Lubiprostone: A novel chloride channel activator for the treatment of constipation

•Abstract

Lubiprostone (Amitiza, Sucampo/Takeda) was approved on January 31, 2006, for the treatment of chronic idiopathic constipation in adults when the cause of the condition is unknown. The agent has a unique mechanism of action compared with current therapies on the market in that it locally activates specific chloride channels (ClC-2) in the lining of the small intestines after oral administration, thereby increasing intestinal fluids and softening bowel movements. In double-blind, placebo-controlled trials, lubiprostone demonstrated efficacy in improving the frequency of spontaneous bowel movements and other related constipation symptoms. Lubiprostone was reported to be well tolerated in clinical trials; the most common adverse effects were mild-to-moderate nausea and headache. The agent is also being investigated for use in constipation-predominant irritable bowel syndrome and post-operative ileus. (Formulary. 2006;41:118–129.)

Chronic constipation is characterized by decreased frequency of bowel movements, persistent symptoms of straining, lumpy or hard stools, and feelings of blockade or incomplete bowel evacuation.¹ A consensus definition is addressed in the Rome II criteria, compiled by gastroenterology experts.¹ These symptoms are prevalent in 4.4 million people and are the primary complaint for approximately 2.5 million doctor visits per year in the United States.^2,3 Chronic constipation is generally differentiated as primary or secondary in nature. Primary is classified as normal transit constipation (functional) or slow transit constipation.⁴ Secondary constipation may have several factors contributing to the condition. These include dietary causes, such as low fiber and fluid consumption, neurological disease, metabolic or endocrine disorders, psychological illness, or medications.⁵ Unknown causes of constipation are identified as chronic idiopathic constipation (CIC).⁴ Patients with constipation-predominant irritable bowel syndrome (IBS-c) frequently present with symptoms similar to functional constipation, but the condition is accompanied by intermittent periods of diarrhea.¹

Lubiprostone (Amitiza, Sucampo/ Takeda) is a new medication in the treatment of CIC, having a unique mechanism of action from available therapies. Lubiprostone received FDA approval on January 31, 2006, for the treatment of CIC in adults when the cause of the condition is unknown.¹⁰ In addition, phase 3 trials are under way for IBS-c.¹¹

CHEMISTRY AND PHARMACOLOGY

Lubiprostone is a bicyclic fatty acid prostaglandin E₁ derivative (PGE₁). It is the first treatment for chronic constipation that has the unique mechanism of action of locally activating specific chloride channels (ClC-2) located the apical lining of the small intestines in a protein kinase A-independent fashion. As a result, increases in intestinal fluid soften stool, facilitating bowel movements.¹⁰ In vitro research suggests lubiprostone is a specific and potent activator of ClC-2, which appears to result in dose-dependent increases.¹² In addition, animal studies have established significant dose-dependent changes in intestinal fluid after oral administration, without affecting serum electrolytes of Na⁺ or K⁺ .¹³

PHARMACOKINETICS

CLINICAL TRIALS

Most clinical evidence for the safety and efficacy of lubiprostone in CIC stem from the phase 2 and 3 trials by Johanson et al.^15–19 Inclusion criteria for these studies have been less than 3 spontaneous bowel movements (SBM) per week for 6 months, plus a 6-month history of at least 1 of the other Rome II criteria for functional constipation.¹ There are no available studies comparing lubiprostone to other agents for CIC.

A multicenter, double-blind, placebo-controlled phase 3 study was conducted in 242 subjects receiving lubiprostone 24 mcg twice daily (total daily dose of 48 mcg) or placebo. After a 2-week wash-out period, subjects received either lubiprostone or placebo for 4 weeks, which was followed by another 2-week drug-free period. Frequency of SBMs and symptoms were again recorded by patients. Efficacy end points were SBM frequency, time to first SBM, straining and stool consistency, and subjects' global assessment of treatment effectiveness. Baseline characteristics included a mean age of 48.6 years, with the majority again being female (90%) and Caucasian (86%). SBM reporting was significantly increased with the lubiprostone group in all weeks of treatment, 5.1 to 5.7 compared with 2.8 to 3.5 for placebo (P<.002). Mean SBM for Weeks 1 to 4 were 5.69±4.42, 5.06±4.08, 5.25±4.88, and 5.30±4.74, respectively, compared with placebo at 3.46±2.29, 3.18±2.53, 2.84±2.23, and 2.91±2.36. However, both groups displayed a significant increase in mean SBM frequency from baseline at Week 1 (4.26±4.34 for lubiprostone and 1.88±2.24 for placebo; P<.0001) and Week 4 (3.87±4.62 for lubiprostone and 1.33±2.52 for placebo; P<.0001). SBM on Day 1 was significantly higher in the treatment group, 57%, compared with 37% in the placebo group (P<.0024). Patient global assessment was also significantly improved with lubiprostone during the active treatment period (P<.0001). Common side effects reported were nausea (37%; P<.001), headache (11.7%; P=.015), and diarrhea. Adverse events caused 9 subjects in the active treatment group to withdraw. Lubiprostone was again demonstrated to be safe and effective for the treatment of CIC.¹⁶

