2012年8月30日，美国食品与药物管理局（FDA）批准了利那洛肽（商品名：Linzess）用于治疗成人慢性特发性便秘和便秘型肠易激综合征（IBS—C）患者。
Linzess（利那洛肽）是FDA唯一批准的可用于临床的肠道局部起效的GC-C（鸟苷酸环化酶-C）激动剂类药物，可用于治疗便秘型肠易激综合征（IBS-C）和慢性特发性便秘（CIC）成年患者。
该药胶囊剂型，口服给药，每日一次。它可以缓解IBS-C导致的疼痛和便秘症状，以及CIC患者的便秘及排便困难表现。
药物的推荐治疗剂量为：便秘型肠易激综合征患者 290微克；慢性特发性便秘患者 145微克。每日首次进餐30分钟之前服用。
研究者发现，Linzess可通过两种途径起效，Linzess可以结合肠道上皮局部的GC-C受体。GC-C受体活化后，肠道内液体分泌量增多，肠道蠕动增加，内脏性疼痛感也减低（这可能是由于疼痛觉神经的活性降低所致）。
在一项包含2800例成人患者的随机、安慰剂对照的人类III期临床研究中，Linzess具有缓解IBS-C患者腹部疼痛的效应，也可以使CIC和IBS-C患者的肠管蠕动频率增加。
在治疗的首周内，患者就报告腹痛症状缓解，且该效应可维持整个12周治疗期。便秘症状最大缓解效应出现于治疗第2周，而腹痛缓解最佳时间出现于第6-9周。
试验研究中，行Linzess治疗的一亚组患者被换用安慰剂治疗，他们报告其原有症状复发，且在7天内即恢复到了治疗前的水平。而行安慰剂治疗的患者换用Linzess治疗后，他们发现其疾病症状很快便得以改善。
Linzess在6岁及以下儿童患者中禁用。6-17岁儿童患者不需禁忌该药物治疗。动物研究表明，成年鼠剂量利那洛肽治疗可导致幼鼠死亡。迄今尚未在儿童患者中开展过试验研究。报告最常见的Linzess治疗相关性副反应为腹泻。
便秘型肠易激综合征（IBS‐C）
在美国，IBS-C患者数量被认为高达1300万人。这是一种慢性功能性肠道疾病。IBS-C的症状可极为严重，以致于严重妨碍患者的日常生活能力。
此类患者通常表现为反复发作的腹部不适、疼痛或便秘等，超过25%的患者表现为排便困难或大便干结，少于25%的患者则表现为软便或水样便。
慢性特发性便秘（CIC）
美国CIC（慢性特发性便秘）的患病人数高达3500万人。这是一种功能性肠道疾病，此类患者在至少3个月内每周排便次数均少于3次，并且CIC患者在如厕后可能仍有排便不尽以及排便困难的感觉。
Linzess（利那洛肽）在美国上市
LINZESS
Pharmacological Class:
Guanylate cyclase-C agonist.
Active Ingredient(s):
Linaclotide 145mcg, 290mcg; capsules.
Company
Forest and Ironwood
Indication(s):
Irritable bowel syndrome with constipation (IBS-C). Chronic idiopathic constipation (CIC).
Pharmacology:
Linaclotide is a guanylate cyclase-C (GC-C) agonist. Both linaclotide and its active metabolite bind to GC-C and act locally on the luminal surface of the intestinal epithelium. Activation of GC-C results in an increase in both intracellular and extracellular concentrations of cyclic guanosine monophosphate (cGMP). Elevation in intracellular cGMP stimulates secretion of chloride and bicarbonate into the intestinal lumen, mainly through activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel, resulting in increased intestinal fluid and accelerated transit.
Clinical Trials:
The efficacy of Linzess for the management of symptoms of IBS-C was established in two placebo-controlled trials. A total of 800 patients in Trial 1 and 804 patients in Trial 2 received treatment with Linzess 290mcg or placebo once daily and were evaluated for efficacy. Efficacy of Linzess was assessed using overall responder analyses and change-from-baseline endpoints. Results for endpoints were based on information provided daily by patients in diaries. In both trials, the proportion of patients who were responders to Linzess 290mcg was statistically significantly higher than with placebo. Improvement from baseline in abdominal pain and complete spontaneous bowel movements (CSBM) frequency was seen over the first 12-weeks of the treatment periods. The mean treatment difference from placebo at week 12 was a decrease in pain score of approximately 1.0 point in both trials (using an 11-point scale). For the change from baseline in CSBM frequency at week 12, the difference between placebo and Linzess was approximately 1.5 CSBMs per week in both trials.
The efficacy of Linzess for the management of symptoms of CIC was established in two double-blind, placebo-controlled, randomized, multicenter clinical trials in adults (Trials 3 and 4). A total of 642 patients in Trial 3 and 630 patients in Trial 4 received treatment with Linzess 145mcg, 290mcg, or placebo once daily and were evaluated for efficacy. Efficacy of Linzess was assessed using overall responder analysis and change-from-baseline endpoints. Results for endpoints were based on information provided daily by patients in diaries. During the individual double-blind placebo-controlled trials, Linzess 290mcg did not consistently offer additional clinically meaningful treatment benefit over placebo than that observed with Linzess 145mcg. The proportion of patients who were CSBM responders was statistically significantly greater with the Linzess 145mcg dose than with placebo. CSBM frequency reached maximum level during week 1 and was also demonstrated over the remainder of the 12-week treatment period in Trial 3 and Trial 4. For the mean change from baseline in CSBM frequency at week 12, the difference between placebo and Linzess was approximately 1.5 CSBMs. On average, patients who received Linzess across the two trials had significantly greater improvements compared with patients receiving placebo in stool frequency (CSBMs/week and SBMs/week), and stool consistency (as measured by the BSFS).
Legal Classification:
Rx
Adults:
Swallow whole. Take on empty stomach, at least 30 minutes before first meal of the day. IBS-C: 290mcg once daily. CIC: 145mcg once daily.
Children:
<6 years: contraindicated. 6–17 years: avoid.
Contraindication(s):
Children up to 6 years old. Known or suspected mechanical GI obstruction.
Warnings/Precautions:
Hold or stop if severe diarrhea occurs. Pregnancy (Cat. C). Nursing mothers.
Adverse Reaction(s)
Diarrhea, abdominal pain, flatulence, abdominal distention.
How Supplied:
Caps—30
LAST UPDATED:
12/17/2012
