Metopimazine

Metopimazine
Clinical data
Trade namesVogalen, Vogalene
Other namesEXP-999; RP-9965; NG-101
AHFS/Drugs.comInternational Drug Names
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Identifiers
  • 1-(3-[2-(methylsulfonyl)-10H-phenothiazin-10-yl]propyl)piperidine-4-carboxamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.034.367 Edit this at Wikidata
Chemical and physical data
FormulaC22H27N3O3S2
Molar mass445.60 g·mol−1
3D model (JSmol)
  • O=S(=O)(c2cc1N(c3c(Sc1cc2)cccc3)CCCN4CCC(C(=O)N)CC4)C
  • InChI=1S/C22H27N3O3S2/c1-30(27,28)17-7-8-21-19(15-17)25(18-5-2-3-6-20(18)29-21)12-4-11-24-13-9-16(10-14-24)22(23)26/h2-3,5-8,15-16H,4,9-14H2,1H3,(H2,23,26) checkY
  • Key:BQDBKDMTIJBJLA-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Metopimazine (INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, BANTooltip British Approved Name), sold under the brand names Vogalen and Vogalene, is an antiemetic of the phenothiazine group which is used to treat nausea and vomiting.[1][2][3][4][5][6] It is marketed in Europe, Canada, and South America.[2][5] As of August 2020, metopimazine has been repurposed and is additionally under development for use in the United States for the treatment of gastroparesis.[6][5]

Metopimazine has antidopaminergic, antihistamine, and anticholinergic activity.[7] However, it has also been described as a highly potent and selective dopamine D2 and D3 receptor antagonist.[5] The D2 receptor antagonism of metopimazine is thought to underlie its antiemetic and gastroprokinetic effects.[5] It is said to not readily cross the blood–brain barrier and hence to have peripheral selectivity, in contrast to metoclopramide but similarly to domperidone.[5] Unlike domperidone however, metopimazine shows no hERG inhibition and hence is expected to have a more favorable cardiovascular profile.[5] In contrast to metoclopramide, metopimazine does not interact with serotonin 5-HT3 and 5-HT4 receptors.[5]

Medical uses

Metopimazine is an approved prescription drug in France under the brand name Vogalene® [8] that has been used for the treatment of nausea and vomiting.[9] Vogalene® is available under different forms, including 15 mg capsules, 7.5 mg orally disintegrating tablets, 5 mg suppository, 0.1% oral liquid, and a 10 mg/mL intravenous (IV) solution approved for the prevention of chemotherapy-induced nausea and vomiting.[10] Metopimazine is also an over-the-counter medication available in pharmacies in France (Vogalib®, 7.5 mg orally disintegrating tablets).[11] The approved dose is 30 mg per day. Most adult prescriptions are for seasonal gastroenteritis or acute nausea and vomiting of various etiologies. The IV formulation is almost exclusively used to treat chemotherapy-induced nausea and vomiting in adults and children.[12]

