Mechanism of Action
Alosetron is a potent and selective 5-HT3 receptor antagonist. 5-HT3 receptors are ligand-gated cation channels that are extensively distributed on enteric neurons in the human gastrointestinal tract, as well as other peripheral and central locations. Activation of these channels and the resulting neuronal depolarization affect the regulation of visceral pain, colonic transit and gastrointestinal secretions, processes that relate to the pathophysiology of irritable bowel syndrome (IBS). 5-HT3 receptor antagonists such as alosetron inhibit activation of non-selective cation channels which results in the modulation of the enteric nervous system.
The cause of IBS is unknown. IBS is characterized by visceral hypersensitivity and hyperactivity of the gastrointestinal tract, which lead to abnormal sensations of pain and motor activity. Following distention of the rectum, IBS patients exhibit pain and discomfort at lower volumes than healthy volunteers. Following such distention, alosetron reduced pain and exaggerated motor responses, possibly due to blockade of 5-HT3 receptors.
In healthy volunteers and IBS patients, alosetron (2 mg orally, twice daily for 8 days) increased colonic transit time without affecting orocecal transit time. In healthy volunteers, alosetron also increased basal jejunal water and sodium absorption after a single 4-mg dose. In IBS patients, multiple oral dosages of alosetron (4 mg twice daily for 6.5 days) significantly increased colonic compliance.
Single oral doses of alosetron administered to healthy men produced a dose-dependent reduction in the flare response seen after intradermal injection of serotonin. Urinary 6-β-hydroxycortisol excretion decreased by 52% in elderly subjects after 27.5 days of alosetron 2 mg orally twice daily. This decrease was not statistically significant. In another study utilizing alosetron 1 mg orally twice daily for 4 days, there was a significant decrease in urinary 6-β-hydroxycortisol excretion. However, there was no change in the ratio of 6-β-hydroxycortisol to cortisol, indicating a possible decrease in cortisol production. The clinical significance of these findings is unknown.
The pharmacokinetics of alosetron have been studied after single oral doses ranging from 0.05 to 16 mg in healthy men. The pharmacokinetics of alosetron have also been evaluated in healthy women and men and in patients with IBS after repeated oral dosages ranging from 1 mg twice daily to 8 mg twice daily.
Alosetron is rapidly absorbed after oral administration with a mean absolute bioavailability of approximately 50% to 60% (approximate range 30% to >90%). After administration of radiolabeled alosetron, only 1% of the dose was recovered in the feces as unchanged drug. Following oral administration of a 1-mg alosetron dose to young men, a peak plasma concentration of approximately 5 ng/mL occurs at 1 hour. In young women, the mean peak plasma concentration is approximately 9 ng/mL, with a similar time to peak.
Alosetron absorption is decreased by approximately 25% by co-administration with food, with a mean delay in time to peak concentration of 15 minutes (see DOSAGE AND ADMINISTRATION: Usual Dosage in Adults).
Alosetron demonstrates a volume of distribution of approximately 65 to 95 L. Plasma protein binding is 82% over a concentration range of 20 to 4,000 ng/mL.
Metabolism and Elimination
Plasma concentrations of alosetron increase proportionately with increasing single oral doses up to 8 mg and more than proportionately at a single oral dose of 16 mg. Twice-daily oral dosing of alosetron does not result in accumulation. The terminal elimination half-life of alosetron is approximately 1.5 hours (plasma clearance is approximately 600 mL/min). Population pharmacokinetic analysis in IBS patients confirmed that alosetron clearance is minimally influenced by doses up to 8 mg.
Renal elimination of unchanged alosetron accounts for only 6% of the dose. Renal clearance is approximately 94 mL/min.
Alosetron is extensively metabolized in humans. The biological activity of the metabolites is unknown. A mass balance study was performed utilizing an orally administered dose of unlabeled and 14C-labeled alosetron. On a molar basis, alosetron metabolites reached additive peak plasma concentrations 9-fold greater than alosetron, and the additive metabolite AUCs were 13-fold greater than the alosetron AUC. Plasma radioactivity declined with a half-life 2-fold longer than that of alosetron, indicating the presence of circulating metabolites. Approximately 73% of the radiolabeled dose was recovered in urine with another 24% of the dose recovered in feces. Only 7% of the dose was recovered as unchanged drug. At least 13 metabolites have been detected in urine. The predominant product in urine was a 6-hydroxy metabolite (15% of the dose). This metabolite was secondarily metabolized to a glucuronide that was also present in urine (14% of the dose). Smaller amounts of the 6-hydroxy metabolite and the 6-O-glucuronide also appear to be present in feces. A bis-oxidized dicarbonyl accounted for 14% of the dose, and its monocarbonyl precursor accounted for another 4% in urine and 6% in feces. No other urinary metabolite accounted for more than 4% of the dose. Glucuronide or sulfate conjugates of unchanged alosetron were not detected in urine.
In studies of Japanese men, an N-desmethyl metabolite was found circulating in plasma in all subjects and accounted for up to 30% of the dose in 1 subject when alosetron was administered with food. The clinical significance of this finding is unknown.
Alosetron is metabolized by human microsomal cytochrome P450 (CYP), shown in vitro to involve enzymes 2C9 (30%), 3A4 (18%), and 1A2 (10%). Non-CYP-mediated Phase I metabolic conversion also contributes to an extent of about 11%. However, in vivo data suggest that CYP1A2 plays a more prominent role in alosetron metabolism, based on correlation of alosetron clearance with in vivo CYP1A2 activity measured by probe substrate, increased clearance induced by smoking, and inhibition of clearance by fluvoxamine (see CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions).
In some studies in healthy men or women, plasma concentrations were elevated by approximately 40% in individuals 65 years and older compared to young adults (see WARNINGS). However, this effect was not consistently observed in men.
Plasma concentrations are 30% to 50% lower and less variable in men compared to women given the same oral dose. Population pharmacokinetic analysis in IBS patients confirmed that alosetron concentrations were influenced by gender (27% lower in men).
Reduced Hepatic Function
A single 1-mg oral dose of alosetron was administered to 1 female and 5 male patients with moderate hepatic impairment (Child-Pugh score of 7 to 9) and to 1 female and 2 male patients with severe hepatic impairment (Child-Pugh score of >9). In comparison with historical data from healthy subjects, patients with severe hepatic impairment displayed higher systemic exposure to alosetron. The female with severe hepatic impairment displayed approximately 14-fold higher exposure, while the female with moderate hepatic impairment displayed approximately 1.6-fold higher exposure, than healthy females. Due to the small number of subjects and high intersubject variability in the pharmacokinetic findings, no definitive quantitative conclusions can be made. However, due to the greater exposure to alosetron in the female with severe hepatic impairment, alosetron should not be used in females with severe hepatic impairment (see CONTRAINDICATIONS, PRECAUTIONS: Hepatic Insufficiency, and DOSAGE AND ADMINISTRATION: Patients With Hepatic Impairment).
Reduced Renal Function
Renal impairment (creatinine clearance 4 to 56 mL/min) has no effect on the renal elimination of alosetron due to the minor contribution of this pathway to elimination. The effect of renal impairment on metabolite kinetics and the effect of end-stage renal disease have not been assessed (see DOSAGE AND ADMINISTRATION: Patients With Renal Impairment).
See CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions.