Clinical Pharmacokinetics

, Volume 41, Issue 13, pp 1021–1042

Clinical Pharmacokinetics of Tegaserod, a Serotonin 5-HT4 Receptor Partial Agonist with Promotile Activity

Review Articles Drug Disposition

Abstract

Tegaserod, a selective serotonin (5-hydroxytryptamine; 5-HT) 5-HT4 receptor partial agonist, is indicated in patients with irritable bowel syndrome (IBS) who identify abdominal pain or discomfort and constipation as their predominant symptoms. Tegaserod at dosages of 1 to 12 mg/day exerts pharmacodynamic actions in the upper and the lower gastrointestinal tract, accelerating small bowel and colonic transit in patients with IBS.

Tegaserod is rapidly absorbed following oral administration; peak plasma concentrations (Cmax) are reached after approximately 1 hour. Absolute bioavailability is about 10% under fasted conditions. Food reduces the bioavailability of tegaserod by 40 to 65% and the Cmax by 20 to 40%. Systemic exposure to tegaserod is not significantly altered at neutral gastric pH compared with the fasted state (pH 2). Tegaserod is approximately 98% bound to plasma proteins, primarily to (α1-acid glycoprotein, and has a volume of distribution at steady-state of 368 ± 223L.

Tegaserod is metabolised mainly via two pathways. The first is a presystemic acid-catalysed hydrolysis in the stomach followed by oxidation and conjugation which produces the main metabolite of tegaserod, 5-methoxyindole-3-carboxylic acid glucuronide (M 29.0). This metabolite has negligible affinity for 5-HT4 receptors and is devoid of promotile activity. The second 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 of 11 ± 5 hours following intravenous administration. Approximately two-thirds of the orally administered dose of tegaserod is excreted unchanged in faeces, with the remainder excreted in urine, primarily as M 29.0. The pharmacokinetics of tegaserod are dose-proportional over the range 2 to 12mg given twice daily for 5 days, with no relevant accumulation.

The pharmacokinetics of tegaserod in patients with IBS are comparable to those in healthy individuals, and similar between men and women. No dosage adjustment is required in elderly patients or those with mild to moderate hepatic or renal impairment. Tegaserod should not be used in patients with severe hepatic or renal impairment.

No clinically relevant drug-drug interactions with tegaserod have been identified. In vivo drug-drug interaction studies with theophylline [a cytochrome P450 (CYP) 1A2 prototype substrate], dextromethorphan (a CYP2D6 prototype substrate), digoxin, warfarin and oral contraceptives have indicated no clinically relevant interactions and no requirement for dosage adjustment.