Adverse effects

Generally, studies in chemotherapy-induced nausea and vomiting suggest that doses of metopimazine higher than approved for common nausea and vomiting conditions tend to be more efficacious while remaining safe and well tolerated. Numerous open-label and randomized, placebo-controlled efficacy studies involving oral administration (ranging from 7.5 mg/day for 4 days, to up to 45 mg/day for ~7–30 days, to 120 mg/day for 4 days) or IV administration (10 mg to 40 mg) of metopimazine have concluded that metopimazine is safe and well tolerated with no report of severe adverse events.[13][14][15][16][17][18][19][20][21] In a dose-ranging, open-label study in patients undergoing chemotherapy, metopimazine administered orally at 20, 30, 40, 50, or 60 mg every 4 hours (q4h) for 48 hours was used to determine its safety and tolerability. Metopimazine was determined to be safe at a dose of 30 mg administered 6 times daily (180 mg/day). The dose-limiting toxicity to metopimazine was moderate-to-severe dizziness caused by orthostatic hypotension, which was observed beginning at 40 mg every 4 hours for 48 hours. Other side effects were few and mild in severity. A single possibly drug-related extrapyramidal adverse event was observed in a patient in the 60 mg q4h or 360 mg daily dose group.[22] In a randomized, double-blind comparison of ondansetron versus ondansetron plus metopimazine as an antiemetic prophylaxis during platinum-based chemotherapy, metopimazine was administered by IV (24-hour continuous infusion) at 35 mg/m2 followed by 30 mg per orally (PO) 4 times a day (120 mg/day) for 4 days. Metopimazine plus ondansetron was more efficacious than ondansetron alone, and adverse reactions were mild and without significant differences between the two treatment groups. However, there was an asymptomatic decrease in standing blood pressure when patients received the combination antiemetic therapy.[19] In a randomized, double-blind study assessing the efficacy and safety of sublingual metopimazine compared to ondansetron in chemotherapy-induced delayed emesis, patients received either 45 mg/day of metopimazine (7.5 mg x 2 every 8 hours) or 16 mg/day of ondansetron (8 mg every 12 hours). Results showed that metopimazine was comparable in efficacy to ondansetron; however, the incidence of gastrointestinal disorders was significantly lower in the metopimazine group, particularly abdominal pain and constipation.[23]

Mechanism of action

Metopimazine, a phenothiazine derivative, is a potent D2/D3 dopamine receptor antagonist. Metopimazine has also shown adrenergic alpha1, histamine H1, serotonin 5HT2a antagonism.[10]

Pharmacokinetics

The pharmacokinetics (PK) profile of metopimazine has been reported as comparable between adults and children. The maximum plasma concentration (Cmax) of metopimazine is reached approximately 60 minutes after oral administration, and the elimination half-life is approximately two hours.[24] Metopimazine is rapidly metabolized to metopimazine acid (Tmax ~2 hours), its major metabolite in humans. Metopimazine is primarily metabolized by a liver amidase in humans and therefore present a low risk on drug-drug interaction.[25] Exposure is reduced by ~30% and 50% (area under the curve (AUC) and Cmax, respectively) when metopimazine is administered with food.[26][10]

The bioavailability of metopimazine in humans is low. A 10 mg dose of metopimazine was reported to have an absolute bioavailability under 20%.[26]

Research

Metopimazine mesylate (NG101), a novel formulation of metopimazine, is under clinical development for idiopathic gastroparesis in the United States.[27] Gastroparesis is a debilitating chronic gastrointestinal disorder characterized by delayed gastric emptying without evidence of mechanical obstruction. Symptoms include nausea, vomiting, early satiety, postprandial fullness, bloating, and upper abdominal pain.[28][29][30]

Synthesis

Thieme Patent:[31] Revised:[32]

For the first step, 2-Methylthiophenothiazine [7643-08-5] (1) is protected by sequential reaction with sodium amide and acetic anhydride to give 1-[2-(Methylthio)-10H-phenothiazin-10-yl]ethanone [23503-69-7] (2). Oxidation with peracid proceeds preferentially on the more electron-rich alkyl thioether to give the sulfone. Upon hydrolysis of the acetate this affords 2-(methylsulfonyl)-10h-phenothiazine [23503-68-6] (3). Alkylation with 1-Bromo-3-chloropropane (4) gives 10-(3-chloropropyl)-2-methylsulfonylphenothiazine [40051-30-7] (5). Alkylation with piperidine-4-carboxamide (Isonipecotamide) [39546-32-2] (6) affords metopimazine (7).

