Chemical formula: C₁₆H₂₃N₅O Molecular mass: 301.394 g/mol PubChem compound: 5362436
Tegaserod is an agonist of serotonin type-4 (5-HT4) receptors that stimulates the peristaltic reflex and intestinal secretion, inhibits visceral sensitivity, enhances basal motor activity, and normalizes impaired motility throughout the gastrointestinal tract.
Based on in vitro binding affinity and functional assessment, at clinically relevant plasma concentrations, tegaserod is an antagonist at 5-HT2B receptors in humans. It is expected to have minimal binding to 5-HT1 receptors. Tegaserod has no affinity for 5-HT3 or dopamine receptors.
The main metabolite, M29, has negligible affinity for 5-HT4 receptors in vitro.
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.
Centrally analyzed ECGs were recorded in 4,605 male and female patients receiving tegaserod 6 mg twice daily or placebo for IBS-C and other related motility disorders. No subject receiving tegaserod had an absolute QTcF above 480 ms. An increase in QTcF of 30 to 60 ms was observed in 7% of patients receiving tegaserod and 8% receiving placebo. An increase in QTcF of greater than 60 ms was observed in 0.3% and 0.2% of subjects, respectively. The effects of tegaserod on the QTcF interval were not considered to be clinically meaningful.
There is a potential for tegaserod and its main metabolite (M29) to increase platelet aggregation in vitro. In one in vitro study, tegaserod, at concentrations up to 10 times the maximum plasma concentration (Cmax) at the recommended dose, significantly increased platelet aggregation in a concentration-dependent manner up to 74% (range 11% to 74%) compared to vehicle control (with potentiation by various agonists). In another in vitro study, M29, at concentrations up to 0.6 times the Cmax of M29 also showed a 5% to 16% increase in platelet aggregation compared to vehicle control. The clinical implications of the in vitro platelet aggregation results are unclear.
The pharmacokinetics of tegaserod in IBS-C patients are comparable to those in healthy subjects. The mean (±SD) peak tegaserod concentration (Cmax) was 2.9 (±1.1) ng/mL, and mean (±SD) AUC was 10.5 (±4.6) h•ng/mL following a single tegaserod dose at 6 mg. Tegaserod systemic exposure at steady state increase proportionally over a dose range of 2 mg to 12 mg twice daily (0.3 to 2 times the approved recommended dosage). There was no significant accumulation (~10%) of tegaserod following the approved recommended dosage.
The absolute bioavailability of tegaserod is approximately 10% when administered to fasting subjects. The median time to peak tegaserod plasma concentration (Tmax) is approximately one hour (range 0.7 to 2 hours).
Compared to under fasted conditions, the tegaserod AUC was reduced by 40% to 65%, Cmax was reduced by approximately 20% to 40% and median Tmax was 0.7 hours when tegaserod was administered 30 minutes before a high-fat, high-calorie meal (approximately 150 calories from protein, 250 calories from carbohydrates, and 500 calories from fat). Plasma concentrations were similar when tegaserod was administered within 30 minutes prior to a meal or 2.5 hours after a meal.
Protein binding of tegaserod is approximately 98%. The mean volume of distribution of tegaserod (± SD) at steady-state is 368 ± 223 L following intravenous administration (tegaserod is not approved for intravenous administration).
The mean tegaserod terminal elimination half-life ranged from 4.6 to 8.1 hours following oral administration and the mean (± SD) plasma clearance was 77 ± 15 L/h following intravenous administration.
Tegaserod is metabolized via hydrolysis and direct glucuronidation. Tegaserod undergoes hydrolysis in the stomach followed by oxidation and conjugation which produces the M29 metabolite.
Approximately two-thirds of a tegaserod dose is excreted unchanged in the feces, with the remaining one-third excreted in the urine as metabolites.
No change in the pharmacokinetics of tegaserod was observed in subjects with end stage renal disease (creatinine clearance normalized by body surface area (CrCL) <15 mL/min/1.73 m²) requiring hemodialysis. Although renal impairment does not affect the pharmacokinetics of tegaserod, the pharmacokinetics of its main metabolite (M29) are altered, the Cmax of M29 doubling and the AUC increasing 10-fold in patients with severe renal impairment (CrCL <15 mL/min/1.73 m²) compared to healthy subjects with normal renal function (CrCL >80 mL/min/1.73 m²).
In subjects with mild hepatic impairment (Child-Pugh A), the mean tegaserod AUC was 31% higher and the Cmax was 16% higher compared to healthy subjects with normal hepatic function. The increase in exposure in subjects with mild impairment is not considered to be clinically relevant.
In a single subject with moderate hepatic impairment, the Cmax and AUC were 140% and 200% of that observed in healthy controls. Tegaserod has not been studied in patients with moderate or severe hepatic impairment (Child-Pugh B or C).
Quinidine: Coadministration of a single dose of 600 mg quinidine (P-gp inhibitor) with a single dose of tegaserod 6 mg increased the mean tegaserod AUC(0-12h) and the mean Cmax by 50% and 44%, respectively, compared to tegaserod administered alone. Coadministration of multiple doses of quinidine (600 mg once daily for three days) with tegaserod 6 mg twice daily for six days increased the mean tegaserod AUC(0-12h) and Cmax by 71% and 63%, respectively, compared to tegaserod administered alone.
Inhibitors of P-gp (e.g., ritonavir, clarithromycin, itraconazole) may modestly increase the oral bioavailability of tegaserod. The clinical relevance of increased systemic exposure as a result of P-gp inhibition is unclear.
Omeprazole: Administration of omeprazole 20 mg once daily for four days followed by tegaserod 6 mg twice daily on day four increased the mean tegaserod AUC and Cmax by 15% and 17%, respectively, compared to tegaserod administered alone. This increase in exposure is not considered clinically relevant.
No clinically significant effects of tegaserod on the pharmacokinetics of the following drugs were observed when used concomitantly with a single dose of tegaserod 6 mg: theophylline (CYP1A2 substrate), dextromethorphan (CYP2D6 substrate), digoxin (P-gp substrate), warfarin (CYP2C9 substrate), or oral contraceptives (ethynyl estradiol and levonorgestrel).
Digoxin: Administration of a single dose of digoxin following tegaserod 6 mg twice daily for 4 days reduced the mean Cmax and AUC of digoxin by approximately 15%. This reduction in digoxin exposure is not considered clinically relevant.
Warfarin: Coadministration of tegaserod 6 mg twice daily with warfarin for seven days did not significantly alter the pharmacokinetics of either R- or S-warfarin or change the prothrombin time in healthy subjects.
Oral Contraceptives: Coadministration of tegaserod 6 mg twice daily with 0.3 mg of ethinyl estradiol and 0.125 mg of levonorgestrel once daily did not affect the steady-state (Day 21) pharmacokinetics of ethinyl estradiol but reduced both the Cmax and AUC of levonorgestrel by 8%. This change in exposure is not considered clinically relevant.
CYP enzymes:
Tegaserod does not inhibit CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, and CYP3A4, and it does not induce CYP3A4 and CYP2B6.
Limited induction of CYP1A2 was observed at tegaserod concentrations in excess of 100 times the clinically relevant range.
M29 does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4, and it does not induce CYP1A2, CYP2B6, or CYP3A4.
Transporters:
Tegaserod is a substrate for BCRP and P-gp, but not a substrate of OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K or BSEP. Drug transporter data indicated a potential inhibition of MATE1, MATE2-K, and BCRP by tegaserod at high concentrations. However, at the clinical dose of tegaserod, a significant in vivo drug interaction via inhibition of these transporters is unlikely.
M29 is a substrate of BCRP, P-gp, OAT3 and BSEP transporters, but not a substrate of OAT1, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, and MATE2-K. M29 does not inhibit the following transporters: OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, BCRP, P-gp, and BSEP.
Inhibition of the hERG (human Ether-a-go-go-Related Gene) channel was evident only in the micromolar concentration range with an IC50 of 13 micromolar (approximately 1300 times the Cmax in humans at the recommended dose). In in vitro studies, tegaserod had no effects on impulse conduction in isolated guinea pig papillary muscle at up to 100 times the Cmax in humans, Langendorff-perfused isolated rabbit heart (QT interval) at up to 1000 times the Cmax in humans, or human atrial myocytes at multiples up to 10 times the Cmax in humans. The major metabolite, M29, had no effect on QT in the Langendorff-perfused isolated rabbit heart at multiples up to 323 times the Cmax in humans.
In anesthetized and conscious dogs, tegaserod at doses up to 92 to 134 times the recommended dose based on Cmax did not alter heart rate, QRS interval duration, QTc or other ECG parameters. In chronic toxicology studies in rats and dogs, there were no treatment-related changes in cardiac morphology after tegaserod administration at doses up to 660 times the recommended dose based on AUC.
Although tegaserod is expected to bind to 5 HT2B receptors in humans at the recommended dose, there does not appear to be any potential for heart valve injury based on functional evidence of 5 HT2B receptor antagonism.
Studies with isolated coronary and mesenteric blood vessels from non-human primates and humans showed no vasoconstrictor effect at concentrations approximately 100 times the human Cmax. Tegaserod exhibited antagonism of 5 HT-mediated vasoconstriction via 5 HT1B receptors. In rat thoracic aortic rings that were pre-constricted with phenylephrine or norepinephrine, tegaserod produced vasorelaxation, with IC50 values 6 and 64 times the Cmax plasma concentrations in humans, respectively. No effects were observed in the basal tone of aortic rings at concentrations up to 1000 times the human Cmax.
In studies with an anesthetized rat model for measuring macro- and micro-circulation of the colon, intraduodenal dosing with tegaserod (approximately 7 times the recommended dose based on Cmax) produced no clinically relevant effect on blood pressure, heart rate, or vascular conductance.
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