Zegerid 临床药理学及生物药剂学评论

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 Review NDA: 21-849 (SN-000)
Brand Name: Zegerid
Generic Name: Omeprazole
Dosage form and Strength: 20 and 40 mg Capsules
Route of administration: Oral
Indication: Related to GI disorders
Sponsor: Santarus, Inc.
Type of submission: Original
Clinical Division: GI and Dermatology Division
OCPB Division: DCPB III
Priority: Standard
Submission date: 04/26/05, O 1 /04/06
OCPB Consult date: OS/10/OS
Reviewer: 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 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 /04/06
OCPB 受理日期: OS/10/OS
评审员: Tien-Mien Chen, Ph.D.
组长: Edward D. Bashaw, Pharm. D.
ⅠExecutive Summary
Omeprazole is a substituted benzimidazole that inhibits gastric acid secretion via specific 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 conditions. 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 bicarbonate,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 pharmacokinetic (PK) and pharmacodynamic (PD) bridging data to support the reference to the Agency's previous finding of safety and efficacy for Prilosec DR 20 and 40 mg capsules.
Ⅰ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 capsules, 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 21-849)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 capsule 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 capsules
Zegerid 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 Agency's 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 capsule, 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 was 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 effects on lowering mean Cm} (45%↓,) when Zegerid IR 40 mg capsule was given 1 hour-postmeal compared to that given 1 hour-premeal. Food, however, had minor effects on the systemic exposure (AUCs), being 10-15% lower, when Zegerid was given 1
hour-postmeal. Therefore, similar to Zegerid IR powder for oral suspension, Zegerid IR capsules should be given at least 1 hour before a meal.
在饭前1小时和饭后1小时给予Zegerid IR 40mg胶囊的研究中，食物对降低平均血药峰浓度有显著的影响。

然而，食物对系统性暴露（曲线下面积）只有次要的影响，饭后1小时给药降低10~15%。

因此，与Zegerid IR口服混悬剂类似，Zegerid IR胶囊应至少在饭前1小时给药。

Comparison of the PD profiles after multiple dosing of Zegerid IR capsules and Prilosec DR capsules indicated that both products are generally similar on all the assessed PD markers for 20and 40 mg dose levels.
多次服用Zegerid IR胶囊和洛赛克DR胶囊的药效学图谱对比可知，20mg和40mg剂量水平的药代动力学标记数据评价结果普遍相似。

A. Recommendations
From the view point of Office of Clinical Pharmacology and Biopharmaceutics (OCPB), NDA21一849 is acceptable provided that a satisfactory agreement is reached between the Agency and the sponsor with respect to proposed language in the package insert. Please see labeling comments (page 11) and Appendix 1 for details.Also, the following dissolution specifications should be conveyed to the sponsor, Q=----min for both Zegerid IR 20 and 40 mg capsules.
A 建议
从临床药理学和生物药剂学办公室的观点，NDA21一849是可以接受的，条件是在代理和申请者之间关于包装上的语言达成一个符合要求的协议。

具体细节请看标签评论（11页）和附录1.另外，接下来的溶出说明将被转达给申请者，Zegerid IR 20and 40mg胶囊都是Q=-----分钟。

B. Phase IV Commitments
None
B 第四阶段的委托
01/03/06
Tien-Mien Chen, Ph.D.
Division of Pharmaceutical Evaluation II
Team Leader
Edward D. Bashaw, Pharm. D.
II. Table of Contents
Page
I. Executive Summary (1)
II. Table of Contents (3)
III. Summary of CPB Findings (3)
IV. QBR (4)
V. Detailed Labeling Recommendations (11)
VI. Appendices (13)
II. 目录
页码
I. 摘要.................................................................................. (1)
II. 目录 (3)
III. CPB 调查结果摘要 (3)
IV. 每季审核 (4)
V. 标签规范说明 (11)
VI. 附件 (13)
III. Summary of Clinical Pharmacology
and Biopharmaceutics Findings
III. CPB 调查结果摘要
Studies OME-IR (CAP)-CO1 and OME-IR (CAP)-C02 are two identical, multiple-dose, BE-type PK/PD studies using a 2 x 2 crossover design with a washout period of at least 10-14 days. In the above PK/PD studies, 1) Zegerid 1 x 20 mg IR capsule (Test) given 1 hour-premeal QD vs. Prilosec 1 x 40 mg DR capsule QD for 7 days, and 2) Zegerid 1 x 20 mg IR capsule (Test) given 1 hour-premeal QD vs. Prilosec 1 x 40 mg DR capsule (Reference) given QD for 7 days respectively, were investigated.
OME-IR(CAP)-CO1和OME-IR(CAP)-C02的研究是两个一模一样的、多剂量的,BE-类型药代动力学/药效学研究。

