美国FDA批准ZENPEP (pancrelipase)延效版胶囊的新药上市申请，治疗胰囊状纤维化症等病人的脏外分泌功能不足(EPI)状况。        胰腺囊性纤维化 [临床表现]       　 本病主要表现为由于胰腺囊性纤维化导致胰导管阻塞，胰腺外分泌功能不全，胰酶分泌减少，使摄入的营养物质酶水解不足，患儿常表现食欲大增而体重不增，生长缓慢，胎粪回肠往往是最早期的症状，粪便巨大且富脂肪，不成形，恶臭，易并发糖尿病，在炎热季节易产生热虚脱。 [遗传规律]   常染色体隐性遗传。 [诊断]   汗液中钠、氯的含量升高3-6倍。 [防治]   有呼吸道感染、肠梗阻者应及时治疗、补充多酶片，注意应多食维生素和低脂肪的食物。 胰腺纤维化的临床表现 （一）腹痛          无痛性慢性胰腺炎相当少见，90%以上慢性胰腺炎患者在病程早期即出现腹痛。腹痛是胰腺纤维化的主要症状，也是临床需要治疗的指征。目前对疼痛的病理生理了解甚少，胰管内高压可能是发生疼痛的主要原因但与胰腺形态学改变之间的关系尚不明确。相当多的病人虽有严重胰腺纤维化，但疼痛却不明显。无痛性胰腺纤维化与胰腺钙化之间无明显相关性。          在开始有腹痛的病人中，有近30%病例腹痛可自行消失，近70%的病人腹痛可部分缓解。85%的酒精钙化性胰腺炎病人在发病后4-5年内可无腹痛。疼痛的减轻甚至消失，常伴随胰腺纤维化、钙化的加重和胰腺外分泌功能的下降。另有研究报道，50%的酒精性慢性胰腺炎和38%的非酒精性慢性胰腺炎发病10年内疼痛可以缓解。对于酒精性慢性胰腺炎疼痛的缓解于外分泌功能的下降是平行的；而对于非酒精性慢性胰腺炎两者并无相关性。酒精性和非酒精性慢性胰腺炎的腹痛过程似乎相同。饮酒影响疼痛的程度，常常由于忌酒或减少饮酒量使疼痛缓解。          对慢性胰腺炎胰腺切除标本的研究表明，胰腺纤维化的程度与疼痛无关，而胰腺组织内的钙基因相关肽类、P物质、生长相关蛋白及免疫细胞的浸润则与疼痛的发生可能有关。腹痛缓解后上述因子的变化规律，尚有待于进一步的研究。假性胰腺囊肿与疼痛关系密切，常识是外科治疗的指征。假性胰腺囊肿的手术后约50%病例腹痛可得以缓解，但另外50%病例疼痛可以复发。疼痛的缓解率随着病程的延长而升高，手术治疗与非手术治疗差别不明显，各种手术疗法对腹痛缓解率也无明显差别。 关注胰腺外分泌功能不足(PEI) 胰腺的外分泌功能主要指分泌胰酶,这对食物的消化、吸收具有十分重要的作用。近年来,胰腺外分泌功能不足(PEI)的诊断和治疗逐渐引起重视,尤其在治疗方面,以往传统的治疗方式逐渐被现代的胰酶替代治疗方法所取代,即应用胰酶微粒制剂(得每通胰酶制剂)。 2008年10月7日至10月11日,德国汉堡伊斯拉埃利特克(Israelitic)医院的莱尔(Layer)教授在中国上海、北京、西安3个城市以PEI为题进行学术巡讲。Layer教授在报告中,着重讲了PEI的病因、诊断与治疗的进展,并与现场听众互动讨论相关问题,学术气氛浓厚而热烈。 病因 胰腺外分泌功能不足(PEI)的病因多样,包括慢性胰腺炎(CP)、遗传性胰腺炎、自身免疫性胰腺炎、胰腺癌、急性胰腺炎(AP)、囊性纤维化、乳糜泻、糖尿病及医源性所致PEI(如胃切除术)等。 慢性胰腺炎 CP是引起PEI的常见和主要病因。在西方国家,长期大量饮酒所致的酒精性CP占70%以上,而在我国,胆道感染和胆石症等胆道疾病所致的CP更为常见。此外,还有特发性、梗阻性、遗传性及其他一些少见因素,亦可导致CP。 饮酒 研究显示,酒精性CP以男性患者为主(72%),发病高峰年龄为35~45岁。CP的发生与酒精摄入量存在剂量累积关系。 大量摄入酒精不但容易导致CP,还促使CP患者发生PEI。随着酒精摄入的增多,CP患者消化酶的最大分泌量逐渐降低。一项研究观察酒精性CP患者在停止饮酒和继续饮酒的4~11年中消化酶的分泌情况,结果证明,酒精的摄入加速了PEI的发生。 吸烟 酒精摄入并不是CP的唯一致病因素,特别应该引起重视的还有吸烟。一项前瞻性队列研究提示,与饮酒相比,吸烟导致的PEI是前者的3倍。            过去人们只知道吸烟与发生CP相关,直到现在,人们才认识到吸烟不但是CP的独立危险因素,还可促进其病情进展。与非吸烟者、曾吸烟者相比,吸烟者的CP风险显著增高,且随着吸烟时间延长,发生CP的几率也逐渐升高。在非吸烟的CP患者中,仅约20%出现胰腺钙化,吸烟的CP患者则全部发生胰腺钙化。 特发性胰腺炎 特发性胰腺炎导致的CP亦占重要比例,尤其在女性CP患者(约占47%)中,25岁前和45岁后为女性发生此病的两个高峰期。 所谓特发性慢性胰腺炎,最初是指病因未明的胰腺炎,但随着医学研究的进展,人们开始逐渐认识到这些疾病发生的真正原因包括了遗传性胰腺炎、自身免疫性胰腺炎、囊性纤维化(微小突变)、乳糜泻、胰腺分裂、炎性肠病及其他一些少见原因。 胰腺癌 胰腺癌患者的胰酶分泌约下降70%,所以超过80%的胰腺癌患者可发生PEI。胰腺癌患者PEI的发生与受累胰管的长度相关,当受累胰管的长度<10 mm时,一般不会出现PEI,但随着受累胰管的延长,PEI程度逐渐加重。因此,所有的胰腺癌患者都需要进行胰酶替代治疗。 急性胰腺炎 全部AP患者都会发生PEI。轻型无坏死的AP患者在急性发作2年后,几乎100%可完全恢复胰腺功能,但坏死性胰腺炎患者在急性发作1年后,仅约20%的胰腺外分泌功能可完全恢复。 在AP恢复期,重症胰腺炎发生PEI的几率是轻型胰腺炎的8倍,发生坏死的胰腺炎发生PEI的几率是无坏死者的9倍多。AP患者的PEI不仅与发病严重程度有关,而且与发病原因、治疗措施等相关。 因此,AP患者发生PEI可能是暂时和轻微的,也可能是持续和严重的,重症坏死性胰腺炎、酒精性AP更容易发生PEI,接受保守治疗的坏死性胰腺炎患者发生PEI的几率低于接受手术切除治疗者,后者发生PEI的几率可高达58%。 其他病因 手术所致PEI的情况多见于胃切除术,70%~90%术后患者出现PEI,须接受胰酶替代治疗。 有研究提示,以不明原因腹泻就诊但超声显像检查胰腺形态正常的部分患者常存在PEI,且29%的PEI患者超声显像检查胰腺形态正常。此外,肠易激综合征(IBS)可能是引起PEI的另一病因而长期被低估,一项研究显示,至少6%的IBS患者有必要接受脂肪酶补充治疗。 诊断 目前,诊断PEI的方法包括:检测粪内脂肪、粪弹力蛋白酶、粪糜蛋白酶等,胰泌素-胆囊收缩素试验和混合甘油三酯呼吸试验。其中,修正的碳(13C)甘油三酯呼吸试验与胰泌素-胆囊收缩素试验之间存在非常好的相关性,其敏感性与特异性分别可达100%和92%。 治疗 治疗的难点 PEI患者接受胰酶替代治疗的关键问题在于补充脂肪酶。首先,PEI患者的脂肪酶分泌较其他消化酶(如糜蛋白酶)减少更为迅速。例如,在酒精性CP患者中,饮酒13年时脂肪酶下降至最大分泌量的10%,即吸收不良的阈值,而饮酒25年后糜蛋白酶的分泌量为最大分泌量的20%左右。            其次,脂肪酶没有足够的内源性替代。例如胰淀粉酶可以由唾液淀粉酶替代,胰蛋白酶可以由胃蛋白酶替代,但脂肪酶没有其他脏器可以分泌相应的酶来替代。 再次,脂肪酶最容易被蛋白水解酶分解破坏,还可被酸破坏。与正常人餐后十二指肠内pH值始终>4不同,胰腺炎患者在餐后2小时十二指肠内pH值逐渐降低至4,而在这样酸性环境下,脂肪酶将被不可逆地破坏。 有效药剂的特点 有研究显示,十二指肠腔内餐后脂肪酶含量必须最低达到(200~400)U/min才可维持正常的消化功能。目前用于替代脂肪酶的药物有很多种,但是进行替代治疗时必须考虑到以下4个问题:①每餐脂肪酶总量必须达到25000~50000 U;② 与底物充分混合;③ 能够对抗胃酸的破坏;④ 有良好的胃排空。餐后颗粒直径≤ (2~3) mm比较容易自胃内排空,否则会在胃内滞留(图1)。 因此,能够有效纠正PEI的胰酶替代治疗要求脂肪酶替代物必须做成抗酸微粒,能够与食物一起进入小肠进行充分的混合。                                        图1 服用耐酸片剂和微粒后胃排空时间不同 正确用法可提高疗效 美国学者萨夫迪(Safdi)等一项研究发表在《胰脏》[Pancreas 2006,33(2)∶156]杂志上。研究显示,与基础值相比, 胰酶微粒制剂约能降低75%的粪脂量,并显著提高脂肪吸收系数(CFA),而安慰剂治疗后无明显疗效。治疗PEI,服用胰酶微粒制剂较安慰剂可显著提高消化道的脂肪吸收功能(P=0.0185,图2)。                                               图2 得每通对脂肪排出的影响            胰酶微粒制剂具有量效关系,即随着使用剂量的增加,其治疗效果将更加显著。