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Cilansetron: A novel 5-HT3 receptor antagonist for the treatment of irritable bowel syndrome

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If approved, cilansetron (Calmactin, Solvay Pharmaceuticals) would be the second selective 5-HT3 antagonist introduced for the treatment of irritable bowel syndrome (IBS). Based on 2 main clinical trials, cilansetron 2 mg orally 3 times daily appears to be effective in the relief of IBS-D symptoms (abdominal pain/discomfort) and abnormal bowel habits in both male and female patients. Adverse effects were minor, with constipation being the most commonly reported adverse effect. No information is currently available on cilansetron's potential for drug interactions, need for dose adjustments in renal or hepatic insufficiency, long-term safety, or cost. Cilansetron was granted priority review status by FDA on September 1, 2004, for the treatment of diarrhea-predominant IBS in men and women. Currently marketed agents for the treatment of IBS are only approved for use in female patients.

Abstract If approved, cilansetron (Calmactin, Solvay Pharmaceuticals) would be the second selective 5-HT3 antagonist introduced for the treatment of irritable bowel syndrome (IBS). Based on 2 main clinical trials, cilansetron 2 mg orally 3 times daily appears to be effective in the relief of IBS-D symptoms (abdominal pain/discomfort) and abnormal bowel habits in both male and female patients. Adverse effects were minor, with constipation being the most commonly reported adverse effect. No information is currently available on cilansetron's potential for drug interactions, need for dose adjustments in renal or hepatic insufficiency, long-term safety, or cost. Cilansetron was granted priority review status by FDA on September 1, 2004, for the treatment of diarrhea-predominant IBS in men and women. Currently marketed agents for the treatment of IBS are only approved for use in female patients. (Formulary. 2005;40:44–48.)

In the past, irritable bowel syndrome (IBS) was referred to as "nervous stomach," "spastic colon," and other nonspecific terms. It is currently defined as a common disorder characterized by alterations in bowel habit and lower abdominal pain/discomfort. Three subgroups have been identified and include constipation-predominant, diarrhea-predominant, and pain-predominant IBS. The age at onset is variable and the impact on patients' quality of life is significant.1 IBS is more common in women than men by a 2:1 ratio.2 The pathophysiology of IBS remains poorly understood but involves the 5-hydroxytryptamine (5-HT) receptors 5-HT3 and 5-HT4. The 5-HT3 receptor modulates visceral sensitivity via extrinsic sensory neurons and increased gastric emptying, whereas the 5-HT4 receptor modulates the peristaltic reflex and visceral sensitivity via the intrinsic sensory neurons. 3

If approved, cilansetron (Calmactin, Solvay Pharmaceuticals) would be the second selective 5-HT3 antagonist introduced for the treatment of IBS. The agent was granted priority review status by FDA on September 1, 2004, for the treatment of diarrhea-predominant IBS in men and women. Published clinical data on cilansetron were mainly limited to abstracts at press time. Other information has not been made available.

CHEMISTRY AND PHARMACOLOGY Cilasetron, a novel 1,7-annelated indole, is a selective antagonist for the serotonin type-3 (5-HT3) receptor. The 5-HT3 receptors are located primarily on enteric nerves. Serotonin is stored and released by the enterochromaffin cells of the gastrointestinal tract to stimulate secretions, visceral sensitivity, and the peristaltic reflex.2 Cilansetron and alosetron are structurally similar to ondansetron; however, cilansetron is reported to be 10 times more potent than ondansetron.6 Alosetron and cilansetron both selectively block the 5-HT3 receptor, resulting in slowed colonic transit and increased stool consistency with minimal effects on visceral sensitivity in patients.7 Alosetron and cilansetron possess negligible affinity for M1 muscarinic and 5-HT4 receptors. Tegaserod, on the other hand, is a selective partial agonist for 5-HT4 receptors, resulting in increased gastrointestinal contractility and peristaltic reflex and a decrease in visceral sensitivity.8