OME-IR(CAP)-CO1和OME-IR(CAP)-C02的研究是两个一模一样的、多剂量的,利用2×2的交叉设计试验和一个至少10~14天的洗脱期的BE-类型药代动力学/药效学研究。

在上述PK / PD研究中，1）Zegerid 1 x 20 mg IR胶囊饭前一小时给药对比Prilosec 1 x 40 mg DR胶囊，为期7天。

2）egerid 1 x 20 mg IR胶囊饭前一小时给药对比Prilosec 1 x 40 mg DR胶囊（参照物），单独进行，也已被研究。

The food effects on Zegerid was also investigated (parallel design), i.e., Zegerid was given 1 hr postmeal on Day 8 compared to those subjects who completed Zegerid IR capsules on Day 7 in
Period 1 for both 20 and 40 mg strengths, however, only the results of food study were analyzed and reported for the 40 mg capsule.
食物对Zegerid的影响也被研究了（平行试验），也就是，第8天饭后1小时给第一阶段完整服用20mg和40mg规格Zegerid IR 胶囊的人服用Zegerid，然而，只有40mg规格胶囊的食物研究结果被分析和报告了。

Note:For subjects completed Zegerid IR 20 mg capsule given 1 hr premeal during Period 1(study OME-IR (CAP)-CO1); some received Zegerid 20 mg capsule postmeal on Day 9 rather than on Day 8 and some received Zegerid 20 mg capsule on Day 8 postmeal in Period 2. Due to mistake, protocol violation, and insufficient number of subjects completed the Day 8 postmeal study during Period 1，none of the dataset was analyzed for food effects on Zegerid IR 20 mg capsules.
注意：课题中完成的在第一阶段中饭前1小时给予Zegerid IR 20mg胶囊（为了研究OME-IR (CAP)-CO1）：在第2阶段，一些在第九天收到Zegerid 20mg胶囊多于第8天和第8天饭后1小时给予Zegerid 20mg胶囊。

由于错误，草案错误，以及在第一阶段中没有足够的人去完成第8天的饭后研究，没有资料组对食物对Zegerid IR 20mg胶囊的影响的结果进行分析。

Based on Agency's bioequivalence acceptance criteria on PK data obtained from Day 7, Zegerid IR 20 or 40 mg capsule is not BE to Prilosec DR 20 or 40 mg capsule, 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 C,naX value of Zegerid IR 40 mg capsule obtained from this NDA was found to be comparable (3% lower) 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. Food had significant effects on lowering mean Cmax (45%↓)of omeprazole when Zegerid IR 40 mg capsule was given 1 hour-postmeal compared to that given 1 hour-premeal. Food had minor effects on the systemic exposure (AUCs), being 10-15% lower, when Zegerid was given 1 hour-postmeal. Therefore, Zegerid IR capsules should be given at least 1 hour before a meal.
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。

在饭前1小时和饭后1小时给予Zegerid IR 40mg胶囊的研究中，食物对降低平均血药峰浓度有显著的影响。

然而，食物对系统性暴露（曲线下面积）只有次要的影响，饭后1小时给药降低10~15%。

因此，与Zegerid IR口服混悬剂类似，Zegerid IR胶囊应至少在饭前1小时给药。

For each omeprazole formulation (Reference or Test), the PD data was obtained, 1)%decease from baseline in integrated gastric acidity for the 24-hr interval after the 7th dose on Day 7 (primary), 2) mean gastric concentration, 3)median gastric pH, and 4)%time gastric pH < 4.0.
每个奥美拉唑剂型(参照药物或被检药物)的药效学数据已知，1）第7天的第7剂之后的24小时间隔中胃酸过多综合症的死亡率底线（初级的）,2）平均胃液浓度，3）中间胃部pH值以及4）胃部pH < 4.0.的时间比例。

