Development, Pharmacology, Therapeutics
Irritable bowel syndrome (IBS) is a disorder of the lower gastrointestinal tract characterized by symptoms such as diarrhea, diarrhea alternating with constipation, abdominal cramping and pain, gas and bloating, and mucus in the stool. This condition is sometimes referred to as “spastic colon” and “functional bowel disease.” IBS is one of the most common medical disorders in the U.S., affecting approximately 20% of all adults. Women account for 70% of IBS sufferers in the U.S. The syndrome is thought to result from dysregulation of intestinal motor, sensory and CNS function. Treatment of IBS has included psychotherapy, dietary changes and pharmacological intervention, including antispasmodics, antidiarrheals, antacids, anti-gas medications and antidepressants. Recent studies of IBS pathophysiology have concentrated on the involvement of serotonin (5-HT) receptors on visceral afferent neurons. Type 3 serotonin receptors (5-HT3) are nonselective cation channels that are extensively distributed on enteric neurons in the GI tract. Activation of 5-HT3 receptors may, in part, bring about many of the symptoms of IBS. Hence, design of new therapy for IBS has centered on the development of 5-HT3 antagonists, so-called neuroenteric modulators (NEMs). In particular, the 5-HT3 antagonist alosetron was recently approved for the treatment of women with IBS whose predominant bowel symptom is diarrhea and who are non-constipated. Alosetron effectively treats multiple symptoms of IBS, including abdominal pain, urgency, stool frequency, and stool consistency. Other selective 5-HT3 antagonists, termed setrons, have found utility as antinauseant and antiemetic agents. These include ondansetron (Zofran), dolasetron (Anzemet) and granisetron (Kytril).
|Table 1. Pharmacokinetics of Alosetron|
|Absorption (1 mg po dose)|
|Plasma protein binding, %||82|
|Volume of distribution, L||65–95|
|Median duration of action, h||~1.5|
|Elimination t1/2, h||93|
|Dose metabolized, %|
Alosetron improves distention-induced visceral pain, most likely related to the drug’s action as an NEM on central and peripheral 5-HT3 receptors. Alosetron has no effect on meal-stimulated intragastric acidity or orocecal transit time in healthy patients. However, in IBS patients alosetron slows colonic transit time, increases colonic compliance and exhibits significant antinociceptive activity.
Efficacy and safety in men have not been established. In two placebo-controlled studies, the efficacy of alosetron at various doses was investigated in more than 1,200 females. In each study, 71% of the patients had diarrhea-predominant IBS, while the majority of the remaining population had IBS symptoms alternating between diarrhea and constipation. Only 1% and 2% of the women in these studies had constipation-predominant IBS.
Results of both studies showed that 1 mg of alosetron administered twice daily was significantly more effective than placebo in relieving a variety of symptoms of IBS in women. Symptom improvement included relief of abdominal pain and discomfort, reduction in the proportion of days with urgency, decreased stool frequency, and firmer stools. The onset of relief ranged from 1–4 weeks after initiation of drug therapy. The therapeutic effects of alosetron were maintained over the course of treatment. On discontinuation of the treatment, there was no significant difference between women who had taken the drug and women who had taken the placebo.
A number of clinicians have concluded that therapeutic management of IBS will be significantly advanced as a result of the development of NEMs. It is likely that female patients with frequent symptoms of diarrhea-predominant or mixed IBS of moderate intensity will benefit from treatment with NEMs such as alosetron. Questions remain about the therapeutic utility of this new drug, including its use in male patients, the optimal mode of administration for long-term therapy, and appropriate use with other regimens for IBS therapy.
Lotronex: Adverse Reactions
The FDA developed a medication guide for distribution with each prescription for alosetron (Lotronex). Pharmacists have a legal obligation to provide this information to patients. This guide is intended to clearly identify possible complications from constipation and risk of ischemic colitis for women receiving alosetron therapy. The guide instructs patients who become severely constipated to immediately discontinue administration of the drug and to contact their physician if they have worsening abdominal pain, bloody diarrhea or blood in their bowel movements. During a four-month period following alosetron approval, the FDA received seven reports of serious complication of constipation and eight reports of ischemic colitis. The official labeling of alosetron has been changed to include warnings that the drug should not be started when women are constipated and that alosetron is now contraindicated in women with a history of intestinal obstruction, stricture, toxic megacolon, GI perforation and/or adhesions, a history of ischemic colitis, active diverticulitis, current Crohn’s disease or ulcerative colitis or a history of such disease. Other reactions included headache, anorexia, nausea, dizziness, loose stools (with 4-mg single doses) and abdominal cramping and flatulence/abdominal discomfort (1 mg BID doses).
Alosetron (Lotronex) has a pregnancy risk factor of B. No adequate and well-controlled studies have been done in pregnant women. Animal studies indicate that alosetron and/or metabolites are excreted in breast milk. It is not known if alosetron in excreted in human milk, hence, caution should be used in administering alosetron to a nursing woman.
No clinically significant interactions have been reported for alosetron with cisapride, theophylline or oral contraceptives. In view of the extensive metabolism of alosetron by CYP2C9 (30%), 3A4 (18%), and 1A2 (10%) isozymes, inducers or inhibitors of these enzymes may change the clearance of alosetron, but this has not been evaluated. Alosetron inhibits N-acetyltransferase, which may influence the metabolism of drugs containing primary aromatic amine structural features; however, this potential interaction has not been adequately studied.
Alosetron (Lotronex) has good oral bioavailability, achieving peak plasma levels within an hour (See Table 1). Steady-state plasma levels are achieved within one day. The duration of action supports its use in twice-daily dosing. The drug is cleared primarily by metabolism and eliminated largely by the kidney. The biodisposition of alosetron is not significantly affected by renal impairment.
Dosage & Administration
Supplied as 1 mg tablets. The recommended adult dosage is 1 mg taken orally twice daily, with or without food. No dosage adjustment is recommended for elderly patients or patients with renal or hepatic impairment.