Alosetron: A New Agent for
the Treatment of Irritable Bowel

Volume III, Number 2 | May/June 2000
Mandy Leonard, Pharm.D., BCPS

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Alosetron (Lotronex®, Glaxo Wellcome), a 5-HT3 receptor antagonist, was FDA-approved on February 9, 2000 for the treatment of irritable bowel syndrome (IBS) in women whose predominant bowel symptom is diarrhea.

IBS is a motility disorder involving the entire gastrointestinal (GI) tract, causing recurring upper and lower GI symptoms (e.g., abdominal pain, constipation, diarrhea, abdominal bloating).

The etiology of IBS is currently unknown, however, changes in intestinal motor and sensory function and altered visceral perception are believed to play an important role in this syndrome. Some factors may precipitate or aggravate heightened GI motility such as psychological issues, diet, drugs, and hormones. IBS tends to occur in the second and third decades of life and affects 14% to 24% of women and 5% to 19% of men. Table 1 lists the diagnostic criteria for IBS.

Table 1: Diagnostic Criteria: Irritable Bowel Syndrome (IBS)
At least three months continuous or recurrent symptoms of:
1. abdominal pain or discomfort which is;
  a. relieved with defecation,
  b. and/or associated with a change in the frequency of stool,
  c. and/or associated with a change in consistency of stool;
2. two or more of the following, at least a quarter of occasions or days;
  a. altered stool frequency,
  b. altered stool form,
  c. altered stool passage,
  d. passage of mucus,
  e. bloating or feeling of abdominal distention.

Adapted from: Thompson WG, Creed F, Drossman DA, et al. Functional bowel disease and abdominal pain. Gastroenterol Int. 1992;5:75-91.

Current treatment of IBS includes education, dietary modification, and drug therapy. The latter is determined based on the patient's presenting symptoms. For example, smooth muscle relaxants, such as dicyclomine, may be used for abdominal pain and bloating and loperamide may be used for diarrhea. Alosetron is a new option for the pharmacologic management of IBS.

5-Hydroxytryptamine (5-HT, or serotonin) mediates peristalsis, secretory reflexes, nausea, vomiting, bloating, and abdominal pain in the GI tract by activating secretory cells and stimulating gut smooth muscle. Alosetron binds with high affinity to 5-HT3 receptors and shows moderate to low affinity for 5-HT1c, histamine3, and "2-adrenoreceptors. Therefore, blockade of the 5-HT3 receptors has the potential to modify the symptoms of IBS by slowing intestinal motility and reducing pain sensitivity.

The pharmacokinetics of alosetron can be found in Table 2. Absorption is rapid, with peak concentrations of alosetron attained within one hour of oral administration and a mean absolute bioavailability of approximately 50% to 60%. Absorption is decreased by approximately 25% when given with food, therefore a mean delay in time to peak concentration of 15 minutes occurs. Alosetron is metabolized extensively in the liver via the cytochrome P450 system and involves enzymes 2C9, 3A4, and 1A2. Only 6% of the unchanged drug is renally eliminated. Plasma concentrations are generally 30% to 50% lower and less variable in men when compared to women given the same oral dose.

Table 2: Pharmacokinetics of Alosetron*
 Bioavailability 50% to 60%
 Peak plasma concentration 9 ng/ml **
 Time to peak plasma concentration 1 hour
 Half-life 1.5 hours
 Plasma protein binding 82 %
 Volume of distribution 65 to 95 liters

Adapted from: Reddy P. Alosetron: a 5-HT3 receptor antagonist for treatment of irritable bowel Syndrome. Formulary 2000;35;404-11. * Based on 1mg dose ** In women (30% - 50% lower in men)

The most frequently reported side effect of alosetron is constipation. In clinical studies, constipation was reported in 25% to 30% of the patients receiving alosetron 1 mg twice daily. Therefore, alosetron should not be used in patients whose primary IBS symptom is constipation. Management of constipation may require laxatives, fiber, or an interruption of therapy. Table 3 represents some other adverse effects reported in 1% or more of the female population taking alosetron 1 mg twice daily.

Table 3: Adverse Effects Associated with Alosetron
Body System (adverse effect) Lotronex®
Cardiovascular  Hypertension 2% < 1%
Ear, Nose, and Throat
 Allergic rhinitis
2% <1%

Adapted from: Lotronex® package insert. Research Triangle Park, NC: Glaxo Wellcome Inc.; 2000 February.

Few studies have evaluated drug interactions with alosetron. In some in vivo and in vitro studies, alosetron inhibited cytochrome P-450 enzymes 1A2 and 2E1. To date, clinical studies have found no significant interaction between alosetron and theophylline, oral contraceptives, or cisapride.

The recommended dosage of alosetron is 1 mg administered orally twice a day and given with or without food. No dosing adjustment is necessary in geriatric patients or in patients with impaired renal function. There have been no conclusive studies in patients with hepatic impairment, however, there is a possibility that elevations in plasma concentration would occur due to the metabolism of alosetron. Currently, alosetron is contraindicated in patients with a hypersensitivity to any component of the product. The safety and effectiveness of this agent in men has yet to be established.

Alosetron (Lotronex®) is supplied as a 1 mg tablet and has an average wholesale price (AWP) of $1.98 per tablet. This product is currently not on the CCF Formulary of accepted drugs.

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