TWI281861B - A pharmaceutical composition comprising SANORG 34006 for treatment and secondary prophylaxis of venous thromboembolic events in patients with deep venous thrombosis - Google Patents
A pharmaceutical composition comprising SANORG 34006 for treatment and secondary prophylaxis of venous thromboembolic events in patients with deep venous thrombosis Download PDFInfo
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- TWI281861B TWI281861B TW092100703A TW92100703A TWI281861B TW I281861 B TWI281861 B TW I281861B TW 092100703 A TW092100703 A TW 092100703A TW 92100703 A TW92100703 A TW 92100703A TW I281861 B TWI281861 B TW I281861B
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- 238000011282 treatment Methods 0.000 title claims abstract description 46
- 208000004043 venous thromboembolism Diseases 0.000 title claims abstract description 18
- 206010051055 Deep vein thrombosis Diseases 0.000 title claims abstract description 17
- 206010047249 Venous thrombosis Diseases 0.000 title claims abstract description 17
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 7
- 238000011321 prophylaxis Methods 0.000 title abstract 2
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 239000002253 acid Substances 0.000 claims abstract description 4
- 206010014522 Embolism venous Diseases 0.000 claims description 16
- 230000009863 secondary prevention Effects 0.000 claims description 5
- 159000000000 sodium salts Chemical class 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 abstract description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract 1
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N benzo-alpha-pyrone Natural products C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 27
- AKGGYBADQZYZPD-UHFFFAOYSA-N benzylacetone Chemical compound CC(=O)CCC1=CC=CC=C1 AKGGYBADQZYZPD-UHFFFAOYSA-N 0.000 description 26
- 229960000956 coumarin Drugs 0.000 description 14
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- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 10
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- 206010028980 Neoplasm Diseases 0.000 description 4
- 239000003146 anticoagulant agent Substances 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 229960002897 heparin Drugs 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 230000002747 voluntary effect Effects 0.000 description 4
- GOLORTLGFDVFDW-UHFFFAOYSA-N 3-(1h-benzimidazol-2-yl)-7-(diethylamino)chromen-2-one Chemical compound C1=CC=C2NC(C3=CC4=CC=C(C=C4OC3=O)N(CC)CC)=NC2=C1 GOLORTLGFDVFDW-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 230000015271 coagulation Effects 0.000 description 3
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- 229940109239 creatinine Drugs 0.000 description 3
- 238000013461 design Methods 0.000 description 3
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- 239000003055 low molecular weight heparin Substances 0.000 description 3
- 229940127215 low-molecular weight heparin Drugs 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 230000001732 thrombotic effect Effects 0.000 description 3
- 210000000689 upper leg Anatomy 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 3
- 229960005080 warfarin Drugs 0.000 description 3
- 208000005189 Embolism Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 230000002785 anti-thrombosis Effects 0.000 description 2
- 108010072035 antithrombin III-protease complex Proteins 0.000 description 2
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- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- MVPQUSQUURLQKF-MCPDASDXSA-E nonasodium;(2s,3s,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3s,4s,5r,6r)-2-carboxylato-4,5-dimethoxy-6-[(2r,3r,4s,5r,6s)-6-methoxy-4,5-disulfonatooxy-2-(sulfonatooxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-4,5-disulfonatooxy-2-(sulfonatooxymethyl)oxan-3-yl]oxy-4,5-di Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[O-]S(=O)(=O)O[C@@H]1[C@@H](OS([O-])(=O)=O)[C@@H](OC)O[C@H](COS([O-])(=O)=O)[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@@H]2[C@@H]([C@@H](OS([O-])(=O)=O)[C@H](O[C@H]3[C@@H]([C@@H](OC)[C@H](O[C@@H]4[C@@H]([C@@H](OC)[C@H](OC)[C@@H](COS([O-])(=O)=O)O4)OC)[C@H](O3)C([O-])=O)OC)[C@@H](COS([O-])(=O)=O)O2)OS([O-])(=O)=O)[C@H](C([O-])=O)O1 MVPQUSQUURLQKF-MCPDASDXSA-E 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
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- 208000024891 symptom Diseases 0.000 description 2
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- 230000003442 weekly effect Effects 0.000 description 2
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 1
- 241000906142 Balistes polylepis Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000208688 Eucommia Species 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910001420 alkaline earth metal ion Inorganic materials 0.000 description 1
- 230000001858 anti-Xa Effects 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- -1 benzyl coumarin Chemical compound 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
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- 230000003247 decreasing effect Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 210000002414 leg Anatomy 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 238000009549 lung scintigraphy Methods 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
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- 238000004519 manufacturing process Methods 0.000 description 1
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- 231100001160 nonlethal Toxicity 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
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- 230000002265 prevention Effects 0.000 description 1
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- 230000000306 recurrent effect Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
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- 229960000103 thrombolytic agent Drugs 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7024—Esters of saccharides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Description
12818®# 2 ·· 第 92 100703 號專利申請案 中文說明書替換頁 民國年2月13日修正 (1) 玖、發明說明 年月日修(更)正本 ^ 1 3 【發明所屬之技術領域】 本發明有關用於帶有深靜脈血栓形成(DVT)之病人中 治療及繼發性預防靜脈血栓性栓塞症(VTE)的姍歐34006 之特定劑量。 【先前技術】
急性DVT治療後復發VTE是完成抗血栓形成療法之 病症急性治療後的常見臨床特徵。因此,爲了降低長期復 發率,需要長期抗血栓形成療法。通常,使用未分級肝素 (UFH)、低分子量肝素(LMWH)、血栓溶解劑與苄丙酮香豆 素處理VTE。目前採用的DVT急性治療後之長期療法係 於診斷時同時開始使用肝素與口服抗凝血劑療法(苄丙酮 香豆素或其他香豆素),並於第四與第七天之間中斷該肝 素療法。帶有VTE之病人的許多隨時試驗已顯示出,開 始肝素療法的5至7天倂用早期苄丙酮香豆素激發與治療 至少3個月有效而且安全[Hyers等人,ACCP 2001,CHEST 2001; 119:1 8 0S]。爲了有效治療,動物與人體試驗已顯示 出血漿肝素水準在0.2-0.4 IU/mL範圍內會抑制血栓增生 [Hyers 等人,ACCP 200 1, CHEST 2001; 119:178S] ° 【發明內容】 令人驚訝而且與技藝中一般實務矛盾的是’發現每週 服用一次劑量低至2.5 mg之五糖甲基-0-(2,3,4-三-〇-甲 -6 - 年月日修(更)正本 96. 2. 13____ 1281861 (2)
基- 6-0-硫代- a -D-吡喃葡糖基)-(l— 4)-〇-(2,3-三-〇-甲基-/5-D-¾喃葡糖基糖醛酸)-(l—4)-〇-(2,3,6-三-〇-硫代-α-吡 喃葡糖基)-(l— 4)-0-(2,3-三-〇-甲基- a -L-艾杜吡喃葡糖基 糖醒酸(i d 〇 p y r a η 〇 s y 1 u r ο n i c a c i d)) - (1 — 4) _ 〇-(2,3,6 -三-〇-硫 代-α -吡喃葡糖,或其藥學可接受鹽(特別是其九鈉鹽姍歐 34006,詳見US 5,37 8,829)有利於帶有DVT之病人中治療 與繼發性預防 VTE,而且相當安全。服用劑量爲2.5 mg 之姍歐34006之後,血漿通過水準(Cmin := 1 26:1:63 ng/mL) 相當於 0.09-0.26 抗 Xa U/mL,然而 0.2-0.4 IU/mL UFH 加 上額外抗Ila活性在VTE治療中通常視爲有效水準(見上 文)。