Comparison of the PD profiles after multiple dosing of Zegerid IR capsules and Prilosec DR capsules indicated that both products are generally similar on all the assessed PD markers for 20 and 40 mg dose levels.
多次服用Zegerid IR胶囊和洛赛克DR胶囊的药效学图谱对比可知，20mg和40mg剂量水平的药代动力学标记数据评价结果普遍相似。

IV. Question Based Review
IV.基于问题的回顾
A.General Attributes:
A 普遍性质
Omeprazole is a substituted benzimidazole that inhibits gastric acid secretion via specific 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) capsules 20 and 40 mg for the treatment of a variety of short- and long-term GI conditions.
奥美拉唑是一种通过特异性抑制腺体壁细胞的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短期及长期胃肠疾病。

It is enteric-coated for delayed release purpose due to the acid-labile nature of omeprazole.Zegerid (omeprazole) IR powder for oral suspension comprised of immediate release omeprazole and sodium bicarbonate, with sodium bicarbonate protecting omeprazole from rapid degradation by gastric acid.
由于奥美拉唑对酸不稳定，该制剂加了肠溶包衣以延缓其释放。

Zegerid (奥美拉唑) IR口服混悬粉末由快速释放的奥美拉唑粉末和碳酸氢钠组成，以碳酸氢钠来阻止奥美拉唑在胃酸中的快速降解。

Santarus' NDAs 21-636 and 21-706 for Zegerid (omeprazole) IR powder for oral suspension 20 and 40 mg, respectively were approved on 06/15/04 and 12/21/04 for the following GI indications: 1) short-term treatment (4-8 weeks) of active duodenal ulcer, 2) short-term treatment (4-8 weeks) of active benign gastric ulcer, 3) heartburn and other symptoms associated with GERD, 4) short-term treatment (4-8 weeks) of erosive esophagitis which has been diagnosed by endoscopy, and 5) maintenance of healing of erosive esophagitis. In addition, with a new clinical trial, a new indication was also approved for the 40 mg oral suspension, i.e.,reduction of risk of upper gastrointestinal bleeding in critically ill patients which was not approved before for any of the marketed omeprazole products.
Santarus'的Zegerid （奥美拉唑）IR20mg和40mg规格的口服混悬粉末21-636 and 21-706的新药申请分别于06/15/04以及12/21/04被核准，适应症如下：1）短期治疗（4~8星期）十二指肠溃疡，2）短期治疗（4~8星期）胃溃疡，3）胃灼热及胃食管反流病的其他相关症状，4）短期治疗（4~8星期）经内窥镜检查确诊的食道炎以及5）食道炎的恢复治疗。

另外，一项新的临床试验，一项40mg口服剂的新指征也被批准了，也就是，在之前不允许应用奥美拉唑市售产品的垂危病人中减少胃出血的风险。

For this NDA (21-849) submitted under 505(b)(2) referencing to NDA 19-810 (Prilosec DR Capsules 20 and 40 mg), the sponsor, Santarus, is seeking approval for another IR dosage form of omeprazole, Zegerid IR 20 and 40 mg capsules. Submitted were two BE-type, PK/PD studies, study Nos. OME-IR (CAP)-CO1 and OME-IR-(CAP)-C02, plus two supportive PK/PD studies for oral suspension, study OME-IR (SUSP)-C02 and study OME-IR (SUSP)-C06, which had been reviewed previously.
从属505(b)(2)的规定提交的新药申请(21-849)，参照新药申请19-810（洛赛克DR胶囊20和40mg），申请者Santarus，正在申请批准奥美拉唑的另一种IR剂型，Zegerid IR 20 和40mg胶囊。

提交两个BE-类型，药代动力学/药效学研究，研究Nos. OME-IR (CAP)-CO1 和OME-IR-(CAP)-C02,另加口服混悬剂的两个药代动力学/药效学支持研究，研究OME-IR (SUSP)-C02 和OME-IR (SUSP)-C06，看哪一个可以预先被评估。