Withdrawal symptoms were assessed in a phase 3 study conducted after 128 patients received lubiprostone 24 mcg twice daily for 4 weeks, then were randomized to continue the regimen or receive placebo for an additional 3 weeks. Patients were instructed to keep a daily log of constipation symptoms. End points included signs of consistency, straining, bloating, discomfort, SBM frequency, and constipation severity assessments. Relapse was defined as <3 SBMs per week when previously experiencing ≥3 SBMs. Through all 4 weeks of initial active treatment, the lubiprostone group had a statistically significant increase in SBMs compared with baseline (1.36 vs 5.52–6.25) as well as for the other end points (P<.0001). At Week 7 in the withdrawal period, the lubiprostone group reported an average of 5.59 SBMs compared with 3.04 for the placebo group (P=.0046), but the placebo group was still significantly better than baseline (P=.002). The relapse rate was 44.4% for placebo with a rate of 18.2% in the lubiprostone group (P=.0223). All other end points remained improved in the placebo group compared with baseline. No serious adverse events were reported during the withdrawal phase. These results display a lack of rebound effects and worsening of symptoms upon discontinuation.¹⁸

Open-label safety studies have been conducted to evaluate the long-term safety of lubiprostone. Over 24 weeks, 308 subjects were enrolled to receive 24 mcg of lubiprostone twice a day with food and water. Similar to previous studies, women and Caucasian subjects (mean age 49) were predominant. Subjects reported statistically significant improvements in constipation severity, bloating, and abdominal symptoms (P<.001) compared with baseline. End point SBMs were not reported. Non-serious adverse events (possibly, probably, or definitely treatment-related) were recorded in 51.6% of subjects. Additionally, 19.6% discontinued because of these adverse reactions. Nausea and headache were commonly reported side effects.¹⁹ According to unpublished data on file with the manufacturer, a 48-week safety study was also completed including 324 patients with reportedly positive results regarding constipation severity, abdominal bloating, and abdominal discomfort (P<.0001).²⁰ Upon FDA approval, the manufacturer summarized unpublished open-label data over 6 to 12 months supporting lubiprostone's long-term efficacy in decreasing abdominal bloating, abdominal discomfort, and constipation severity.¹⁰

ADVERSE EFFECTS

Overall, lubiprostone (24 mcg twice daily) appears to be safe and well tolerated in clinical trials. Side effects reported during double-blind placebo-controlled trials included nausea, diarrhea, headache (13%), abdominal bloating (7%), abdominal pain (7%), flatulence (6%), sinusitis (5%), and vomiting (5%). The most predominant complaint, nausea, was reported in 31.1% of study subjects (3.4% severe), causing 8.7% to withdraw from treatment. Nausea is thought to be a dose-related effect, while long-term administration does not increase the risk. When taken with food, nausea has reportedly been decreased. Diarrhea has occurred in 13.2% of patients (3.4% severe), and 2.2% discontinued treatment because of diarrhea. No clinically significant electrolyte changes were observed, nor were any secondary serious adverse events.¹⁴ Lubiprostone is labeled as a Pregnancy Category C. Women becoming pregnant in clinical trials discontinued the medication per protocol. Animal studies consisting of rats receiving more than 300 times the recommended oral dose (up to 2,000 mcg/kg/d) and rabbits receiving more than 30 times the recommended dose (up to 100 mcg/kg/d) reported no teratogenic effects. During 40 to 53 days of gestation, fetal loss was reported in guinea pig studies at 10 to 25 mcg/kg/d (2–6 times the recommended dose). It is unknown if lubiprostone is excreted into breast milk.¹⁴

DRUG INTERACTIONS

There are no documented drug interactions occurring with the administration of lubiprostone. The cytochrome P450 system is not involved in the metabolism of lubiprostone, and the agent has not demonstrated induction or inhibition. Drug interactions are unlikely to occur via protein-binding interactions based on current pharmacokinetic data.¹⁴

DOSAGE AND ADMINISTRATION

In clinical trials, 24 mcg of lubiprostone twice daily was administered orally, with food and water.^15–19 Product labeling recommends twice-daily dosing with food. Lubiprostone is available in 24 mcg gelatin capsules. Lubiprostone has not been studied in patients with renal or hepatic disease, and there are no dosage recommendations for these patients. The use of lubiprostone is contraindicated in patients with known hypersensitivity to lubiprostone or patients with a history of mechanical gastrointestinal obstruction. It is recommended that providers and patients monitor and periodically assess symptoms.¹⁴

Dr Orr is clinical assistant professor, University of Rhode Island College of Pharmacy, Kingston, RI. She can be reached at kellyo@etal.uri.edu

Disclosure Information: The author reports no financial disclosures as related to products discussed in this article.

