Mechanism of Action
Irritable bowel syndrome with constipation and chronic idiopathic constipation are both lower gastrointestinal dysmotility disorders. Clinical investigations have shown that both motor and sensory functions of the gut appear to be altered in patients suffering from irritable bowel syndrome (IBS), while in patients with chronic idiopathic constipation, reduced intestinal motility is the predominant cause of the condition. Both the enteric nervous system, which acts to integrate and process information in the gut, and 5-hydroxytryptamine (5-HT, serotonin) are thought to represent key elements in the etiology of both IBS and idiopathic constipation. Approximately 95% of serotonin is found throughout the gastrointestinal tract, primarily stored in enterochromaffin cells but also in enteric nerves acting as a neurotransmitter. Serotonin has been shown to be involved in regulating motility, visceral sensitivity and intestinal secretion. Investigations suggest an important role of serotonin Type-4 (5-HT4) receptors in the maintenance of gastrointestinal functions in humans. 5-HT4 receptor mRNA has been found throughout the human gastrointestinal tract.
Tegaserod is a 5-HT4 receptor partial agonist that binds with high affinity at human 5-HT4 receptors, whereas it has no appreciable affinity for 5-HT3 or dopamine receptors. It has moderate affinity for 5-HT1 receptors. Tegaserod, by acting as an agonist at neuronal 5-HT4 receptors, triggers the release of further neurotransmitters such as calcitonin gene-related peptide from sensory neurons. The activation of 5-HT4 receptors in the gastrointestinal tract stimulates the peristaltic reflex and intestinal secretion, as well as inhibits visceral sensitivity. In vivo studies showed that tegaserod enhanced basal motor activity and normalized impaired motility throughout the gastrointestinal tract. In addition, studies demonstrated that tegaserod moderated visceral sensitivity during colorectal distension in animals.
Peak plasma concentrations are reached approximately 1 hour after oral dosing. The absolute bioavailability of tegaserod when administered to fasting subjects is approximately 10%. The pharmacokinetics are dose proportional over the 2 mg to 12 mg range given twice daily for 5 days. There was no clinically relevant accumulation of tegaserod in plasma when a 6 mg b.i.d. dose was given for 5 days. (See DOSAGE AND ADMINISTRATION.)
When the drug is administered with food, the bioavailability of tegaserod is reduced by 40%-65% and Cmax by approximately 20%-40%. Similar reductions in plasma concentration occur when tegaserod is administered to subjects within 30 minutes prior to a meal, or 2.5 hours after a meal. Tmax of tegaserod is prolonged from approximately 1 hour to 2 hours when taken following a meal, but decreased to 0.7 hours when taken 30 minutes prior to a meal.
Tegaserod is approximately 98% bound to plasma proteins, predominantly alpha-1-acid glycoprotein. Tegaserod exhibits pronounced distribution into tissues following intravenous dosing with a volume of distribution at steady-state of 368 ± 223 L.
Tegaserod is metabolized mainly via two pathways. The first is a presystemic acid catalyzed hydrolysis in the stomach followed by oxidation and conjugation which produces the main metabolite of tegaserod, 5-methoxyindole-3-carboxylic acid glucuronide. The main metabolite has negligible affinity for 5-HT4 receptors in vitro. In humans, systemic exposure to tegaserod was not altered at neutral gastric pH values. The second metabolic pathway of tegaserod is direct glucuronidation which leads to generation of three isomeric N-glucuronides.
The plasma clearance of tegaserod is 77 ± 15 L/h with an estimated terminal half-life (T1/2) of 11 ± 5 hours following intravenous dosing. Approximately two-thirds of the orally administered dose of tegaserod is excreted unchanged in the feces, with the remaining one-third excreted in the urine, primarily as the main metabolite.
Patients: The pharmacokinetics of tegaserod in IBS patients are comparable to those in healthy subjects. The pharmacokinetics of tegaserod in patients with chronic idiopathic constipation have not been studied.
Reduced Renal Function: No change in the pharmacokinetics of tegaserod was observed in subjects with severe renal impairment requiring hemodialysis (creatinine clearance < 15 mL/min/1.73 m2). Cmax and AUC of the main pharmacologically inactive metabolite of tegaserod, 5-methoxy-indole-3-carboxylic acid glucuronide, increased 2- and 10-fold respectively, in subjects with severe renal impairment compared to healthy controls. No dosage adjustment is required in patients with mild-to-moderate renal impairment. Tegaserod is not recommended in patients with severe renal impairment.