B.General Clinical Pharmacology:
B:一般临床药理学
Ql: Are Zegerid IR 20 and 40 mg capsules BE to Prilosec 20 and 40 mg DR capsules respectively?
问题1：Zegerid IR 20 and 40 mg胶囊与Prilosec 20 and 40 mg DR胶囊有区别吗？
Al: Zegerid IR 20 and 40 mg capsules are not BE to their respective Pril.sec IIR 20 and 40 mg capsules. As expected, Zegerid IR capsules had higher mean Cmax values.
(about 17%↑for 40 mg and 45%↑for 20 mg doses) as compared to that of Prilosec
DR capsules on Day 7. They, however, showed comparable systemic exposure in
terms of AUCs.
The higher mean Cmax value of Zegerid IR 40 mg capsule obtained from this NDA was found to be comparable (3% lower) to the mean Cmax value obtained from Zegerid 40 mg IR powder for oral suspension which was determined to be safe based on a previous clinical safety study.
回答：Zegerid IR 20 and 40 mg胶囊与Prilosec 20 and 40 mg DR胶囊各自都不同。

正如预期，Zegerid IR 20 and 40 mg胶囊与Prilosec 20 and 40 mg DR胶囊在第7天相比较具有更高的平均血药峰值（40mg的高17%，20mg的高45%）。

尽管如此，他们显示了相似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。

Only the study results obtained from study OME-IR (CAP)-C02 for the 40 mg-dose comparisons are shown in Table 1 and Figure 1:
表1及图1中只列出了40mg规格的OME-IR (CAP)-C02对比研究结果
Table 1. Mean PK Parameters of Omeprazole for Zegerid IR 40 mg Capsule vs.Prilosec DR 40 mg Capsule on Day 7
表1 第7天Zegerid IR 40 mg 胶囊与Prilosec DR 40 mg 胶囊中的奥美拉唑药代动力学
When given 1 hour-premeal, Zegerid IR 40 mg capsule had higher Cmax value (about 17%↑)compared to that of Prilosec DR 40 mg capsule on Day 7. However, Zegerid and Prilosec showed comparable systemic exposure in terms of AUCs on Day 7.
饭前1小时给药第7天，相比于Prilosec DR 40 mg 胶囊，Zegerid IR 40mg胶囊具有更高的最高血药浓度（高17%）。

尽管如此，按照曲线下面积计算，Zegerid 和Prilosec在第7天表现出了近似的系统暴露。

Figure 1. Mean Plasma Profiles of Omeprazole for Zegerid IR 40 mg Capsule vs. Prilosec 40 mg Capsule on Day 7
图1 Zegerid IR 40mg胶囊与Prilosec 40mg胶囊在第7天的奥美拉唑平均血浆分布图比较
Complete PK parameters/profiles (and PD parameters) of Zegerid IR capsules and Prilosec DR capsules for 1) comparison on 40 mg dose at Day 1 and 2) comparison on 20 mg dose at both Days 1 and 7 are shown in individual study reports in Appendix 2.
Zegerid IR胶囊和Prilosec DR胶囊的完整药代动力学参数/图（以及药效学）：1)d第一天40mg剂量的比较2）第一天和第七天20mg剂量的比较见附录2中的独立研究报告。

Both Cmax, and AUCs for Zegerid IR 40 mg capsule and Prilosec DR 40 mg capsule increased upon repeated daily dosing. An increase in bioavailability (Cmax and AUCs) of omeprazole had been reported in the previous NDAs for Zegerid IR powder for oral suspension and for Prilosec DR capsules as well as in the literature which could be due to 1) increase absorption due to increased pH in stomach, 2) auto inhibition of metabolizing enzymes, and 3) decreased clearance of omeprazole.
反复每日使用后Zegerid IR40mg胶囊和Prilosec DR40mg胶囊后，最大血药浓度和曲线下面积都增加了。

奥美拉唑生物利用度（最大血药浓度和曲线下面积）的增加，在之前的新药Zegerid IR申请中已被报道，与他们所依据的文献一样1）吸收的增长归结于胃部pH 值的增加，2）酶新陈代谢的自动抑制，以及3）奥美拉唑清除的减少
Q2. Does food (a standardized high fat breakfast) have significant effects on the PIE of Zegerid IR capsules?
问题2：食物（一份标准的高脂肪早餐）对Zegerid IR胶囊的PIE有重大的影响吗？
A2. Yes, similar to previously approved Zegerid IR powder for oral suspension, food had significant effects on Zegerid IR 40 mg capsule. When given 1 hour-postmeal(on Day 8), the mean Cmax of Zegerid was decreased (about 45%↓)and AUC was decreased (about 22%↓)compared to that given 1 hour-premeal (on Day 7).Therefore, Zegerid IR capsules should be given at least one hour before a meal.
回答：是的，与先前批准的Zegerid IR口服混悬粉末相似，食物对Zegerid IR 40 mg胶囊有重大的影响。