To compare the efficacy of intravenous (IV) and intraluminal cilansetron on antagonizing the effects of 10 mcg/kg of IV 5-HT on mesenteric afferent nerves, 15 Wistar rats initially received increasing IV doses of cilansetron (0.2-20 mcg/kg).9 The lowest IV dose required to elicit the antagonistic effect was the 2 mcg/kg dose. The 2 mcg/kg IV dose was then compared to a 2 mcg/kg intraluminal dose to determine if the intraluminal dose would result in a higher degree of inhibition. A statistically significant reduction in response to 5-HT3-mediated excitation favoring the intraluminal dose (76.9 vs 47.9%; P=.008) was reported. These findings suggest that cilansetron is effectively absorbed at the site and therefore may decrease the potential for adverse effects compared to agents with systemic administration.

PHARMACOKINETICS Cilansetron is rapidly absorbed orally with a bioavailability of greater than 80% in rats.9 Peak plasma concentrations occurred 1 to 1.5 hours after oral doses of 4 to 64 mg daily. Cilansetron has a duration of action of approximately 6 hours. The elimination half-life after 4- and 8-mg oral doses administered 3 times daily for 6 days was reported to be 1.6 to 1.9 hours.10 No data were available at press time on the reported bioavailability of cilansetron in human subjects, volume of distribution, route of elimination, effect of food, and metabolic pathway. This lack of available data significantly limits the evaluation of this agent.

To determine the effects of cilansetron on colon transit time, 3 small, placebo-controlled crossover studies were conducted.11 Patients were administered cilansetron 4 or 8 mg or placebo 3 times daily for 14 days. In the first study of 12 healthy young patients, no significant differences in transit times were reported. Likewise, in the other 2 studies involving 16 healthy older patients (>65 years of age), no significant effect on transit time was noted, mainly due to a wide range of standard deviations reported in the results.

To assess the effect of a liquid antacid (200 mg MgOH and 225 mg AlOH/5 mL) on the pharmacokinetics of cilansetron, a randomized, single-dose crossover study was performed.12 Twenty-two healthy volunteers received either a single 16-mg dose of cilansetron alone or with the antacid. Peak plasma concentrations and mean time to peak were significantly decreased (P<.05), but mean AUC, half-life, clearance, and volume of distribution were not significantly changed.

CLINICAL TRIALS The majority of clinical trial data for cilansetron in patients with IBS-D are currently reported only as abstracts, with limited details and results available.

In a double-blind study, 44 healthy volunteers were randomized to receive either high-dose cilansetron 8 mg orally 3 times daily or placebo for 7 days.13 Threshold for gastric pain was assessed by response to increased intra-balloon pressure. Statistically, more patients in the cilansetron group had an increased threshold for gastric pain than placebo (P<.001).

Bradette et al15 evaluated the efficacy of cilansetron 2 mg orally 3 times daily in 806 male and female patients (792 ITT) with confirmed IBS-D. In this 6-month, randomized, double-blind, placebo-controlled study, improvements in IBS symptoms and abnormal bowel habits were reported weekly via an interactive voice message system. Over the first 3 months, patients reported significant improvement in IBS symptoms with cilansetron compared to placebo (56% vs 38%; P<.001). Statistically significant improvements in both IBS symptoms (61% vs 46%; P<.001) and bowel habits (63% vs 46%; P<.001) were reported with cilansetron compared to placebo at 6 months. Compliance rates were >98%, with more than 77% of patients completing the entire study (Table 1).

Greater rates of relief in as early as 1 month were reported in both studies in patients receiving cilansetron compared to placebo (50%-56% vs 34%-36%; P<.001). In the S1 study, adequate relief of pain was reported in 52% of cilansetron and 37% of placebo patients at 3 months (P<.001). In the S2 study, similar findings were reported for cilansetron versus placebo (61% vs 46%; P<.001), demonstrating that the beneficial effects can be maintained for 6 months. Rates of discontinuation were similar between the 2 groups.