References

  1. ^ J. Elks, ed. (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 817–. ISBN 978-1-4757-2085-3. OCLC 1058412474.
  2. ^ a b Swiss Pharmaceutical Society (2000). Swiss Pharmaceutical Society (ed.). Index Nominum 2000: International Drug Directory. Taylor & Francis. pp. 683–. ISBN 978-3-88763-075-1.
  3. ^ Morton IK, Hall JM (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 180–. ISBN 9789401144391. OCLC 1243535030.
  4. ^ Herrstedt J (September 1998). "Chemotherapy-induced nausea and vomiting with special emphasis on metopimazine". Danish Medical Bulletin. 45 (4): 412–422. PMID 9777292.
  5. ^ a b c d e f g h Heckroth M, Luckett RT, Moser C, Parajuli D, Abell TL (April 2021). "Nausea and Vomiting in 2021: A Comprehensive Update". Journal of Clinical Gastroenterology. 55 (4): 279–299. doi:10.1097/MCG.0000000000001485. PMC 7933092. PMID 33471485.
  6. ^ a b "Metopimazine - Neurogastrx - AdisInsight".
  7. ^ Bezin J, Noize P, Mansiaux Y, Jarne A, Pariente A (March 2021). "Antidopaminergic antiemetics and trauma-related hospitalization: A population-based self-controlled case series study". British Journal of Clinical Pharmacology. 87 (3): 1303–1309. doi:10.1111/bcp.14510. PMID 32737898. S2CID 220909387.
  8. ^ "Vogalene®". www.rxreasoner.com.
  9. ^ "Accueil - ANSM". ansm.sante.fr (in French). Retrieved 26 March 2023.
  10. ^ a b c Croom KF, Keating GM (March 2006). "Metopimazine". American Journal of Cancer. 5 (2): 123–136. doi:10.2165/00024669-200605020-00006. ISSN 1175-6357. S2CID 76202219.
  11. ^ "Vogalib". www.rxreasoner.com.
  12. ^ Shirley, Matt (July 2021). "Netupitant/Palonosetron: A Review in Chemotherapy-Induced Nausea and Vomiting". Drugs. 81 (11): 1331–1342. doi:10.1007/s40265-021-01558-2. ISSN 1179-1950. PMC 8463343. PMID 34292534.
  13. ^ Paradis B, Brault R (December 1967). "[A new antiemetic: vogalen (metopimazine or 9965 RP)]". Laval Medical. 38 (10): 901–907. PMID 5596819.
  14. ^ Guerin MT, Guerin RA, Salaün O (May 1969). "[Therapeutic value of metopimazine as an antiemetic in cancerology]". La Presse Médicale. 77 (24): 893. PMID 5797645.
  15. ^ Arbus L, Parente C (May 1971). "[Use of metopimazine in certain vomitings from central origin]". Therapeutique. 47 (5): 469–471. PMID 5314918.
  16. ^ Berry GH, Duncan W, Bowman CM (October 1971). "The prevention of radiation sickness. Report of a double blind random clinical trial using prochlorperazine and metopimazine". Clinical Radiology. 22 (4): 534–537. doi:10.1016/s0009-9260(71)80130-7. PMID 4944444.
  17. ^ Arnaud B, Sportouch M (January 1972). "[Value of metopimazine (Vogalene) in the prevention and treatment of postoperative vomiting in ocular surgery. (Apropos of 100 cases)]". Archives d'Ophtalmologie et Revue Generale d'Ophtalmologie. 32 (1): 63–68. PMID 4261213.
  18. ^ Rodary C, Elman A, Durand M, Cohen-Solal J, Maillard JN (1979). "[Double blind randomized trial of metopimazine: for postoperative nausea and vomiting after cholecystectomy]". Annales de l'Anesthésiologie Française. 20 (2): 118–120. PMID 38705.
  19. ^ a b Herrstedt J, Sigsgaard T, Handberg J, Schousboe BM, Hansen M, Dombernowsky P (April 1997). "Randomized, double-blind comparison of ondansetron versus ondansetron plus metopimazine as antiemetic prophylaxis during platinum-based chemotherapy in patients with cancer". Journal of Clinical Oncology. 15 (4): 1690–1696. doi:10.1200/JCO.1997.15.4.1690. PMID 9193370.