由於帶有DVT病人中治療與繼發性預防VTE的治療 性攝藥方法可能伴隨出血風險提高,故有效而且安全的抗 凝血劑最低劑量是最佳劑量。本發明每週服用一次之低劑 量姍歐34006形成非常低血漿含量,出乎意料地,其仍然 有利於預防與治療VTE。 本發明之治療療法不需要後續監控與劑量調整。 【實施方式】 「藥學可接受鹽」一辭意指具有相對離子之鹽,諸如 鹼金屬或鹼土金屬離子,諸如鈉、鈣或鎂。 本發明之五糖劑量係以皮下注射方式對進行治療的病 人施打。該病人係人類爲佳。作爲藥學組成物之五糖包含 該五糖以及藥學可接受輔助用劑與選擇性其他治療藥學。 (3) 1281861 「可接受」一辭意指可與該組成物其他成份相同,而且對 其受者無害。 非經腸施用本發明五糖之劑量的藥學組成物係以單元 劑量或多劑量保存,例如,預定量之注射液體,例如密封 在管瓶或小玻璃瓶中,而且亦可在冷凍乾燥條件條件下貯 存,於使用前僅需要添加無菌液體載體,例如水。 與此等藥學可接受輔助用劑與液體(例如,標準參考 資料 Gennaro 等人之 RemingtonJ s Pharmaceutical Sciences, (第 18 版,Mack Publishing Company,1 990,詳見第 8 部分 :Pharmaceutical Preparations and Their Manufacture))混合 ,該五糖可以液態組成物、注射製劑、溶液、懸浮液或乳 液形式施用。可使用水性懸浮液、等滲鹽水與無菌可注射 溶液,其包含藥學可接受分散劑及/或濕潤劑,諸如丙二 醇或丁二醇。較佳之藥學組成物係五糖之等滲鹽水溶液。 本發明之五糖組成物亦可以獸醫組成物形成存在,諸如以 本技術中習用方法製備之此等組成物。 以下列實施例進一步說明本發明。 實施例 臨床資料證實,與苄丙酮香豆素相較,(使用)劑量 2.5 mg之姍歐34006對於帶有深靜脈血栓形成(DVT)之病 人中治療與繼發性預防靜脈血栓性栓塞症顯示出功效與安 全性。 (4) 1281861 整體硏究設計 該硏究是五個平行組中的第二階段多中心無規則硏究 ,爲姍歐34006劑量的雙重空白試驗,以及口服苄丙酮香 豆素(對照組)開放命名評估空白試驗。該硏究設計圖示於 圖1。 以伊諾薩巴林(enoxaparin)(代表LMWH)開始對所有病 人施以注射9-14次(相當於6± 1天)治療,將爲數650位 已確認症狀基部DVT的病人隨機分配到治療組之一(2.5 mg、5 mg、7.5 mg 或 10 mg SC 姍歐 34006,或口服苄丙酮 香豆素)。每個治療組是由1 30位病人組成,其中至少1 00 位病人屬於自願治療(ITT)組。在最終評估後的四週期間 內,追蹤姍歐3 4 0 0 6治療組的對象。 目的: 此硏究的主要(相關)目的是: •評估姍歐34006的劑量-效用關係,避免以伊諾薩 巴林(enoxaparin)開始治療症狀基部D VT —段時間之後, VTE復發或擴散; •測定姍歐34006的最佳劑量,其將用於進一步對照 治療硏究。在考量功效、安全性、凝血標記與整體性能之 下選用此種最佳劑量。 第二目的是評估姍歐34006的整體藥物動力學。 診斷與歸納標準: -9- (5) 1281861 •以CUS(壓縮超音波/迴音)或靜脈造影確認症狀基部 DVT(界定爲腿彎部靜脈、大腿表面靜脈或大腿一般靜脈) 9 •男性或未懷孕女性; •簽名同意者 治療期間= 每個病人注射9-14次伊諾薩巴林(En〇xaparin)(相當於 治療5-7天),然後每週施用一次姍歐34006,進行12週 ,或是進行12週之苄丙酮香豆素療程。 參與硏究期間: 6± 1天伊諾薩巴林(Enoxaparin)治療與最長達12週± 1 天之隨機治療,並對姍歐34006治療組額外追蹤4週。 評估標準: •功效 主要功效參數 在包括對於實質改良進行補充分析之基線測量(即, 惡化、正常化、或無相關變化)的隨機治療1 2週之後,由 中央評審委員會使用3點結果順序標度評估血栓形成負荷 量。 * 次要功效參數 使用二元標度之血栓形成負荷量的變化(即,惡化與 -10- (6) 1281861 未惡化);CUS在3點順序標度之變化;PLS在3點順序 標度之變化;複合臨床結果(非致死症狀PE及/或復發 DVT、因PE及/或DVT或未解釋原因死亡,以及血栓形成 栓塞症治療管理中的任何重大變化);凝血標記;血漿D 一聚物(纖維蛋白破片、測量中形成中之血栓)以及硏究治 療期間之TAT(凝血酶-抗凝血酶複合物)之濃度。
主要安全性參數:引發大出血及血小板數減少 次要功效參數:(嚴重)不良栓塞症、實驗參數(血液學、生 物化學、凝血狀態、血小板數),以及生命跡象(血壓、心 率、體重)。 •藥物動力學