Similarly, results of a subset analysis of male patients in S1 and S2 studies showed sustained improvement in IBS symptoms over both 3- and 6-month study periods.17 Results of a subset analysis of female patients in S1 and S2 studies also showed significant relief of IBS symptoms with cilansetron over placebo at 3 and 6 months.18

Clouse et al19 reported the analysis of 2 previous, double-blind, placebo-controlled studies (S1 and S2)in 1,484 ITT patients with confirmed IBS-D. In both the 3-month US study and the 6-month multinational study, patients were randomized to receive either cilansetron 2 mg orally 3 times daily or placebo. Primary end points were adequate relief of urgency, stool frequency, and stool consistency. Improvements in all end points were noted in both studies compared to baseline.

To explore the effect of cilansetron on quality of life (QOL) in patients meeting the Rome criteria for IBS-D, 338 subjects were randomized to receive either cilansetron 2 mg orally 3 times daily or placebo for 6 months in a double-blind, placebo-controlled, study of male and female subjects.20 Assessment of QOL was performed using the validated, 34-item IBS-QOL survey administered at baseline and at the end of the study period. This survey utilizes 8 subscales (interference with activity, body image, health worry, food avoidance, social reaction, sexual, relationships, and dysphoria) with response noted on a scale of 1 (none) to 5 (all the time). Compared with placebo, patients who received cilansetron for 6 months reported a statistically significant improvement in all IBS-QOL subscales from baseline (P<.005), except for the sexual subscale.

ADVERSE EFFECTS Cilansetron has been well tolerated in patients with IBS-D.14,15,19 The most commonly reported adverse effects in clinical trials included constipation (8%-19%), abdominal pain (5%-8%), headache (6%-11%), increased creatinine phosphokinase (CPK) (2% in the 6-month study and 10% in the 3-month study) and nasopharyngitis (2%). The overall incidence of ischemic colitis in clinical trials of cilansetron was 5.36/1,000 patients, compared to an incidence of 1.33/1,000 patients in trials of alosetron.7,14,15 Proposed mechanisms for this adverse effect with alosetron, and most likely cilansetron, include an exaggerated vasoconstrictor response in elderly patients with diabetes and those with atherosclerosis or lipid dysfunction.21 Adverse effects were not reported to be duration- or dose-dependent. Rates of constipation with cilansetron in clinical trials were 8%-19% compared to 20%-30% with alosetron.7 Constipation was the major reason for discontinuation of both drugs in clinical trials. It is interesting to note that no increases in CPK levels were noted with alosetron in clinical trials.

DRUG INTERACTIONS No studies have been published to date on the potential for drug interactions with cilansetron.

DOSING AND ADMINISTRATION Since cilansetron is not currently FDA approved, no dosing information is available. However, based on the limited clinical data from pharmacokinetic and pharmacotherapeutic studies, the initial recommended dose will likely be 2 mg orally 3 times daily. No information regarding dose adjustment in renal or hepatic dysfunction is available at this time.

Dr Zimmermann is an associate professor of pharmacy practice at the Massachusetts College of Pharmacy/Health Sciences-Worcester, Worcester, Mass, and a critical care specialist at Mercy Medical Center, Department of Pharmacy, Springfield, Mass.

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 associate clinical 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. Drossman DA, Patrick DL, Whitehead WE, et al. Further validation of the IBS-QOL: a disease-specific quality-of-life questionnaire. Am J Gastroenterol. 2000;95:999-1007.

2. Mertz HR. Irritable bowel syndrome. N Engl J Med. 2003;349:2136-2146.

3. Gershon MD. Review article: roles played by 5-hydroxytryptamine in the physiology of the bowel. Aliment Pharmacol Ther. 1999;13(suppl 2):15-30.

4. Vanner SJ, Depew WT, Paterson WG, et al. Predictive value of the Rome criteria for diagnosing the irritable bowel syndrome. Am J Gastroenterol. 1999;94;2912-2917.

5. FDA website. FDA approves restricted marketing of Lotronex [press release]. Available at: http:// http://www.fda.gov/bbs/topics/NEWS/2002/NEW00814.html. Accessed December 29, 2004.

