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PN0496-Acotiamide.Pdf Acotiamide hydrochloride hydrate (Acofide®) 盐酸阿考替胺 Z-338 in Zeria; YM-443 in Astellas Tablet, oral, EQ 100 mg acotiamide Acotiamide is a peripheral acetylcholinesterase inhibitor, indicated for the treatment of functional dyspepsia (FD), which was first-in-class drug to treat FD in the world and approved in 2013 by Japan PMDA. It was originally discovered by Zeria, and co-developed with Astellas. The drug is co-marketing in Japan with a single brand name. The human recommended starting dose is 100 mg at a time, and 3 times a day before meals. Worldwide Key Approvals Global Sales ($Million) Key Substance Patent Expiration 2016-May (US5981557A) 2016-May (EP0870765B1) 2013-Mar (JP) Not available 2021-May (JP3181919B2) 2016-May (CN1063442C) Mechanism of Action Acotiamide hydrochloride hydrate is an acetylcholinesterase (AChE) inhibitor and enhanced the acetylcholine (ACh)-induced contraction and motility of the gastric antrum and the gastric body. Target Binding Selectivity In vitro Efficacy In vivo Efficacy Mixed pattern: Ki1= 0.61 µM Effect dose of contraction in gastric sample: Significantly improved the gastrointestinal motility: Ki2= 2.7 µM ACh-induced: at 1 µM In normal and gastric hypomotility dogs: at 10 mg/kg. Inhibition: IC50= 3 µM Electrical-induced: at 0.3 µM In gastric hypomotility rats: at 100 mg/kg. Pharmacokinetics Parameters Rats Dogs Healthy Humans 3 10 3 10 50 mg 100 mg 200 mg 400 mg 800 mg Dose (mg/kg) (i.v.) (p.o.) (i.v.) (p.o.) (p.o.) (p.o.) (p.o.) (p.o.) (p.o.) Tmax (hr) - 0.08 - 0.5 2.75 2.42 2.08 2.25 2.13 Cmax (ng/mL) - 282.1 - 839.4 16.37 30.82 72.4 185.9 318.4 AUCinf (ng·hr/mL) 586.3 271.5 1179.6 1470.5 52.2 171.3 312.8 752.3 1655 T (hr) 0.8 3.7 1.3 3.0 12.9 13.31 10.92 21.69 17.14 In 1/2 Vivo CL or CL/F (L/hr/kg) 4.3 30.7 2.1 6.0 823.1 L/hr 537 L/hr 580.8 L/hr 464.1 L/hr 440.3 L/hr Vd or Vd/F (L/kg) 4.9 165.6 4.2 26.5 NA 1.694 L NA NA NA F (%) - 13.9 - 37.5 NA NA NA NA NA Major Component in Plasma (%) M-1 (70.09) Parent (74.22) Parent Major Metabolite in Plasma (%) M-1 (70.09) M-1 (12.75) M-1, M2 (inactive) Excretion by Urine/Feces (%) 7/91 7/93 5/87 -6 Permeability Papp (A→B) = 0.8 ~1.3 ×10 cm/s at concentrations of 1 – 500 µM in Caco-2 cells. In PPB (%Bound) 75.16-77.52 53.39-61.02 84.21-85.95 Vitro Metabolic stability in LM (%Remaining) 90.3 100 42.3 Drug-Drug Interaction CYP Enzymes Other Enzymes Transporters Substrate CYP2C8 UGT1A8, UGT1A9 P-gp Inhibitor Not NA P-gp (low) Inducer Not NA NA Non-clinical Toxicology Single Dose Rats: 2000 mg/kg Safety • Nothing special observed in a bunch of safety pharmacology studies Dogs: 2000 mg/kg Pharmacology Toxicity (MTD) Genotoxicity • No genetic toxicity was found. • Fertility: NOAEL: 1000 mg/kg/day in rats. Rats: 300 mg/kg/day • Embryo-fetal developemt: maternal NOAEL: 300 & 100 mg/kg/day (13 29 & 12×MRHD Repeated Dose Reproductive & 2.2×MRHD); developmental NOAEL: 1000 & 300 mg/kg/day (19 & Dogs: 30&100mg/kg/day Toxicity Toxicity 24×MRHD). (rats & rabbits) 6 & 10×MRHD (NOAEL) • Postnatal development: NOAEL: 1000 mg/kg/day for F0 and F1 in rats. (Male & Female) • Transferred