References

  1. 1.
    Drossman DA. An integrated approach to the irritable bowel syndrome. Aliment Pharmacol Ther 1999; 13: 3–14PubMedCrossRefGoogle Scholar
  2. 2.
    Drossman DA, Whitehead WE, Camilleri M. Irritable bowel syndrome: a technical review for practice guideline development. Gastroenterology 1997; 112: 2120–37PubMedCrossRefGoogle Scholar
  3. 3.
    Drossman DA, Thompson WG, Talley NJ, et al. Identification of sub-groups of functional gastro-intestinal disorders. Gas-troenterol Int 1990; 3: 159–72Google Scholar
  4. 4.
    Thompson WG, Longstreth GF, Drossman DA, et al. Functional bowel disorders and functional abdominal pain. Gut 1999; 45 Suppl. II: 43–7Google Scholar
  5. 5.
    Talley NJ. 5-Hydroxytryptamine agonists and antagonists in the modulation of gastrointestinal motility and sensation: clinical implications. Aliment Pharmacol Ther 1992; 6: 273–89PubMedCrossRefGoogle Scholar
  6. 6.
    Drossman DA, Li Z, Andruzzi E, et al. US householder survey of functional gastrointestinal disorders. Dig Dis Sci 1993; 38: 1569–80PubMedCrossRefGoogle Scholar
  7. 7.
    Talley NJ, Gabriel SE, Harmsen WS, et al. Medical costs in community subjects with irritable bowel syndrome. Gastro-enterology 1995; 109: 1736–41CrossRefGoogle Scholar
  8. 8.
    Hahn BA, Yan S, Strasseis S. Impact of irritable bowel syndrome on quality of life and resource use in the United States and United Kingdom. Digestion 1999; 60: 77–81PubMedCrossRefGoogle Scholar
  9. 9.
    Scott LJ, Perry CM. Tegaserod. Drugs 1999; 58: 491–6PubMedCrossRefGoogle Scholar
  10. 10.
    Graul A, Silvestre J, Castaner J. Tegaserod maleate. Drugs Future 1999; 24: 38–44CrossRefGoogle Scholar
  11. 11.
    Norman P. Zelmac. IDrugs 1999; 2: 265–9PubMedGoogle Scholar
  12. 12.
    Hoyer D, Clarke DE, Fozard JR, et al. VII International Union of Pharmacology. Classification of receptors for 5-hydroxy-tryptamine (serotonin). Pharmacol Rev 1994; 46: 157–203PubMedGoogle Scholar
  13. 13.
    Blondel O, Gastineau M, Dahmoune Y, et al. Cloning, expression, and pharmacology of four human 5-hydroxytrypt-amine4 receptor isoforms produced by alternative splicing in the carboxyl terminus. J Neurochem 1998; 70: 2252–61PubMedCrossRefGoogle Scholar
  14. 14.
    Claeysen S, Faye P, Sebben M, et al. 5-HT4 receptors: cloning and expression of new splice variants. Ann N Y Acad Sci 1998; 861: 49–56PubMedCrossRefGoogle Scholar
  15. 15.
    Bender E, Pindon A, Van Oers I, et al. Structure of the human serotonin 5-HT4 receptor gene and cloning of a novel 5-HT4 splice variant. J Neurochem 2000; 74: 478–89PubMedCrossRefGoogle Scholar
  16. 16.
    Hegde SS, Eglen RM. Peripheral 5-HT4 receptors. FASEB J 1996; 10: 1398–407PubMedGoogle Scholar
  17. 17.
    Pfannkuche HJ, Buhl T, Gamse R, et al. The properties of a new prokinetically active drug, SDZ HTF 919 [abstract]. Neuro Gastroenterology Motil 1995; 7: 280Google Scholar
  18. 18.
    Sanger GJ, Wardle KA, Shapcott S, et al. In: Fozard JR, Saxena PR, editors. Serotonin: molecular biology, receptors and functional effects. Basel: Birkhäuser Verlag, 1991: 381–8Google Scholar
  19. 19.
    Sowers JR, Sharp B, McCallum RW. Effect of domperidone, an extracerebral inhibitor of dopamine receptors, on thy-reotropin, prolactin, renin, aldosteron and 18-hydroxy-cortisone secretion in man. Endocrinol Metab 1982; 54: 869–71CrossRefGoogle Scholar
  20. 20.
    Hoyer D, Fehlmann D, Langenegger D, et al. High affinity of SDZ HTF 919 and related molecules for calf and human caudate 5-HT4 receptors. Ann N Y Acad Sci 1998; 861: 267–8PubMedCrossRefGoogle Scholar
  21. 21.
    Grider JR, Foxx-Orenstein AE, Jin JG. 5-Hydroxytryptamine4 receptor agonists initiate the peristaltic reflex in human, rat, and guinea pig intestine. Gastroenterology 1998; 115: 370–80PubMedCrossRefGoogle Scholar
  22. 22.
    Jin JG, Foxx-Orenstein AE, Grider JR. Propulsion in guinea pig colon induced by 5-hydroxytryptamine (HT) via 5-HT4 and 5-HT3 receptors. J Pharmacol Exp Ther 1999; 288: 93–7PubMedGoogle Scholar
  23. 23.
    Nguyen A, Camilleri M, Kost LJ, et al. SDZ HTF 919 stimulates canine colonic motility and transit in vivo. J Pharmacol Exp Ther 1997; 280: 1270–6PubMedGoogle Scholar
  24. 24.
    Stoner MC, Arcuni JC, Lee J, et al. A selective 5-HT4 receptor agonist induces cAMP-mediated Cl efflux from rat colonocytes [abstract]. Gastroenterology 1999; 116: A648Google Scholar
  25. 25.
    Schikowski A, Mathis C, Thewissen M, et al. Dose-dependent modulation of rectal afferent sensitivity by a 5HT4 receptor agonist [abstract]. Gastroenterology 1999; 116: A643CrossRefGoogle Scholar
  26. 26.
    Coelho AM, Rovira P, Fioramonti J, et al. Antinociceptive properties of HTF 919 (tegaserod), a 5-HT4 receptor partial agonist, on colorectal distension in rats [abstract]. Gastroenterology 2000, 118: A835CrossRefGoogle Scholar
  27. 27.
    Kaumann AJ. Do human atrial 5-HT4 receptors mediate arrhythmia? Trends Pharmacol Sci 1994; 15: 451–5PubMedCrossRefGoogle Scholar
