^ "Pharmaceutical Processing". GSK Ends Regulatory Filings for Zunrisa/Rezonic.
  8. ^ a b Zamuner, S; Rabiner, EA; Fernandes, SA; Bani, M; Gunn, RN; Gomeni, R; Ratti, E; Cunningham, VJ (February 2012). "A pharmacokinetic PET study of NK₁ receptor occupancy". European Journal of Nuclear Medicine and Molecular Imaging. 39 (2): 226–35. doi:10.1007/s00259-011-1954-2. PMID 21993526. S2CID 23428914.
  9. ^ Minthorn, E; Mencken, T; King, AG; Shu, A; Rominger, D; Gontarek, RR; Han, C; Bambal, R; Davis, CB (September 2008). "Pharmacokinetics and brain penetration of casopitant, a potent and selective neurokinin-1 receptor antagonist, in the ferret". Drug Metabolism and Disposition: The Biological Fate of Chemicals. 36 (9): 1846–52. doi:10.1124/dmd.108.021758. PMID 18556439. S2CID 26034060.
  10. ^ a b Pellegatti, M; Bordini, E; Fizzotti, P; Roberts, A; Johnson, BM (August 2009). "Disposition and metabolism of radiolabeled casopitant in humans". Drug Metabolism and Disposition: The Biological Fate of Chemicals. 37 (8): 1635–45. doi:10.1124/dmd.109.026781. PMID 19420128. S2CID 9622959.
  11. ^ Miraglia, L; Pagliarusco, S; Bordini, E; Martinucci, S; Pellegatti, M (October 2010). "Metabolic disposition of casopitant, a potent neurokinin-1 receptor antagonist, in mice, rats, and dogs". Drug Metabolism and Disposition: The Biological Fate of Chemicals. 38 (10): 1876–91. doi:10.1124/dmd.110.033092. PMID 20622044. S2CID 13595366.
  12. ^ Altorjay, A; Melson, T; Chinachoit, T; Kett, A; Aqua, K; Levin, J; Blackburn, LM; Lane, S; Pergolizzi JV, Jr (February 2011). "Casopitant and ondansetron for postoperative nausea and vomiting prevention in women at high risk for emesis: a phase 3 study". Archives of Surgery (Chicago, Ill. : 1960). 146 (2): 201–6. doi:10.1001/archsurg.2010.327. PMID 21339433.
  13. ^ Johnson, B; Adams, L; Lu, E; Zhang, K; Lebowitz, P; Lates, C; Blum, R (September 2009). "Impact of casopitant, a novel NK-1 antagonist, on the pharmacokinetics of ondansetron and dexamethasone". Supportive Care in Cancer : Official Journal of the Multinational Association of Supportive Care in Cancer. 17 (9): 1177–85. doi:10.1007/s00520-008-0571-5. PMC 2726912. PMID 19205755.
  14. ^ Kirby, LC; Johnson, BM; Adams, LM; Eberwein, DJ; Zhang, K; Murray, SC; Lates, CD; Blum, RA; Morris, SR (May 2010). "Effect of casopitant, a novel NK-1 receptor antagonist, on the pharmacokinetics and pharmacodynamics of steady-state warfarin". Journal of Clinical Pharmacology. 50 (5): 566–75. doi:10.1177/0091270009346965. PMID 20220045. S2CID 20568105.
  15. ^ Adams, Laurel M.; Johnson, Brendan; Murray, Sharon (March 2014). "A pharmacokinetic, pharmacodynamic, and safety study of intravenous cyclophosphamide with an oral casopitant antiemetic regimen in cancer patients". Clinical Pharmacology in Drug Development. 3 (2): 93–100. doi:10.1002/cpdd.57. PMID 27128454. S2CID 34207113.

Category:Antiemetics Category:NK1 receptor antagonists Category:Amides Category:Piperazines Category:Piperidines Category:Organofluorides


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