当饭后一小时给药的时候（第8天），与饭前1小时给药相比（第7天），Zegerid的平均最高血药浓度降低了（大约45%↓）并且药时曲线下面积也下降了（大约22%↓）。

因此，Zegerid IR胶囊应在饭前至少1小时给药。

The food effects on Zegerid IR 40 mg capsules when given 1-hour premeal (Day 7) vs. 1 hour-postmeal (Day 8) are shown below in Table 2 and Figure 2:
饭前1小时给药（第7天）与饭后一小时给药（第8天）时食物对Zegerid IR胶囊的影响见表2和图2
Table 2.
Zegerid IR 40 mg capsules given 1 hour- postmeal (Day 8) vs.1-hour premeal (Day 7)
Note: This reviewer could not verify/reproduce by either SAS or WinNonlin method for the reported 90% CIs for%Mean Ratio as shown in Table 2, i.e., 43.07-71.45 for ln(Cmax),70.21-85.70 for ln(AUC0_t), and 70.67一85.93 for ln(AUC0-∞) when postmeal (Day 8)and premeal (Day 7) of Zegerid 40 mg capsules were compared. Upon request on 12/06/05, the sponsor submitted on 12/08/05 the detailed analyses including SAS control files used for model, design (parallel), random factors, etc. The 90% CIs determined by this reviewer are as follows below, 37.95-81.1 for ln(Cmax), 47.4-126.92 for ln(AUCo-t), and 47.4-128.12 for ln(AUC0-∞). It should also be noted that for systemic exposure (area under the curve), AUCo-24 should be used (instead of AUC0-∞).The results of PD analyses are summarized below for 40 mg-dose comparison in Table 3:
注：当Zegerid 40 mg胶囊的饭后１小说和饭前１小时进行比较时，审核专家不能通过焦虑自评量表或WinNonlin方法确认/复制表２中已报告的平均比率的９０％Cis，也就是，ln(Cmax)为43.07-71.45, ln(AUC0_t)为70.21-85.70, 以及ln(AUC0-∞)为70.67-85.93。

经12/06/05要求，申请者于12/08/05提交了详细的分析，包括模型，设计（平行），随机因素等的焦虑自评量表管理文件。

90% Cis决定于如下的审核专家，ln(Cmax) 为37.95-81.1 , ln(AUCo-t)为47.4-126.92以及ln(AUC0-∞)为47.4-128.12。

同时也需注意的是系统性暴露（曲线下面积），应用AUCo-24（代替AUC0-∞）。

４０ｍｇ剂型的药效学比较分析结果摘要见表３。

The above study showed that on Day 7, Zegerid IR 40 mg capsule and Prilosec DR 40 mg
capsule had comparable PD results in terms of %decrease from baseline for integrated gastric
acidity, claimed as a primary PD endpoint by the sponsor, (77% vs. 79%). In general, the other
PD parameters (as secondary endpoints) also showed comparable results. Similar and
comparable PD results were obtained for Zegerid IR 20 mg capsule compared to Prilosec DR 20
mg capsule (e.g.,%decrease from baseline for integrated gastric acidity being 72% vs. 70%).
Please see individual study reports for detailed PD results (Appendix 2).
第７天的研究结果表明，Zegerid IR 40 mg胶囊和Prilosec DR 40 mg胶囊，按照申请者提供的原始药代动力学最终数据报告的综合胃酸基线下减少量来讲具有相当的药代动力学数据。

Zegerid IR 40 mg 胶囊和Prilosec DR 40 mg胶囊相比，具有相似的和可比较的药代动力学数据（例如综合胃酸基线下减少量为72% vs. 70%）。

