General Information

Amitiza (lubiprostone) is an orally available, locally acting ClC-2 chloride channel activator, designed to increase the production of chloride-rich intestinal fluid without significantly affecting serum sodium or potassium concentrations. Increased intestinal fluid production has been shown to promote gastrointestinal motility.

Amitiza is specifically indicated for the treatment of adults with chronic idiopathic constipation, defined as low frequency or difficulty in stool passage potentially related to poor colonic motility.

Amitiza is supplied as a gelatin capsule for oral administration. Recommended initial dosing is 24 mcg twice daily, with food. Need for maintained dosing should be periodically assessed by patients and physicians.

Clinical Results

FDA Approval
Approval of Amitiza was based on 6 clinical trials: a phase II trial, a pair of double-blind, placebo-controlled studies, and three long term safety studies.

Phase II Trial
This dose-finding, double-blind, placebo-controlled, parallel-group study was designed to investigate the efficacy of the drug in promoting spontaneous bowel movements (SBMs). The trial enrolled 127 patients, who went through a 2 week drug-free baseline washout and were than randomized to receive one of 3 regimens of the drug (24 mcg once, twice, or thrice daily) or placebo for 3 weeks with meals. Trial data indicated that all three regimens of the drug significantly increased frequency of SBMs from baseline; there was no significant difference in response between the treatment groups.

Double Blind Trials
These identical-design, double blind, placebo controlled studies were designed to investigate the efficacy of the drug in increasing SBM frequency. A total of 479 patients went through a 2 week drug-free washout/baseline, followed by randomization to receive either 24 mcg Amitiza or placebo twice daily for 4 weeks. Trial data indicated that subjects receiving the drug experienced significantly more SBMs at the end of week 1 than placebo. Similar results were observed for weeks 2-4, and no significant "rebound-effect" relapse was noted following the conclusion of treatment. Further, patients receiving the drug were more likely to experience their first SBM within 24 hours of dosing than placebo (56.7% vs. 36.9% for study 1; 62.9% vs. 31.9% for study 2), and time to first SBM was reduced. Signs and symptoms of constipation (including bloating, discomfort, poor stool consistency and straining) were also reduced for subjects receiving Amitiza.

Long-Term Safety Studies
Three long term open-label safety studies enrolled a combined 871 patients, who received 24 mcg Amitiza twice daily. The drug was shown to significantly reduce abdominal bloating, abdominal discomfort, and constipation severity over treatment periods lasting 6-12 months.

Ongoing Study Commitments

• Deferred pediatric studies under PREA for the treatment of chronic idiopathic constipation in pediatric patients ages 0 to 17 years.
  Protocol Submission: by July 31, 2006
  Study Start: by January 31, 2007
  Final Report Submission: by January 31, 2008
• Perform a Phase IV study to assess the need for potential dose adjustment in patients with renal impairment
  Protocol Submission: by July 31, 2006
  Study Start: by January 31, 2007
  Final Report Submission: by January 31, 2008
• Perform a Phase IV study to assess the need for potential dose adjustment in patients with hepatic impairment.
  Protocol Submission: by July 31, 2006
  Study Start: by January 31, 2007
  Final Report Submission: by January 31, 2008

Side Effects

Adverse events associated with the use of Amitiza may include, but are not limited to, the following:

• Nausea
• Diarrhea
• Headache
• Abdominal Distension
• Abdominal Pain
• Flatulence
• Sinusitis

Mechanism of Action

Amitiza activates CIC-2, a chloride channel present in the apical membrane of the intestine in a protein kinase A-independent fashion, thereby increasing secretion of chloride-rich intestinal fluid. This in turn increases intestinal motility, reducing symptoms of chronic constipation and increasing stool passage. The drug has low systemic availability (below 10 pg/ml), limiting potential side effects.

Literature References

Lubiprostone: RU 0211, SPI 0211. Drugs in R&D 2005;6(4):245-8

Cuppoletti J, Malinowska DH, Tewari KP, Li QJ, Sherry AM, Patchen ML, Ueno R SPI-0211 activates T84 cell chloride transport and recombinant human ClC-2 chloride currents. American Journal of Physiology: Cell Physiology 2004 Nov;287(5):C1173-83. Epub 2004 Jun 22

Additional Information

For additional information regarding Amitiza or Chronic Idiopathic Constipation, please visit the Amitiza web page.