Metopimazine is an approvedprescription drug in France under the brand nameVogalene®[8] that has been used for the treatment ofnausea andvomiting.[9] Vogalene® is available under different forms, including 15 mg capsules, 7.5 mg orally disintegrating tablets, 5 mgsuppository, 0.1% oral liquid, and a 10 mg/mLintravenous (IV) solution approved for the prevention of chemotherapy-induced nausea and vomiting.[10] Metopimazine is also anover-the-counter medication available inpharmacies in France (Vogalib®, 7.5 mg orally disintegrating tablets).[11] The approved dose is 30 mg per day. Most adult prescriptions are for seasonalgastroenteritis or acute nausea and vomiting of variousetiologies. The IV formulation is almost exclusively used to treat chemotherapy-induced nausea and vomiting in adults and children.[12]
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 moreefficacious while remaining safe and well tolerated. Numerousopen-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 severeadverse events.[13][14][15][16][17][18][19][20][21] In adose-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 andtolerability. Metopimazine was determined to be safe at a dose of 30 mg administered 6 times daily (180 mg/day). The dose-limitingtoxicity to metopimazine was moderate-to-severedizziness caused byorthostatic 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-relatedextrapyramidal 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 ofondansetron versus ondansetron plus metopimazine as an antiemetic prophylaxis duringplatinum-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 anasymptomatic decrease in standingblood pressure when patients received the combination antiemetic therapy.[19]In a randomized, double-blind study assessing the efficacy and safety ofsublingual metopimazine compared to ondansetron in chemotherapy-induced delayedemesis, 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, theincidence ofgastrointestinal disorders was significantly lower in the metopimazine group, particularlyabdominal pain andconstipation.[23]
Metopimazine, aphenothiazine derivative, is a potent D2/D3dopamine receptor antagonist. Metopimazine has also shown adrenergic alpha1, histamine H1, serotonin 5HT2a antagonism.[10]
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 rapidlymetabolized to metopimazine acid (Tmax ~2 hours), its majormetabolite in humans. Metopimazine is primarily metabolized by aliveramidase 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]
Thebioavailability of metopimazine in humans is low. A 10 mg dose of metopimazine was reported to have an absolute bioavailability under 20%.[26]
Metopimazine mesylate (NG101), a novelformulation 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]
For the first step, 2-Methylthiophenothiazine [7643-08-5] (1) is protected by sequential reaction with sodium amide andacetic 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 with1-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).
^Herrstedt J (September 1998). "Chemotherapy-induced nausea and vomiting with special emphasis on metopimazine".Danish Medical Bulletin.45 (4):412–422.PMID9777292.
^Paradis B, Brault R (December 1967). "[A new antiemetic: vogalen (metopimazine or 9965 RP)]".Laval Medical.38 (10):901–907.PMID5596819.
^Guerin MT, Guerin RA, Salaün O (May 1969). "[Therapeutic value of metopimazine as an antiemetic in cancerology]".La Presse Médicale.77 (24): 893.PMID5797645.
^Arbus L, Parente C (May 1971). "[Use of metopimazine in certain vomitings from central origin]".Therapeutique.47 (5):469–471.PMID5314918.
^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.PMID4944444.
^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.PMID4261213.
^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.PMID38705.
^abHerrstedt 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.PMID9193370.
^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.PMID11283143.
^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.PMID9010988.S2CID24370010.
^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.PMID16428941.S2CID8708071.
^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.PMID25874755.
^DE 1092476, Jacob RM, Robert JG, issued 1960, assigned to Rhone Poulenc SA.
^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.S2CID102478746.
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