一项研究对比了3种不同治疗剂量的胰酶微粒制剂用于重度PEI,结果显示,患者接受每餐30 kU的脂肪酶治疗,则24小时粪脂量最低,接近10 g(图3)。                                           图3 胰酶微粒制剂对重度PEI治疗有效            应用胰酶替代疗法治疗PEI时,药物的服用方法是否合理及服用剂量是否足够是非常重要的。首先,每餐及每次加餐时都必须服药,用餐期间(或刚开始用餐时)服用。原则上,每消化1 g脂肪需要补充2000 U脂肪酶 (1000~4000 U/g脂肪),那么成人每餐至少补充40000 U脂肪酶。其次,应该按照个体化治疗方案,视疾病严重程度、食物结构、体重等情况而调整用药剂量。最后,根据13C甘油三酯呼吸试验,与餐前、餐后服用胰酶微粒相比,餐间服用效果最好。  FDA Approves Zenpep Delayed-Release Capsules PHILADELPHIA, PA — Eurand N.V., a specialty pharmaceutical company, today announced U.S. Food and Drug Administration (FDA) approval of its New Drug Application (NDA) for Zenpep (pancrelipase) Delayed-Release Capsules for the treatment of exocrine pancreatic insufficiency (EPI) in patients with cystic fibrosis (CF) or other conditions. Zenpep is the only FDA-approved pancreatic enzyme product (PEP) that has been evaluated in clinical studies in adults and children — including children from one to 12 years old — and will offer four dosage strengths to meet the varied needs of infants, toddlers, adolescents and adults with EPI. “The availability of clinical evidence in a pediatric population is particularly important for EPI patients with CF and their caregivers, as early improvements in BMI (Body Mass Index) significantly affect long-term survivability,” said Jamie Wooldridge, M.D., Assistant Professor, Department of Pediatrics, Division of Pulmonary Medicine at Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, and a principal investigator in the Zenpep pediatric trial. Zenpep capsules were formulated to allow the contents to be sprinkled on food where necessary, which is a key attribute to support the developmental needs of very young children as well as older patients. EPI is the inability to properly digest food due to a lack of digestive enzymes made by the pancreas. Loss of digestive enzymes leads to maldigestion and malabsorption of nutrients. This is a common disorder for those suffering from cystic fibrosis and other conditions compromising the exocrine function of the pancreas, such as pancreatic cancer, gastrointestinal surgery and chronic pancreatitis. EPI results in malnutrition and, especially in CF patients, impaired growth in children, compromised immune response and shortened life expectancy. Zenpep replaces these missing enzymes and improves digestion and absorption. In addition, Zenpep’s stability and precise range of dosage strengths will allow health care professionals to dose a patient’s treatment regimen for optimal symptom control and potentially reduce their pill burden. Zenpep was developed specifically to meet the FDA’s guidelines on PEPs. Historically, PEPs have not been regulated and approved by the FDA. In 2004, due to inconsistent quality that affected the safety and efficacy of PEPs, the FDA determined it was necessary to better control these products. All manufacturers of EPI drug products were required to file NDAs and receive marketing approvals by April 2010. “For years, patients with EPI taking unapproved PEPs have lived with far too much variability in the control of their gastrointestinal symptoms as a result of product instability and dosing inconsistency,” said Gearoid Faherty, Chairman and Chief Executive Officer. “The approval of Zenpep is a major milestone for patients suffering from EPI and for Eurand. In preparation for our U.S. launch we have built and continue to expand a first-rate commercial organization to help Zenpep reach its full market potential.” According to IMS Health, the market for PEPs was an estimated $1.13 billion worldwide in 2008. The U.S. commercial launch of Zenpep is planned for the fourth quarter of 2009. Eurand will market Zenpep