In each issue, the "Focus on" feature reviews a newly approved or investigational drug of interest to pharmacy and therapeutics committee members. The column is coordinated by Robert A. Quercia, MS, RPh, director of Drug Information Services at Hartford Hospital in Hartford, Conn, and adjunct associate professor, University of Connecticut School of Pharmacy, Storrs, Conn; and by Craig I. Coleman, PharmD, assistant professor of pharmacy practice, University of Connecticut School of Pharmacy, and director, Pharmacoeconomics and Outcomes Studies Group, Hartford Hospital.
Editors’ note: The clinical information provided in "Focus on" articles is as current as possible. Due to regularly emerging data on developmental or newly approved drug therapies, articles include information published or presented and available to the author up until the time of the manuscript submission.

REFERENCES

1. Thompson WG, Longstreth GF, Drossman DA, Heaton KW, Irvine EJ, M�Lissner SA. Functional bowel disorders and functional abdominal pain. Gut. 1999;45(suppl 2):II43-II477. Available at: http:// http://www.romecriteria.org/documents/GUTII/ibs997.pdf. Accessed March 1, 2006.

2. Everhart, J. E. (Ed.). (1994). Digestive diseases in the United States: Epidemiology and impact. (NIH Publication No. 94–1447). U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Washington, DC: U.S. Government Printing Office.

3. Sonnenberg A, Koch TR. Physician visits in the United States for constipation: 1958 to 1986. Dig Dis Sci. 1989; 34:606–611.

4. Velio P, Bassotti G. Chronic idiopathic constipation: Pathophysiology and treatment. J Clin Gastroenterol. 1996;22:190–196.

5. Talley NJ, Jones M, Nutys G, Dubois D. Risk factors for chronic constipation based on a general practice sample. Am J Gastroenterol. 2003;98:110-111.

6. OTC sales by category. Consumer Healthcare Products Association. Available at: http:// http://www.chpa-info.org/web/press_room/statistics/otc_sales.aspx/. Accessed March 1, 2006.

7. Curry CE, Butler DM. Constipation. In: Berardi RR, ed. Handbook of Non-Prescription Drugs: An Interactive Approach to Self Care. 14th ed. Washington DC: American Pharmacists Association; 2004:367-403.

8. Zelnorm [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2004.

9. Locke GR III, Pemberton JH, Phillips SF. American Gastroenterological Association Medical Position Statement: Guidelines on Constipation. Gastroenterology. 2000;119:1761-1778.

10. Sucampo Pharmaceuticals Inc. Sucampo obtains FDA approval for Amitiza capsules as treatment of chronic idiopathic constipation in adults. Media Release: January 31, 2006. Available at: http:// http://www.sucampo.com/article_62.shtml. Accessed March 1, 2006.

11. Sucampo Pharmaceuticals Inc. Phase III clinical program evaluates lubiprostone. Media release, May 16, 2005. Available at: http:// http://www.sucampo.com/article_58.shtml. Accessed March 1, 2006.

12. Cuppoletti J, Malinowska DH, Tewari KP, et al. SPI-0211 activates T84 cell chloride transport and recombinant human CIC-2 chloride currents. Am J Physiol Cell Physiol. 2004;287: C1173–C1183.

13. Ueno R, Osama H, Habe T, Engelke K, Patchen M. Oral SP-0211 increases intestinal fluid secretion and chloride concentration without altering serum electrolyte levels [abstract]. Gastroenterology. 2004;126(suppl 2):A-100.

14. Amitiza [package insert]. Bethesda, MD: Sucampo Pharmaceuticals, Inc; 2006.

15. Johanson JF, Gargano MA, Patchen ML, Ueno R. Efficacy and safety of a novel compound, RU-0211, for the treatment of constipation [abstract]. Gastroenterology. 2002;122(suppl 1):A-315.

16. Johanson JF, Gargano MA, Patchen ML, Ueno R. Phase III efficacy and safety of RU-0211, a novel chloride channel activator, for the treatment of constipation [abstract]. Gastroenterology. 2003;124(suppl 1):A-48.

17. Johanson JF, Gargano MA, Patchen ML, Ueno R. Phase III study of lubiprostone, a chloride channel-2 (CIC-2) activator for treatment of constipation: safety and primary efficacy. [abstract]. Am J Gastroenterol. 2005;100(suppl 7):S328.

18. Johanson JF, Gargano MA, Patchen ML, Ueno R. Phase III, randomized withdrawal study of RU-0211, a novel chloride channel activator for the treatment of constipation [abstract]. Gastroenterology. 2004;126(suppl 2):S100.

19. Johanson JF, Gargano MA, Patchen ML, Ueno R. Multi-center open-label study of lubiprostone for the treatment of chronic constipation. [abstract]. Am J Gastroenterol. 2005;100 (suppl 7):S331.

20. Data on file. Lubiprostone. Clinical study report (RTU/0211SC02S3). Bethesda, Md: Sucampo Pharmaceuticals, Inc. 2006.

21.Sucampo Pharmaceuticals Inc. Sucampo completes treatment in a phase II safety and efficacy IBS study with its chloride channel activator SP-0211. Media release, May 14, 2004. Available at: http:// http://www.sucampo.com/article_42.shtml. Accessed March 1, 2006.