  20. ^ Lebeau B, Depierre A, Giovannini M, Rivière A, Kaluzinski L, Votan B, et al. (September 1997). "The efficacy of a combination of ondansetron, methylprednisolone and metopimazine in patients previously uncontrolled with a dual antiemetic treatment in cisplatin-based chemotherapy. The French Ondansetron Study Group". Annals of Oncology. 8 (9): 887–892. doi:10.1023/a:1008276412559. PMID 9358940.
  21. ^ Sigsgaard T, Herrstedt J, Handberg J, Kjaer M, Dombernowsky P (April 2001). "Ondansetron plus metopimazine compared with ondansetron plus metopimazine plus prednisolone as antiemetic prophylaxis in patients receiving multiple cycles of moderately emetogenic chemotherapy". Journal of Clinical Oncology. 19 (7): 2091–2097. doi:10.1200/JCO.2001.19.7.2091. PMID 11283143.
  22. ^ Herrstedt J, Sigsgaard T, Angelo HR, Kampmann JP, Hansen M (January 1997). "Dose-finding study of oral metopimazine". Supportive Care in Cancer. 5 (1): 38–43. doi:10.1007/BF01681960. PMID 9010988. S2CID 24370010.
  23. ^ Khamales S, Bethune-Volters A, Chidiac J, Bensaoula O, Delgado A, Di Palma M (February 2006). "A randomized, double-blind trial assessing the efficacy and safety of sublingual metopimazine and ondansetron in the prophylaxis of chemotherapy-induced delayed emesis". Anti-Cancer Drugs. 17 (2): 217–224. doi:10.1097/00001813-200602000-00014. PMID 16428941. S2CID 8708071.
  24. ^ Mallet E, Bounoure F, Skiba M, Saussereau E, Goullé JP, Castanet M (June 2015). "Pharmacokinetic study of metopimazine by oral route in children". Pharmacology Research & Perspectives. 3 (3): e00130. doi:10.1002/prp2.130. PMC 4492748. PMID 26171218.
  25. ^ Busby RW, Cai X, Yang S, Ramos L, Venkatarangan L, Shen H, et al. (February 2022). "Metopimazine is primarily metabolized by a liver amidase in humans". Pharmacology Research & Perspectives. 10 (1): e00903. doi:10.1002/prp2.903. PMC 8929364. PMID 34918875.
  26. ^ a b Herrstedt J, Jørgensen M, Angelo HR (August 1990). "The effect of food on serum concentrations of metopimazine". British Journal of Clinical Pharmacology. 30 (2): 237–243. doi:10.1111/j.1365-2125.1990.tb03770.x. PMC 1368223. PMID 2206785.
  27. ^ "A Phase 2 Randomized, Double-blind, Placebo-Controlled, Parallel-Group Study, of the Safety and Efficacy of NG101 Administered Orally to Patients With Gastroparesis". clinicaltrials.gov. 4 November 2022.
  28. ^ Camilleri M, Kuo B, Nguyen L, Vaughn VM, Petrey J, Greer K, et al. (August 2022). "ACG Clinical Guideline: Gastroparesis". The American Journal of Gastroenterology. 117 (8): 1197–1220. doi:10.14309/ajg.0000000000001874. PMC 9373497. PMID 35926490.
  29. ^ De Colle C, van der Hart M, Chen J, Rassoulpour A, Pasricha PJ (2016). "1079 NG101: A potent and selective dopamine D2 receptor antagonist as a potential alternative to metoclopramide and domperidone for the treatment of gastroparesis". Gastroenterology. 150 (4): S214. doi:10.1016/S0016-5085(16)30794-6.
  30. ^ Stein B, Everhart KK, Lacy BE (August 2015). "Gastroparesis: A Review of Current Diagnosis and Treatment Options". Journal of Clinical Gastroenterology. 49 (7): 550–558. doi:10.1097/MCG.0000000000000320. PMID 25874755.
  31. ^ DE 1092476, Jacob RM, Robert JG, issued 1960, assigned to Rhone Poulenc SA. 
  32. ^ Karicherla V, Phani K, Bodireddy MR, Prashanth KB, Gajula MR, Pramod K (May 2017). "A simple and commercially viable process for improved yields of metopimazine, a dopamine D2-receptor antagonist". Organic Process Research & Development. 21 (5): 720–731. doi:10.1021/acs.oprd.7b00052. S2CID 102478746.