for the approved indication through its own sales force to the different physician groups that treat EPI within each of the target CF and non-CF patient populations. “Eurand is committed to a successful launch of Zenpep and intends to deploy a sales force of sufficient size and scope to address these distinct market segments. To accelerate adoption, we will also have an extensive sampling and patient support program for a period of time following the launch,” Faherty said. “The Cystic Fibrosis Foundation encouraged the FDA to mandate the NDA process for pancreatic enzymes in order to ensure that all of these products are of the highest quality,” said Robert J. Beall, Ph.D., President and Chief Executive Officer of the Cystic Fibrosis Foundation, a leading patient advocacy group. “Pancreatic enzymes approved through this process will help ensure that CF patients receive products that are documented to be safe and effective. The approved formulations will allow for more precise dosing, which will help ensure patients receive the proper nutrients to support growth and development and may reduce their treatment burden. We are pleased that people with CF will have the option of using Eurand’s newly approved pancreatic enzyme, Zenpep, and are grateful to all those who participated in the clinical trials that made this approval possible.” Zenpep was shown to be safe and effective for the treatment of EPI in two Phase III multicenter clinical trials — one in older children, adolescents and adults, and one in young children (ages 1 through 6). Both studies established efficacy and safety of Zenpep in CF patients with EPI. In the placebo-controlled, randomized, double-blind pivotal study in older children and adult patients, ages 7-23 years, the primary efficacy endpoint was mean Coefficient of Fat Absorption (CFA), the gold standard for assessing the severity of EPI. CFA was statistically higher with Zenpep treatment (88.3%) than placebo (62.8%)(p less than 0.001). In the open-label, single-arm study in young patients, patients maintained symptom control when switched from their usual PEP regimen to Zenpep at similar doses. The safety and efficacy in pediatric patients evaluated in this study were similar to adult patients. Zenpep was not associated with any serious drug-related adverse events in any of the clinical trials. The most common adverse events were gastrointestinal complaints, which were similar in type and frequency across all age ranges in the two studies. The most commonly reported adverse events occurring in at least two patients (greater than or equal to 6% of patients) included: abdominal pain, flatulence, headache, cough, decreased weight, early satiety, and contusion. The type and incidence of adverse events were similar in children and adults. Zenpep is the sixth Eurand-developed product to be approved by the FDA since 2001 and the second this year following the May 8th approval of Lamictal ODT. About Exocrine Pancreatic Insufficiency (EPI) Exocrine Pancreatic Insufficiency (EPI) is the inability to properly digest food due to a lack of digestive enzymes made by the pancreas. EPI can result from a number of diseases, including cystic fibrosis, pancreatic cancer, gastrointestinal surgery, and chronic pancreatitis. The FDA estimates that more than 200,000 Americans suffer from EPI. If left untreated, EPI causes malnutrition and, especially in CF patients, impaired growth in children, compromised immune response and shortened life expectancy. EPI is treated by porcine-derived pancreatic enzyme products, which have been marketed in the U.S. without FDA approval for more than 70 years. About Zenpep (pancrelipase) Delayed-Release