请看详细药代动力学结果的独立研究报告（附录２）。

Note: On 06/13/05, OCPB sent a request to Division of Scientific Investigation (DSI) through GI Division for an audit for study OME-IR (CAP)-C02 (Zegerid IR 40 mg capsule). At
the time of this review, DSI had only completed the audit of the analytical part of the
study. An audit of the clinical site in Canada will be conducted at the end of Feb. 06. At
the present time, no issues have been identified by DSI that would preclude approval of
the application. Once DSI completes the audit at the clinical site and the finalized report
becomes available, OCPB will write an addendum to this review documenting those
finding and the need for any additional follow-up actions.
注：06/13/05，为了OME-IR (CAP)-C02 (Zegerid IR 40 mg 胶囊)研究的审计，OCPB通过胃肠部给科学调查部门(DSI)发送了一个请求。

在此评审过程中，DSI只完成了研究的分析审计部分。

加拿大临床现场的审计将在０６年的２月底开展。

目前为止，没有发现妨碍DSI批准该申请的问题。

只要DSI完成了临床现场的审计，最终报告将生效，OCPB将会为此评论书写一份附件以及后续的附加要求。

C. Intrinsic Factors: None
D. Extrinsic Factors: None
E. General Biopharmaceutics:
C. 内在因素: 无
D. 外在因素: 无
E. 一般生物药剂学:
Santarus' NDAs 21-636 and 21-706 for Zegerid (omeprazole) IR 20 and 40 mg powder for oral suspension, respectively were the first IR omeprazole formulations approved for indications
related to GI disorders and sodium bicarbonate (1,680 mg or 20 meq.) was included in the
formulation to protect omeprazole from rapid degradation by gastric acid.
Santarus的新药申请编号为21-636 和21-706 的Zegerid (奥美拉唑) IR 20 和40 mg口服混悬粉末，是
奥美拉唑制剂第一次有了新的适应症，那就是胃肠失调，并且本制剂中含有了防止奥美拉唑在胃液中快速讲解的碳酸氢钠。

The sponsor further developed omeprazole IR capsules which also included sodium bicarbonate
(1,100 mg or 13 meq.). The formulation/compositions of Zegerid 20 and 40 mg capsules are
shown below in Table 5:
申请者进一步开发了也含有碳酸氢钠(1,100 mg 或者13 meq.)的奥美拉唑IR胶囊，Zegerid 20和40 mg 胶囊的处方及成分见表５。

Both 20 and 40 mg dosage strengths are compositionally identical except for the amounts of omeprazole. The following dissolution methodology was used which is similar to that employed
in NDAs for Zegerid IR powder for oral suspension except for paddle speed of 50 rather than 75
rpm (Table 5). The sponsor proposed Q=------at 45 min for both strengths.
除了奥美拉唑的量以外，20 和４0 mg胶囊中其他组分的组成是一摸一样的。

接下来的溶出度方法与审评中心Zegerid IR口服混悬粉末相似，除了其搅拌桨的转速是５０转而不是７０转以外（表５）。

申请者申请将两个品种的取样点都设为４５ｍｉｎ。

It should be noted that the original dissolution specification using 50 rpm was picked up based the stability data at 0, 3, and 6 months. However, the dissolution method using 75 rprn was implemented at 6-month stability data. Therefore, the mean dissolution profiles are only available at 6 months (the clinically used biobatch and 3 stability batches). As shown below in Table 6 and Figures 3 and 4 are for Zegerid IR 20 and 40 mg capsules used in the PK/PD studies.
应当注意的是，最初在０，３，６月稳定性试验中采用的转速是５０转/分钟，但是，在稳定性６月的试验中采用了７５转/分钟。

但是，稳定是试验６月的数据中平均溶出度采用７５转的是有效的（临床采用稳定性三批样品）。

表６和图３所示的是Zegerid IR 20和40 mg胶囊在PK/PD研究中的应用。

2. Mean (CV%) dissolution data obtained from 6 capsules.
2.６粒胶囊的平均溶出度数据(CV%)
Figure 3.Mean Dissolution Profile Obtained From The 6-month stability Data of Zegerid IR 20 mg Capsule
图３Zegerid IR 20 mg胶囊的稳定性６月平均溶出数据
Figure 4. Mean Dissolution Profile Obtained From The 6-month Stability Data of Zegerid IR 40 mg Capsule
图４Zegerid IR ４0 mg胶囊的稳定性６月平均溶出数据
The difficulty in setting a dissolution specification for this product lies in limited dissolution
Data available at 6-month stability testing. Based on the limited dissolution data provided,
the following dissolution specifications for both Zegerid IR 20 and 40 mg capsules
are recommended: Q=--% at 30 min. Once additional data becomes available, the Sponsor may request a data-driven revision to the specification should a large rejection incidence be noted.
为本产品建立一个溶出度方法的难点在于稳定性６月试验的溶出度数据部分有效。