於第2、4與7週服用姍歐34006之前48小時內評估 姍歐3 4 0 0 6的血漿濃度。此外,在第7週期間,於〇. 5 - 2 小時、2-6小時、6-4 8小時與120-168小時遞送劑量。在 一組病人亞組當中,在每次用藥之前,以前劑量樣本進行 更廣泛取樣模式’第7週之系列模式亦應用於第丨與第 12週。由第7週(以及前述亞組之第1與ι2週)的更廣泛 資料計算參數、Cmin與AUC(u68)。 11 - (7) 1281861 主要功效分析 表1 由CAC(3點標度)所評估之自願治療組的血栓 形成負荷量的整體變化總論,資料包括未解釋 死亡、症狀(惡化)、大腿的壓縮超音波(沒有) 變化,以及肺的閃爍照相(沒有)變化 結果 姍歐 34006 苄丙酮香豆素 (N=124) 2.5 mg (N=125) 5 mg (N-128) 7.5 mg (N=l 18) 10 mg (N=l 19) n(%) n(%) n(%) n(%) n(%) 正常化 32(25.6) 31(24.2) 29(24.6) 30(25.2) 31(25.0) 無相關 87(69.9) 89(69.5) 81(68.6) 74(62.2) 84(67.7) 變化 惡化 6(4.8) 8(6.3) 8(6.8) 15(12.6) 9(7.3) 逐對比 0.936 0.906 0.984 0.360 較* 百分比係以可評估分數爲基準。CAC=中央評審委員會
*與苄丙酮香豆素比較之P値,以CMH試驗爲基準, 層化活性癌症 婿歐34006之劑量趨向P値爲p = 0.388,以Chchran-Mnatel-Haenszel(非零相關)之劑量趨向試驗爲基準,層化 活性癌症。 -12- (8) 1281861 次要功效分析 表2由CAC評估之自願治療組的複合臨床結果總論 致死或非致死 復發DVT、症 狀PE或未解釋 死亡1 姍歐34006 苄丙酮香豆素 (N=124) 2.5 mg (N=125) 5 mg (N=128) 7.5 mg (N=118) 10 mg (N=119) 否 π(%) 125(100.0) 126(98.4) 118(100.0) 116(97.5 122(98.4) 95% CI [97.1,100] [94.5,99.8] [96.9,100] [92.8, 99.5] [94.3, 99.8] 是 η(%) 0(0.0) 2(1.6) 0(0.0) 3(2.5) 2(1.6) 95% CI [0.0, 2.9] [0.2, 5.5] [0.0, 3.1] [0.5, 7.2] [0.2, 5.7] CI =可信區間 表3 由CAC評估之自願治療組的血栓形成負荷 量的整體變化總論 姍歐34006 苄丙酮香豆素 2.5 mg 5 mg 7.5 mg 10 mg (N=124) (N=125) (N=128) (N=118) (N=119) 未 n(%) 119(95.2) 120(93.8) 110(93.2) 104(87.4) 115(92.7) 惡化95%CI [89.8, 98.2] [88.1,97.3] [87.1,97.0] [80.1,92.8] [86.7, 96.6] 惡化n(%) 6(4.8) 8(6.3) 8(6.8) 15(12.6) 9(7.3) 95% CI [1.8,10.2] [2.7,11.9] [3.0,12.9] [7.2,19.9] [3.4,13.3] 逐對比較1 0.570 0.550 0.655 0.219 -13- 1 與苄丙酮香豆素比較之P値,以CMH試驗爲基準,層化 活性癌症 姍歐34006之劑量趨向p値爲p = 0.062,以CMH(非零 相關)試驗爲基準,層化活性癌症。 1281861 Ο) 出血評估與相關標準 表4 隨機治療期間之出血症;針對進行隨機治療 組的所有病人做評估 姍歐34006 2.5 mg 5 mg 7.5 mg 10 mg 苄丙酮香豆素 (N=131) (N=135) (N 二130) (N=131) (N=132) 結果 n(%) n(%) n(%) n(%) n(%) 大出血 0(0.0) 4(3.0) 2(1.5) 9(6.9) 1(0.8) 無大出血 131(100.0) 131(97.0) 128(98.5) 122(93.1) 131(99.2) 逐對比較* 0.318 0-184 0.533 0.010
百分比係以可評估分數爲基準 *與苄丙酮香豆素比較之P値,以Cochran-Armitage 試驗爲基準,10 mg的重要性。
姍歐34006之劑量趨向P値爲p = 0.003,以Cochran-Armitage試驗爲基準。 -14- (10) 1281861 表5 隨機治療期間之出血症;針對進行隨機治療 組的所有病人做評估 婿歐34006 2.5 mg 5 mg 7.5 mg 10 mg 苄丙酮香豆素 (N=131) (N=135) (N=130) (N=131) (N 二 132) 結果 n(%) 11(%) n(%) n(%) n(%) 任何出血 3(2.3) 16(11.9) 18(13.8) 20(15.3) 11(8.3) 無出血 128(97.7) 119(88.1) 112(86.2) 111(84.7) 121(91.7) 逐對比較* 0.029 0.340 0.155 0.081 百分比係以可評估分數爲基準
*與;丙酮香豆素比較之P値,以Cochran-Armitage 試驗爲基準,2.5 mg的重要性。 姍歐34006之劑量趨向P値爲p = 0.001,以Cochi*an-Armitage試驗爲基準。