Capsules Zenpep is an innovatively formulated pancreatic enzyme product for the treatment of exocrine pancreatic insufficiency. The product was developed in response to the 2004 FDA initial guidance on pancreatic enzyme products, which outlined the need to reduce the variability in enzyme levels, address stability issues associated with unapproved enzyme therapies and regulate them under NDAs. Zenpep is a highly stable formulation of a porcine pancreatic extract that is biologically similar to the endogenous human pancreatic secretions necessary for proper human digestion. Every dose of Zenpep provides patients and physicians with a consistent amount of the main pancreatic enzymes lipase, protease and amylase due to its highly stable formulation. These features allow health care professionals to fine tune treatment regimens to achieve optimal symptom control with improved dosing precision. Safety and efficacy of Zenpep in EPI were demonstrated in two multicenter Phase III clinical trials in adult and pediatric patients of all ages, down to one year old. Good nutrition is considered to be critically important to growth characteristics in children with cystic fibrosis, resulting in improvement in lung function and overall quality of life for these patients. Important Information Zenpep has been approved with a Risk Evaluation and Mitigation Strategy (REMS) to ensure that the benefits of the drug outweigh its risks. As part of the REMS, a Medication Guide with important dosing and safety information about Zenpep will be handed out with each new prescription and refill. The REMS and Medication Guide address the risk associated with the use of Zenpep, including fibrosing colonopathy, a rare, serious adverse reaction that has been reported following treatment with high-dose use of pancreatic enzyme replacement therapy in the treatment of cystic fibrosis patients usually over a prolonged time period. The total daily dose of Zenpep should not exceed 10,000 lipase units/kg of body weight per day, and caution should be used with doses exceeding 2,500 lipase units/kg of body weight per meal. Also, there is a theoretical risk of transmission of viral disease, since Zenpep, as other porcine-derived pancreatic enzymes, is sourced from pancreatic tissue from swine used for food consumption. No cases of transmission of an infectious illness associated with the use of porcine pancreatic extracts have been reported. Care should be taken to ensure that Zenpep is not chewed or retained in the mouth to avoid irritation of oral mucosa and the capsules or beads should be swallowed immediately with adequate amounts of liquid. Caution should be exercised when using Zenpep in patients with gout, renal impairment, or hyperuricemia; porcine-derived pancreatic enzyme products may increase blood uric acid levels. Caution should be exercised for patients with known allergies to proteins of porcine origin. In rare instances, severe allergic reactions including anaphylaxis, asthma, hives, and pruritus have been reported with other pancreatic enzyme products with different formulations of the same active ingredient, pancrelipase, as that of Zenpep. In clinical trials assessing the short-term safety of Zenpep, the incidence of adverse events (regardless of causality) was similar during double-blind Zenpep treatment and placebo treatment. The most commonly reported adverse events occurring in at least two patients (greater than or equal to 6% of patients) included: abdominal pain, flatulence, headache, cough, decreased weight, early satiety, and contusion. The type and incidence of adverse events were similar in children and adults. Please see full