6. Stacher G. Cilansetron. Curr Opin Invest Drugs. 2001;2:1432-1436.

7. Lembo A, Weber C, Farraye FA. Alosetron in irritable bowel syndrome. Drugs. 2003;63: 1895-1905.

8. Zimmermann AE. Tegaserod: a 5-HT4 agonist for women with constipation-predominant irritable bowel syndrome. 2002;37:449-461.

9. Hillsley K, Eeckhout C, Grundy D. Cilansetron acts at its site of absorption to antagonize the sensitivity of mesenteric afferent fibres to 5-hydroxytryptamine in the rat jejunum. Neurosci Lett. 2000;278:137-140.

10. Stacher G, Weber U, Stacher-Janotta G, et al. Effects of the 5-HT3 antagonist cilansetron vs placebo on phasic sigmoid colonic motility in healthy men: a double-blind crossover trial. Br J Clin Pharmacol. 2000;49:429-436.

11. Drewe J, Beglinger C, Meier R, Krause G, Steinborn C. Oral cilansetron produced increases in colonic transit time and gastric emptying in young and old healthy volunteers [abstract]. Digestion. 1998;59(suppl 3):665. Abstract 5051.

12. Pardue R, ZummBrunnen T, Fritsch H, et al. A randomized, single-dose, two-period, crossover study to determine the effect of a liquid antacid on the pharmacokinetics of a 16 mg dose of cilansetron in healthy male and female volunteers [abstract]. Pharmacotherapy. 2002;22:410. Abstract 41.

13. Bruley des Varannes S, Zerbib F, Ropert A, Golmiche JP, Krause G, Steinborn C. Oral cilansetron increased threshold of gastric visceral perception in a placebo-controlled, double-blind study in healthy volunteers [abstract]. Digestion. 1998;59(suppl 3):226. Abstract 2075.

14. Miner P, Stanton DB, Carter F, et al. Cilansetron in irritable bowel syndrome with diarrhea predominance (IBS-D): Efficacy and safety in a 3 month US study. Paper presented at: 69th Annual Scientific Meeting of the American College of Gastroenterology (ACG); October 29-November 3, 2004; Orlando, Fla.

15. Bradette M, Moennikes H, Carter F, Krause G, Caras S, Steinborn C. Cilansetron in irritable bowel syndrome with diarrhea predominance (IBS-D): Efficacy and safety in a 6 month global study [abstract]. Gastroenterology. 2004;126(suppl 2):A-42. Abstract 351.

16. Mueller-Lissner S, Stanghellini V, Caras S, et al. Cilansetron is efficacious in relieving abdominal pain/discomfort in men and women with irritable bowel syndrome with diarrhea predominance (IBS-D) in two multicenter studies. Paper presented at: United European Gastroenterology Week; September 25-29, 2004; Prague, Czech Republic.

17.Coremans G, Clouse RE, Carter F, et al. Cilansetron, a novel 5-HT3 antagonist, demonstrated efficacy in males and females with irritable bowel syndrome with diarrhea predominance (IBS-D) [abstract]. Gastroenterology. 2004;126; 4(suppl 2):A-643. Abstract W1471.

18. Mayer EA, Miner PB, Caras S, et al. Cilansetron is efficacious in the treatment of women with irritable bowel syndrome with diarrhea predominance (IBS-D): results from two multicenter trials. Paper presented at: United European Gastroenterology Week; September 25-29, 2004; Prague, Czech Republic.

19. Clouse RE, Caras S, Cataldi F, et al. Cilansetron is efficacious for relief of urgency in patients with irritable bowel syndrome with diarrhea predominance (IBS-D). Paper presented at: 1st European Society for Pediatric Gastroenterology, Hepatology and Nutrition meeting; May 27-29, 2004; Capri, Italy.

20. Olden KW, Drossman DA, Carter F, et al. Cilansetron improves health related quality of life in patients with irritable bowel syndrome with diarrhea predominance (IBS-D). Paper presented at: 69th Annual Scientific Meeting of the American College of Gastroenterology (ACG); October 29-November 3, 2004; Orlando, Fla.

21. Beck IT. Possible mechanisms for ischemic colitis during alosetron therapy. Gastroenterol. 2001;121:231-2.

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