-15- (11) 1281861 結論 • 觀察到受測姍歐34006劑量的主要與次要功效終 點並無重大統計劑量-反應關係 • 觀察到受測苄丙酮香豆素與姍歐3 4 0 0 6劑量間並 to差里 • 與苄丙酮香豆素相較,在統計上於2 · 5 m g姍歐 3 4 0 0 6組所發生之出血症明顯較少。觀察到引發出血症與 大出血症之統計重要劑量趨向。 • 10 mg姍歐34006劑量組適用於大出血停藥規則 ,故此劑量組提早中止用藥。 • 所有姍歐34006劑量與苄丙酮香豆素對於不良症 (出血症除外)、實驗參數與生命跡象等方面的耐受性大致 良好。 • 觀察劑量比例藥物動力學,在第12週,凹谷濃 度是第一次用藥後,而AUC値是第一次用藥後對應値的2 倍高時,達到穩定狀態。 • 體重與肌酸酐廓淸率顯示出與姍歐34006最強關 係,造成姍歐34006暴露量隨著體重或肌酸酐廓淸率下降 而提高。 • 出血症(大出血與所有出血)與姍歐34006暴露量 較高一致,在協方差分析中,主要伴隨年齡及肌酸酐廓淸 率發生。 • 以2 · 5 m g姍歐3 4 0 0 6治療後的所有血漿濃度均 保持在伴隨出血風險提高的水準以下。 -16- (12) 1281861 進一步分析 下圖2顯示以上述硏究結果爲基礎,每週施用2.5 mg 伊卓巴林諾克斯(idraparinux)治療VTE病人期間之預測姍 歐3 4006的平均血漿濃度與時間計劃。ACCP建議的範圍 □詳見[Hyers 等人,ACCP 200 1,CHEST 200 1; 119:178S]介 於虛線之間。
已知若開始治療當週內治療不當,對於進一步病症發 生率的影響最大[即,即使隨後已恢復精確性亦有影響(參 考 Brandjes 等人之 NEJM 1 992;3 27 (2 1 ):1 485 -9)]。須注意 ,‘Brandjes’試驗有關急性治療不全。不過,急性治療週 之後的不當治療的影響更大:在接下來1 2週之不當治療 可能造成25%之 VTE復發率(Cl Lagerstedt等人,Lancet 1 9 8 5; Sep 7:515-8; R. Hull 等人,HEJM 1 979; 30 1 ( 1 6):85 5 -8) 0
本硏究中之姍歐34006的第一週實際上是治療的第二 週。因此,若治療早期以姍歐34006治療不當,可預測該 治療期晚期會引發血栓形成負荷量惡化。 不過,以ACCP觀測線來看,即使75%之病人的2.5 mg劑量的血漿水準「太低」,與在ACCP範圍內之較高 劑量病人相較時,並未觀察到惡化率提高。此結果顯示於 下表6。 -17- (13) 1281861 表6 於第7週期間觀察到最小伊卓巴林諾克斯 (idraparinux)血獎濃度之不同等級中,12週 治療期間整體血栓形成負荷量惡化引發率 (%; n/N),其中資料係自所有隨機病人收集 ;具有可評估功效終點與適當PK評估之 ITT病人 C「nin等級 惡化率 <3 00 ng/mL 3.1% 3/96 300- 600 ng/mL 5.4% 8/148 600-900 ng/mL 6.3% 9/142 900- 1 200 ng/mL 7.8 4/51 ^ 1200 ng/mL 4.5% 1/22 PK =藥物動力學;適當的PK評估係指CnHn,其係於下一次 施藥之前的濃度,亦指c凹谷或凹谷水準’可偵測每次施 用之下一劑量的最低水準。 【圖式簡單說明】 圖1示硏究設計 圖2以上述硏究結果爲基礎,每週施用2.5 mg伊卓巴 -18- 1281861 (14) 林諾克斯(idraparinux)治療 VTE病人期間之預測姍歐 34006的平均血漿濃度與時間計劃。
Claims (1)
1281861 r™—^~—Ί 年月日修(更)正本 96, 2, 13 拾、申請專利範面 附件4Α: 第92 1 00703號專利申請案 中文申請專利範圍替換本 民國96年2月13日修正 1 · 一種用於帶有深靜脈血栓形成之病人治療靜脈血 栓性栓塞症及/或繼發性預防彼之藥學組成物,其包含用 於一星期投服一次之2.5 mg五糖甲基-0-(2,3,4-三-0-甲 基- 6- 0-硫代-a -D -吡喃葡糖基)-(1— 4)-0-(2,3-二-0-甲基· /3-D-卩lt喃葡糖基糖醛酸)-(l->4)-0-(2,3,6-三-0-硫代-α-D-批喃葡糖基)-(1— 4)-0-(2,3-二-0-甲基-^-1>-艾杜吡喃 葡糖基糖醒酸(idopyranosyl uronic acid))-(l — 4)-2,3,6-三-〇-硫代-a -D-吡喃葡糖苷或其藥學可接受鹽。 2 ·如申請專利範圍第1項之藥學組成物,其中該五 糖呈其九鈉鹽(姍歐34006)形式。 3. —種劑量爲2.5 mg之五糖甲基-0-(2,3,4-三-0-甲 基- 6-0-硫代- a -D-D 比喃葡糖基)-(1— 4)-0-(2,3-二-0-甲基-/5-D-吼喃葡糖基糖醛酸)-(l44)-0-(2,3,6-三-0-硫代-α-D- 〇比喃葡糖基)-(1->4)-0-(2,3_二-0-甲基- α-L-艾杜吡喃 葡糖基糖醒酸(i d 〇 p y r a η 〇 s y 1 ur ο ni c a c i d)) · (1 — 4) - 2,3,6-三-〇-硫代- a -D-吡喃葡糖苷或其藥學可接受鹽之用途, 其係用以製備用於在帶有深靜脈血栓形成之病人中治療及 繼發性預防靜脈血栓性栓塞症一星期投服一次的藥品。 4. 如申請專利範圍第3項之用途,其中該五糖呈其 1281861 九鈉鹽(姍歐34006)形式。 1281861 陸、(一0、本案指定代表圖爲:第_匱 (二)、本代表圖之元件代表符號簡單說明: ^frrp Μ 柒、本案若有化學式時,請揭示最能顯示發明特徵的 化學式:
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