Reduced Hepatic Function: In subjects with mild hepatic impairment, mean AUC was 31% higher and Cmax 16% higher compared to subjects with normal hepatic function. No dosage adjustment is required in patients with mild impairment, however, caution is recommended when using tegaserod in this patient population. Tegaserod has not adequately been studied in patients with moderate and severe hepatic impairment, and is therefore not recommended in these patients.
Gender: Gender has no effect on the pharmacokinetics of tegaserod.
Race: Data were inadequate to assess the effect of race on the pharmacokinetics of tegaserod.
Age: In a clinical pharmacology study conducted to assess the pharmacokinetics of tegaserod administered to healthy young (18-40 years) and healthy elderly (65-85 years) subjects, peak plasma concentration and exposure were 22% and 40% greater, respectively, in elderly females than young females but still within the variability seen in tegaserod pharmacokinetics in healthy subjects. Based on an analysis across several pharmacokinetic studies in healthy subjects, there is no age effect on the pharmacokinetics of tegaserod when allowing for body weight as a covariate. Therefore, dose adjustment in elderly patients who have IBS with constipation is not necessary.
IBS with Constipation
RESULTS IN WOMEN: In three multicenter, double-blind, placebo-controlled studies, 2,470 women (mean age 43 years [range 17-89 years]; 86% Caucasian, 10% African American) with at least a 3-month history of IBS symptoms prior to the study baseline period that included abdominal pain, bloating and constipation received either Zelnorm® (tegaserod maleate) 6 mg b.i.d. or placebo. In all patients, constipation was characterized by at least two of the following three symptoms each occurring ≥25% of the time over a 3-month period:< 3 bowel movements/week, hard or lumpy stools, or straining with a bowel movement. The study design consisted of a 4-week placebo-free baseline period followed by a 12-week double-blind treatment period. Study 1 and 2 evaluated a fixed dose regimen of tegaserod 6 mg b.i.d. while Study 3 utilized a dose-titration design.
Each week of the 4-week placebo-free baseline period and the 12-week double-blind treatment period, patients were asked the question, “Please consider how you felt this past week in regard to your IBS, in particular your overall well-being, and symptoms of abdominal discomfort, pain and altered bowel habit. Compared to the way you usually felt before entering the study, how would you rate your relief of symptoms during the past week?” The response variable consisted of the following 5 categories: completely relieved, considerably relieved, somewhat relieved, unchanged, or worse. Patients were classified as responders within a month if they were considerably or completely relieved for at least two of the four weeks, or if they were at least somewhat relieved for each of the four weeks.
Calculated response rates during month 1 and during month 3 as described above are shown in the table below. The differences in response rates vs. placebo were greater at month 1 than month 3.
| Month 1 || Month 3 |
| Proportion of Responders (Females) || Proportion of Responders (Females) |
| Study || Zelnorm ®|
6 mg b.i.d.
| Placebo || Difference |
(95% C onfidence
| Zelnorm ® |
6 mg b.i.d.
| Placebo |
| Difference |
|(31%)||(17%)||(6% to 21%)||(39%)||(28%)||(3% to 20%)|
|(35%)||(22%)||(8% to 17%)||(44%)||(39%)||(0% to 10%)|
|(34%)||(20%)||(6% to 22%)||(43%)||(38%)||(-4% to 14%)|
Response: ≥ 2 of 4 weeks complete or considerable relief or 4 of 4 weeks with at least somewhat relief.
The same efficacy variable (i.e., complete relief, considerable relief, somewhat relief, unchanged, worse) was analyzed on a weekly basis. The proportion of female patients with complete, considerable or somewhat relief at weeks 1, 4, 6, 8 and 12 are shown in the figure below.
In addition, individual symptoms of abdominal pain/discomfort and bloating were assessed daily using a 6 or 7 point intensity scale. A positive response was defined as at least a 1 point reduction in the scale. During the first four weeks in the fixed dose studies, 8 to 11% more Zelnorm-treated patients than placebo patients were responders for abdominal pain/discomfort. Similarly, 9 to 12% more Zelnorm-treated patients were responders for bloating. Corresponding differences at month 3 were 1 to 10% for abdominal pain/discomfort and 4 to 11% for bloating. Patients on Zelnorm also experienced an increase in median number of stools from 3.8/week at baseline to 6.3/week at month 1 and 6.0/week at month 3, while placebo patients increased from 4.0/week to 5.1/week at month 1 and 5.5/week at month 3.
