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1、药物评价和研究中心申请编号21-849临床药理学与生物药剂学评价Clinical Pharmacology and Biopharmaceutics ReviewNDA: 21-849 (SN-000)Brand Name: ZegeridGeneric Name: OmeprazoleDosage form and Strength: 20 and 40 mg CapsulesRoute of administration: OralIndication: Related to GI disordersSponsor: Santarus, Inc.Type of submission: Or
2、iginalClinical Division: GI and Dermatology DivisionOCPB Division: DCPB IIIPriority: StandardSubmission date: 04/26/05, O 1 /04/06OCPB Consult date: OS/10/OSReviewer: Tien-Mien Chen, Ph.D.Team leader: Edward D. Bashaw, Pharm. D.Zegerid 临床药理学及生物药剂学评论新药申请: 21-849 (SN-000)商品名: Zegerid通用名: 奥美拉唑剂型及规格: 20
3、 and 40 mg 胶囊剂给药途径: 口服不良反应: 肠胃系统紊乱申请者: Santarus, Inc.提交种类: 原研 临床部: 胃肠和皮肤部OCPB 部: DCPB III优先次序: 标准提交日期: 04/26/05, 01 /04/06OCPB 受理日期: OS/10/OS评审员: Tien-Mien Chen, Ph.D.组长: Edward D. Bashaw, Pharm. D. Executive SummaryOmeprazole is a substituted benzimidazole that inhibits gastric acid secretion via s
4、pecific inhibition of H+/K+ ATPase enzyme system at the secretory surface of the gastric parietal cell.Omeprazole has been approved and marketed in the US since 1989 as Prilosec delayed release (DR) 20 and 40 mg capsules given once daily for the treatment of a variety of shoal:- and long-term GI con
5、ditions. Prilosec is an enteric-coated dosage form for delayed release purpose due tothe acid-labile nature of omeprazole.Santarus previously developed an immediate release (IR) formulation of omeprazole powder fororal suspension (Zegerid) comprised of immediate release omeprazole and sodium bicarbo
6、nate,with sodium bicarbonate protecting omeprazole from rapid degradation by gastric acid. In 2004,two dosage strengths of Zegerid IR powder for oral suspension (20 mg under NDA 21-636 and 40 mg under NDA 21-706, respectively) were approved in the US based on 505(b)(2) provision relying on pharmacok
7、inetic (PK) and pharmacodynamic (PD) bridging data to support the reference to the Agencys previous finding of safety and efficacy for Prilosec DR 20 and 40 mg capsules. 概 要奥美拉唑是一种通过特异性抑制腺体表面的 H+/K+ATPase 酶系统来抑制胃酸分泌的苯并咪唑替代物。奥美拉唑于 1989 年在美国被批准并上市销售，奥美拉唑 20mg 和40mg 缓释胶囊治疗一系列的胃肠疾病。洛赛克是基于奥美拉唑对酸不稳定而制作的一种
8、肠溶缓释剂。Santarus 先前开发了由奥美拉唑和碳酸氢钠粉末混合而成的奥美拉唑直接释放口服制剂，以碳酸氢钠防止奥美拉唑在胃酸中的快速降解。2004 年，Zegerid IR 的两个优势剂型，口服悬浮剂（NDA 编号为 21-636 的 20mg 和 NDA 编号为 21-706 的 40mg，单独的）在美国基于 505(b)(2)规定被批准。其药代动力学和药效学数据支持了之前涉及到管理中心发现的洛赛克 20mg 和 40mg 胶囊安全性和有效性的问题。The current submission (NDA 21-849) for Zegerid 20 and 40 mg IR capsul
9、es, also filed under 505(b)(2) provisions, consists of two clinical pharmacology studies,OME-IR (CAP)-CO1 and OME-IR (CAP)-C02, plus supportive studies. Study OME-IR (CAP)-COl evaluated the PK and PD of omeprazole when Zegerid IR 20 mg capsule was DR 20 mg capsule given QD for 7 days. 当前提交(NDA 21-84
10、9)的 Zegerid20mg 和 40mg 胶囊,也是基于 505(b)(2)条款，有两种临床药理学，OME-IR (CAP)-CO1 和 OME-IR (CAP)-C02,加上支持研究。在给予 Zegerid IR 20 mg 胶囊给予 7 天研究其药效学的同时评价了 OME-IR (CAP)-CO1 药代动力学和药效学。Study OME-IR given 1 hour-premeal QD vs. Prilosec (CAP)-C02 evaluated similarly the PK and PD of omeprazole when Zegerid IR 40 mg capsul
11、e was given 1 hour-premeal QD vs.Prilosec DR 40 mg capsule QD for 7 days. on Day 8 vs. Zegerid given 1 hour-premeal were also investigated. The food effects on Zegerid given 1 hour-postmeal on Day 7 for both Zegerid IR 20 and 40 mg capsulesZegerid IR 40 mg 胶囊与 Prilosec DR 40 mg 胶囊在为期 7 日饭前 1 小时给药的药效
12、学对比研究中，OME-IR 和洛赛克 (CAP)-C02 中奥美拉唑的药代动力学和药效学评价结果相似。同时也研究了第 8 天的饭前 1 小时给药。在饭前一小时给药的 7 日研究中，进食对Zegerid IR 20 and 40 mg 胶囊都有影响。Based on the Agencys bioequivalence acceptance criteria for PK data obtained from Day 7, Zegerid IR 20 or 40 mg capsule is not bioequivalent (BE) to Prilosec DR 20 or 40 mg cap
13、sule, respectively. Zegerid capsules had higher mean CmaX values than those of Prilosec capsules (17% for 40 mg dose and 45%for 20 mg dose). However, Zegerid and Prilosec capsules had comparable systemic exposure (AUCs). The higher mean CmaX value of Zegerid IR 40 mg capsule obtained from this NDA w
14、as found to be comparable (3% lower) compared to the mean Cmax value obtained from Zegerid 40 mg IR powder for oral suspension which has been determined to be safe based on a previous clinical safety study.通过第 7 天获得的药代动力学数据，以审评中心的的生物等效性验收标准为依据，Zegerid IR 20 or 40 mg 与 Prilosec DR 20 or 40 mg 不是生物等效的，而是独立的。Zegerid 胶囊比洛赛克胶囊(17% 使用 40mg 剂量和 45%使用 20mg 剂量)具有更高的平均血药峰浓度。然而， Zegerid 和 Prilosec 胶囊具有可比较的系统性暴露（曲线下面积） 。在此项新药申请中获取的 Zegerid IR 40mg 胶囊具有更高平均血药峰值的价值在于，将基于之前的临床安全性研究确定其与 Zegerid 40 mg IR 口服混悬粉末谁更安全。Food had significant