Prescribing Information and Medication Guide at  for complete information about safety, warnings and precautions for Zenpep. About Cystic Fibrosis Cystic fibrosis (CF) is a life-threatening genetic disease that affects approximately 30,000 children and adults in the United States and nearly 70,000 people worldwide. It causes life-threatening lung infections and serious digestive complications. CF is caused by a mutation in the CFTR (Cystic Fibrosis Transmembrane conductance Regulator) gene whose lack of proper function leads to the symptoms, complications and premature mortality in people with CF. About the Cystic Fibrosis Foundation The Cystic Fibrosis Foundation, the leading organization in the United States devoted to curing and controlling cystic fibrosis, has invested more than $320 million in drug research with biotech companies since 1998 to develop therapies to fight CF. As a result, the Foundation has built a drug pipeline with more than 30 promising therapies in development. Based in Bethesda, Md., the Foundation has 80 chapters and branch offices, and supports and accredits a nationwide network of 110 CF care centers that provide treatment and vital resources to patients and families. For more information, visit About Eurand Eurand is a specialty pharmaceutical company that develops, manufactures and commercializes enhanced pharmaceutical and biopharmaceutical products based on its proprietary pharmaceutical technologies. Eurand has had six products approved by the FDA since 2001 and has a pipeline of product candidates in development for itself and its collaboration partners. The Company’s technology platforms include bioavailability enhancement of poorly soluble drugs, custom release profiles, taste-masking orally disintegrating tablet (ODT) formulations, and drug conjugation. Eurand is a global company with facilities in the U.S. and Europe. For more information, visit All websites referenced herein are for informational purposes only and shall not be incorporated by reference. Eurand Forward-Looking Statement This release, and oral statements made with respect to information contained in this release, constitutes forward-looking statements. Such forward-looking statements include those which express plan, anticipation, intent, contingency, goals, targets or future development and/or otherwise are not statements of historical fact including, but not limited to the future and status of our regulatory filings or commercial plans for Zenpep or our partnered products, enrollment and future plans for our clinical trials, progress of and reports of results from clinical studies, clinical development plans and product development activities. The words “expects,” “potentially,” “anticipates,” “could,” “calls for” and similar expressions also identify forward-looking statements. These statements are based upon management’s current expectations and are subject to risks and uncertainties, known and unknown, which could cause actual results and developments to differ materially from those expressed or implied in such statements. Factors that could affect actual results include risks associated with unexpected delays or additional requirements in preparing for commercial launch; the outcome of any discussions with the FDA or other regulatory agencies; and those risks and uncertainties set forth in the Company’s Annual Report on Form 20-F and subsequent filings. Forward-looking statements contained in this press release are made as of this date, and we undertake no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Actual events could differ materially from those anticipated in the forward-looking statements. – Drugs.com