基于提供的这些有限的数据，为Zegerid IR 20and40mg胶囊建立了如下溶出度操作规范：３０分钟时Q=------%。

后期的数据获得之后，申请者可以申请依照标准进行处理，这件事很容易被忽略。

F. Analytical Section method was developed at--------- and the LLQ was determined to
be 5.0 ng/ml.. The same assay method was used previously for Zegerid IR powder for oral
suspension and it was validated and found acceptable. The summary of the assay results and validation are shown below:
Ｆ分析部方法已经建立……确定LLQ为5.0 ng/ml 。

相同的分析方法之前也应用于Zegerid IR口服混悬粉末并且经验证可靠。

分析结果及其有效性的摘要如下：
I. Study OME-IR (Cap)-C01: Zegerid IR 20 mg capsule
. I. OME-IR (Cap)-C01的研究: Zegerid IR 20 mg 胶囊
Standard Curve :5, 7.5, 10, 25, 50, 100, 200, 500, 600, and 750 ng/mL. (n=10)
Accuracy:
-0.6% (n=36), 1.6% (n=38)，-2.2% (n=38)，-0.4% (n=38), 1.0% (n=37),
0.0% (n=37), 1.5% (n=35)，-0.4% (n=37)，-0.5% (n=38), and 0.4%
(n=37)
Precision (CV%): 6.1% (n=36), 4.9% (n=38), 5.1%(n=38)，-3.9% (n=38), 3.8% (n=37),
3.6% (n=37), 2.4% (n=35), 3.6% (n=37), 2.4% (n=38), and 2.4% (n=37)
QC: 15, 100, and 565 ng/mL (n=3)
Accuracy:-4.7%(n=75)，-3.9% (n=76), and -3.5% (n=76)
Inter-day variation(CV%): 7.3% (n=75), 6.1% (n=76), and 6.5%(n=76)
标准曲线:5, 7.5, 10, 25, 50, 100, 200, 500, 600, and 750 ng/mL. (n=10)
准确性:
-0.6% (n=36), 1.6% (n=38)，-2.2% (n=38)，-0.4% (n=38), 1.0% (n=37),
0.0% (n=37), 1.5% (n=35)，-0.4% (n=37)，-0.5% (n=38), and 0.4%
(n=37)
精密度：(CV%): 6.1% (n=36), 4.9% (n=38), 5.1%(n=38)，-3.9% (n=38), 3.8% (n=37),
3.6% (n=37), 2.4% (n=35), 3.6% (n=37), 2.4% (n=38), and 2.4% (n=37)
质量控制: 15, 100, and 565 ng/mL (n=3)
准确性:-4.7%(n=75)，-3.9% (n=76), and -3.5% (n=76)
日间差异(CV%): 7.3% (n=75), 6.1% (n=76), and 6.5%(n=76)
II. Study OME-IR (Cap)-C02: Zegerid IR 40 mg capsule
II. OME-IR (Cap)-C0２的研究: Zegerid IR ４0 mg 胶囊
.Standard Curve: 5, 7.5, 10, 25, 50, 100, 200, 500, 600, and 750 ng/mL (n=10)
Accuracy: -1.2% (n=36), 1.5% (n=36)，-2.8%(n=37), 0.8% (n=36), 1.2% (n=37)
0.0% (n=37), 1.0% (n=37)，-0.8%(n=37) 0.5% (n=36), and -0.3%
(n=37),
Precision (CV%): 6.0% (n=36), 5.6% (n=36), 4.7% (n=37), 3.7% (n=36), 4.1%(n=37),
3.7% (n=37),
4.3% (n=37), 3.5% (n=37), 2.4% (n=36), and 2.5% (n=37)
QC: 15, 100, and 565 ng/mL (n=3)
Accuracy:-2.0% (n=97), 1.0% (n=97), and 0.4% (n=96)
Inter-day variation(CV%): 7.6% (n=97), 4.7%(n=97), and 8.3% (n=96)
.标准曲线: 5, 7.5, 10, 25, 50, 100, 200, 500, 600, and 750 ng/mL (n=10)