RESULTS IN MEN: In two randomized, placebo-controlled, double-blind studies enrolling 288 males, there were no significant differences between placebo and Zelnorm response rates in subgroup analyses by gender.
Chronic Idiopathic Constipation
In two multicenter, double-blind, placebo-controlled studies, 2,612 patients with chronic constipation were randomized to receive either Zelnorm® (tegaserod maleate) 6 mg b.i.d., 2 mg b.i.d., or placebo.
RESULTS IN PATIENTS UNDER AGE 65 : A total of 2,281 patients were less than 65 years of age. Patients (91% female, mean age 43 [range 18-64], 90% Caucasian, 4.3% African American) had constipation defined as less than 3 complete spontaneous bowel movements [CSBM] per week and at least one of the following symptoms for at least 25% of defecations: straining, hard/very hard stools, incomplete evacuation. A bowel movement was evaluated by the patient as complete if it resulted in a feeling of complete emptying of their bowel. A bowel movement was considered to be spontaneous [SBM] if no laxatives were taken in the preceding 24 hours. The study population consisted of patients with a 6 month or longer history of constipation symptoms (median 12 years). Patients with constipation known to be due to other known colon diseases, pelvic floor dysfunction, metabolic or neurological disturbances, or concomitant medications were excluded.
After a 2-week baseline, patients were randomized to a 12-week double-blind treatment with Zelnorm 6 mg b.i.d., Zelnorm 2 mg b.i.d., or placebo. This treatment period was followed, in Study 1, by an extension period where patients received either 6 mg b.i.d. or 2 mg b.i.d. for an additional 13 months. The drop out rate for lack of efficacy for the additional 13-month period was 19% for 6 mg b.i.d. and 22% for 2 mg b.i.d.. In Study 2, the 12-week treatment period was followed by a 4-week drug-free withdrawal period.
Patients were classified as responders (primary efficacy variable) if they achieved an average increase of at least one CSBM per week during the first four weeks of treatment compared to baseline, and had at least 7 days of exposure in the study.
The response rate for the primary efficacy variable in patients under 65 years of age was higher in the Zelnorm 6 mg b.i.d. group compared to the placebo group for each of the 2 trials (p <0.0001, Table 2). This difference was statistically significant for CSBM changes averaged over the first 4 weeks of treatment and the full 12 weeks of treatment. The results with Zelnorm 2 mg b.i.d. showed significant changes during the first 4 weeks, however, no statistically significant changes were observed over 12 weeks in one study.
Proportion of Patients Under Age 65 with an Increase of 1 or More CSBM for the Two Trials Combined
| Zelnorm ® |
6 mg b.i.d.
| Zelnorm ® |
2 mg b.i.d.
| Placebo |
|Weeks 1-4||43% (337/789)||39% (286/732)||25% (184/737)|
|Weeks 1-12||45% (355/789)||38% (281/732)|| 28% (206/737)|
Infrequent d efecation
At baseline, the median number of CSBM’s per week was zero and the mean number of CSBM’s per week was 0.5. Regardless of baseline, Zelnorm significantly increased the number of complete spontaneous bowel movements compared to placebo at each week (p<0.05).
Frequency of Complete Spontaneous Bowel Movement (CSBM) over 12 Week Treatment and 4 Week Withdrawal Period in Study 2
Zelnorm also significantly increased the number of SBM’s compared to placebo at each week (p<0.05).
Patients treated with Zelnorm experienced a statistically significant reduction in the individual symptoms of straining, abdominal distension/bloating, and abdominal discomfort/pain, and a statistically significant improvement in stool consistency and frequency compared to placebo when averaged over the 12 weeks (p<0.05). In addition, a global constipation relief score, computed as an average of 4 scores measuring abdominal discomfort/pain, abdominal distension/bloating, bothersomeness of constipation and satisfaction with bowel habits, showed statistically significant improvement for Zelnorm compared to placebo when averaged over the 12 weeks (p<0.05).
RESULTS IN PATIENTS AGE 65 AND OVER: Subgroup analyses of patients 65 and older (n=331) showed no significant treatment effects for Zelnorm over placebo.