through placenta and excreted through milk. • Endometrial adenocarcinoma incidence increased was found in 2-year Carcinogenicity rat tests, but not found in rasH2 transgenic accelerating tests. Acotiamide hydrochloride hydrate 1 Acotiamide hydrochloride hydrate (Acofide®) 盐酸阿考替胺 Research code: Z-338 in Zeria; YM-443 in Astellas §1 General Information Acotiamide is a peripheral acetylcholinesterase (AChE) in- hibitor, is the first-in-class drug to treat FD in the world, which was approved in 2013 by PMDA of Japan. It was originally discovered by Zeria, and co-developed with Astellas. The drug is co-marketing in Japan with a sin- gle brand name. Acotiamide prevents the hydrolysis of acetylcholine by in- hibiting peripheral acetylcholinesterase, and produces the . improvement of impaired gastric motility and delayed gas- Molecular formula: C21H30N4O5S HCl 3H2O tric emptying, and consequently the symptoms of FD. Molecular weight: 541.06 Acotiamide is indicated for the treatment of postprandial CAS No.: 185106-16-5 (acotiamide) fullness, upper abdominal bloating, and early satiation due 773092-05-0 (acotiamide hydrochloride trihy- to functional dyspepsia. drate) Available as orally tablets, containing 100 mg of acoti- amide hydrochloride hydrate and the recommended start- Parameters of Lipinski’s “Rule of 5” ing dose is 100 mg at a time, and 3 times a day before meals. a b b b MW HD HA FRB PSA CLogP --Key Approvals around the World-- 450.55 3 9 10 141Å2 4.873±0.434 a: molecular weight of acotiamide; b: Calculated by ACD/Labs software V11.02 Country Japan (PMDA) (or Area) --Drug Product-- First Ap- 2013/3/25 proval Date Dosage route: Oral. NDA NO. 22500AMX00868000 Strengths: 100 mg (EQ to Acotiamide) Dosage forms: Tablet, film coated Brand Name Acofide Inactive ingredients: Indication Functional dyspepsia Lactose hydrate, Crystalline cellulose, Low-substituted Authorization hydroxypropyl cellulose, Hydroxypropyl cellulose, Zeria/Astalles Holder Light anhydrous silicic acid, Magnesium stearate, *: Till May. 2015, it has not been approved by FDA (US), EMA (EU) and CFDA Hypromellose, Carnauba wax and Titanium oxide. (China). Recommended dose: --Worldwide Sales-- In general, for adults, take 1 tablet at a time, 3 times a day before meals. * Sourced from the Japan PMDA drug label information *: The sale data of Acofide® was not available. --Active Ingredient-- The Pharmaceutical Index – Worldwide 2013 NCEs 2 --Key Patents-- Patent 1 Title Aminothiazole derivatives, drug containing the same and intermediate in the production of the compounds International International Patent Type Applicants WO Patent NO. Priority Date Application NO. Filling Date Product(Substance) Zeria Pharm Co Ltd WO9636619A1 WOJP96001297 1995/5/18 1996/5/16 Drug Approval National Patent NO. Application Date Granted Date Patent Extension Patent Expiration Date US5981557A 1996/5/16 1999/11/9 NA / 2016/5/16 EP0870765B1 1996/5/16 2003/11/19 NA / 2016/5/16 JP3181919B2 1996/5/16 2001/7/3 2013/3/25 5 years 2021/5/16 CN1063442C 1996/5/16 2001/3/21 NA / 2016/5/16 Patent 2 Title Method for treatment of climacteric disorders in woman during or after the menopause International International Patent Type Applicants WO Patent NO. Priority Date Application NO. Filling Date Uses Hormos Medical Co. WO0207718A1 PCT/FI01/00414 2000/7/21 2001/5/2 Drug Approval National Patent NO. Application Date Granted Date Patent Extension Patent Expiration Date US6245819B1 2000/7/21 2001/6/12 2013/2/26 0 day 2020/7/21 US6984665B2 2001/5/2 2001/6/12 2013/2/26 354 days 2022/4/21 EP1305014B1 2001/5/2 2006/1/10 NA / 2021/5/2 JP5575351B2 2001/5/2 2005/7/27 2013/3/25 NA 2021/5/2 JP5629746B2 2001/5/2 2014/8/20 2013/3/25 NA 2021/5/2 CN1287775C 2001/5/2 2014/11/26 NA / 2021/5/2 Acotiamide hydrochloride hydrate 3 §2 Chemistry Route 1: Original Discovery Route[1] Journal Citation/ Reference Title Comments Patent NO. Aminothiazole derivatives, drug containing the same and intermedi- WO9636619A1 1 Key Ref. ate in the production of the compounds US5981557A Route 2[2, 3]: Journal Citation/ Reference Title Comments Patent NO. Preparation of 2-bromo-4,5-dialkoxybenzoic WO2012077673A1 2 Key Ref. acid in high efficiency at low cost US20130253222A1 Method for producing aminothiazole derivative and production inter- WO2006022252A1 3 mediate US8772528B2 The Pharmaceutical Index – Worldwide 2013 NCEs 4 Route 3[4, 5]: Journal Citation/ Reference Title Comments Patent NO. WO9858918A1 4 Process for producing 2-hydroxybenzamide derivatives Key Ref. US6197970B1 5 Synthetic method of acotiamide hydrochloride hydrate CN103709191A Route 4[6]: Journal Citation/ Reference Title Comments Patent NO. 6 One-pot method for preparing acotiamide hydrochloride CN104045606A Key Ref. Acotiamide hydrochloride hydrate 5 Route 5[7]: Journal Citation/ Reference Title Comments Patent NO. 7 Method for preparing acotiamide hydrochloride CN103387552A Key Ref. The Pharmaceutical Index – Worldwide 2013 NCEs 6 §3 Pharmacology Mechanism of Action Acotiamide hydrochloride hydrate is an acetylcholinesterase (AChE) inhib- itor and enhanced the acetylcholine (ACh)-induced contraction and motility of the gastric antrum and the gastric body. Acotiamide inhibited AChE with mixed pattern (Ki1=0.61±0.03 µM , Ki2=2.7±0.2 µM , and IC50=3 µM) and suppressed the degradation of acetyl- choline (ACh) released from cholinergic nerve terminals[8]. The AChE inhibitory effect of Acotiamide almost disappeared by dialysis, [8] it was shown to be reversible . Acotiamide did not show a high affinity to the muscarinic M1, M2, M3 re- ceptors, dopamine D2S receptors and serotonin 5-HT4 receptors involved in the regulation of gastrointestinal motility[8]. In Vitro Efficacy Acotiamide improved ACh-induced contraction in gastric sample in vitro at 1 µM[8]. Acotiamide improved electrical-induced contraction in gastric sample in vitro at 0.3 µM[8]. In Vivo Efficacy [8] Acotiamide significantly improved the gastrointestinal motility : In normal and clonidine-induced gastric antrum hypomotility dogs: at 10 mg/kg dose. In normal rats: at 30 mg/kg dose. In clonidine-induced gastric antrum hypomotility rats: at 100 mg/kg. [8] Significantly improved clonidine-induced delayed gastric emptying in rats: at 100 mg/kg, s.c.
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