准确性:
-1.2% (n=36), 1.5% (n=36)，-2.8%(n=37), 0.8% (n=36), 1.2% (n=37)
0.0% (n=37), 1.0% (n=37)，-0.8%(n=37) 0.5% (n=36), and -0.3%
(n=37),
精密度：(CV%): 6.0% (n=36), 5.6% (n=36), 4.7% (n=37), 3.7% (n=36), 4.1%(n=37),
3.7% (n=37),
4.3% (n=37), 3.5% (n=37), 2.4% (n=36), and 2.5% (n=37)
质量控制: 15, 100, and 565 ng/mL (n=3)
准确性:-2.0% (n=97), 1.0% (n=97), and 0.4% (n=96)
日间差异(CV%): 7.6% (n=97), 4.7%(n=97), and 8.3% (n=96)
III. Assay Method Validation:
.Standard Curve: 5, 7.5, 10, 25, 50, 100, 200, 500, 600, and 750 ng/mL (n=10) Accuracy: -3.4% (n=5), 4.0% (n=4), 0.8% (n=5), 3.2% (n=4), 3.4% (n=5), 1.4% (n=4), 2.5% (n=5)，-3.4% (n=5)，一1.9% (n=5), and -4.9% (n=5) Precision: Inter-batch variation (CV%)
2.5% (n=5), 2.2% (n=4), 5.7% (n=5), 4.9% (n=4), 4.9% (n=5), 4.2%
(n=4), 2.5% (n=5), 4.5% (n=5), 4.2% (n=5), and 3.4% (n=5)
QC: 15, 100, and 565 ng/mL (n=3)
Inter-batch variation (CV%): 10.5% (n=30), 5.0% (n=30), and 5.1%(n=3 0)
Intra-batch variation (CV%): 5.9% (n=6), 2.6% (n=6), and 3.2% (n=6)
III. 分析方法确认
标准曲线: 5, 7.5, 10, 25, 50, 100, 200, 500, 600, and 750 ng/mL (n=10)
准确性: -3.4% (n=5), 4.0% (n=4), 0.8% (n=5), 3.2% (n=4), 3.4% (n=5), 1.4% (n=4), 2.5% (n=5)，-3.4% (n=5)，一1.9% (n=5), and -4.9% (n=5) 精密度: Inter-batch variation (CV%)
2.5% (n=5), 2.2% (n=4), 5.7% (n=5), 4.9% (n=4), 4.9% (n=5), 4.2%
(n=4), 2.5% (n=5), 4.5% (n=5), 4.2% (n=5), and 3.4% (n=5)
质量控制: 15, 100, and 565 ng/mL (n=3)
批间差异(CV%): 10.5% (n=30), 5.0% (n=30), and 5.1%(n=3 0)
批内差异(CV%): 5.9% (n=6), 2.6% (n=6), and 3.2% (n=6)
V.Detailed Labeling Recommendations
详细标签说明书
Page(s) Withheld
Trade Secret/Confidential Draft labeling Deliberative Process
缺失页
行业机密
草稿标签
审议过程
VI. Appendices
VI. 附件
1.Proposed Package Insert (Original)
2.Individual Study Review
3.Cover Sheet and OCPB Filing/Review Form
１.申报资料（原始）
２.独立研究审核
３.封面以及OCPB归档/复审表
appears This Way
on original
此处原件
NDA 21-849 for Zegerid IR 20 and 40 mg Capsules
Zegerid IR 20 and 40 mg胶囊新药申请21-849
Appendix 1
附件１
Sponsor's Proposed PI (April, 05 Version)
申请人提交(April, 05 Version)
-------Page(s)Withheld
-------Trade Secret/Confidential -------DraFt Labeling
-------Deliberative Process
缺失页
行业机密
草稿标签
审议过程
NDA 21-849 for Zegerid IR 20 and 40 mg Capsules
Appendix 2
Zegerid IR 20 and 40 mg胶囊新药申请21-849
附件２
Synopses of Individual Study reviews
独立研究报告梗概。