  28. 28.
    Tonini M, Candura SM. 5-HT4 receptor agonists and bladder disorders. Trends Pharmacol Sci 1996; 17: 314–6PubMedGoogle Scholar
  29. 29.
    Lefebvre H, Contesse V, Delarue C, et al. Serotonergic regulation of adrenocortical function. Horm Metab Res 1998; 30: 398–403PubMedCrossRefGoogle Scholar
  30. 30.
    Bockaert J, Fagni L, Dumuis A. 5-HT4 receptors: an update. Serotoninergic neurons and 5-HT receptors in the CNS. In: Baumgarten HH, Göthert M, editors. Handbook of experimental pharmacology. Berlin and Heidelberg: Springer-Verlag, 1997: 439–74Google Scholar
  31. 31.
    Drici M, Ebert SN, Wang WX, et al. Comparison of tegaserod (HTF 919) and its main human metabolite with cisapride and erythromycin on cardiac repolarization in the isolated rabbit heart. J Cardiovascular Pharmacol 1999; 34: 82–8CrossRefGoogle Scholar
  32. 32.
    Briner U, Pless J. Effects of SDZ 216-919 on different endocrine parameters in male rats [data on file]. Document 103-186. Basel, Switzerland: Novartis Pharma AG, 1994Google Scholar
  33. 33.
    Briner U, Pless J. Effects of SDZ 216-919 on prolactin secretion in male rats [data on file]. Document 103-187. Basel, Switzerland: Novartis Pharma AG, 1994Google Scholar
  34. 34.
    Appel S, Kumle A, Hubert M, et al. First pharmacokinetic-phar-macodynamic study in humans with a selective 5-hydroxy-tryptamine4 receptor agonist. J Clin Pharmacol 1997; 37: 229–37PubMedGoogle Scholar
  35. 35.
    Appel-Dingemanse S, Lemaréchal M-O, Kumle A, et al. Integrated modelling of the clinical pharmacokinetics of SDZ HTF 919, anovel selective 5-HT4 receptor agonist, following oral and intravenous administration. Br J Clin Pharmacol 1999; 47: 483–91PubMedCrossRefGoogle Scholar
  36. 36.
    Hubert M. Determination of HTF 919 in human plasma by high performance liquid chromatography with ultra-violet detection [data on file]. DMPK (F) R98-086. Rueil-Malmaison, France: Novartis Pharma SA, 1999Google Scholar
  37. 37.
    Hubert M. Determination of HTF 919 acid-glucuronide in plasma by gas chromatography-mass spectrometry [data on file]. DMPK (F) R98-054. Rueil-Malmaison, France: Novartis Pharma SA, 1999Google Scholar
  38. 38.
    Dannecker R, Appel S, Hubert M, et al. Evaluation of the absorption, distribution, metabolism, and excretion of [14C]-SDZ HTF 919 following a single-dose oral administration in healthy male subjects [data on file]. Document 303-236. Basel, Switzerland: Novartis Pharma AG, 1997Google Scholar
  39. 39.
    Vickers AEM, Zollinger M, Dannecker R, et al. In vitro metabolism of tegaserod in human liver and intestine: assessment of drug interactions. Drug Metab Dispos 2001; 29_(10): 1269–76Google Scholar
  40. 40.
    Andres H. Labelling of tegaserod (HTF 919) with stable and radioactive isotopes. 8th Conference of the International Isotope Society; 1999 June 10–11; Bad Soden, GermanyGoogle Scholar
  41. 41.
    Zollinger M. SDZ HTF 919: structural characterization of metabolites in rat and human by liquid chromatography-mass spectrometry [data on file]. Document 303-224. Basel, Switzerland: Novartis Pharma AG, 1996Google Scholar
  42. 42.
    Müller-Lissner SA, Fumagalli I, Bardhan KD, et al. Tegaserod, a 5-HT4 receptor partial agonist, relieves symptoms in irritable bowel syndrome patients with abdominal pain, bloating and constipation. Aliment Pharmacol Ther 2001; 15(10): 1655–66PubMedCrossRefGoogle Scholar
  43. 43.
    Appel-Dingemanse S, Hirschberg Y, Osborne S, et al. Multiple-dose pharmacokinetics confirm no accumulation and dose proportionality of the novel promotile drug tegaserod HTF 919 (Zelmac®). Eur J Clin Pharmacol 2001; 56: 889–91PubMedCrossRefGoogle Scholar
  44. 44.
    Degen L, Matzinger D, Merz M, et al. Tegaserod, a 5-HT4 receptor partial agonist, accelerates gastric emptying and gastrointestinal transit in healthy male subjects. Aliment Pharmacol Ther 2001; 15(11): 1745–51PubMedCrossRefGoogle Scholar
  45. 45.
    Camenisch G. Transport studies across Caco-2 cell monolayers [data on file]. DMPK (CH) R99-1639. Basel, Switzerland: Novartis Pharma AG, 1999Google Scholar
  46. 46.
    Gwynne JT, Kumle A, Appel S, et al. A study investigating the food effect on the pharmacokinetics of SDZ HTF 919 given as single oral doses of 25 mg to healthy male subjects [data on file]. Document 303-221. Basel, Switzerland: Novartis Pharma AG, 1995Google Scholar
  47. 47.
    Zhou H, Khalilieh S, Lau H, et al. Effect of meal timing not critical for the pharmacokinetics of tegaserod (HTF 919). J Clin Pharmacol 1999; 39: 911–9PubMedCrossRefGoogle Scholar
  48. 48.
    Djordjevic N. SDZ HTF 919 hml: drug substance properties in solution [data on file]. Basel, Switzerland: Novartis Pharma AG, 1994Google Scholar
  49. 49.
    Lemaire M. SDZ HTF 919: blood distribution and plasma protein binding [data on file]. Document 303-214. Basel, Switzerland: Novartis Pharma AG, 1995Google Scholar
  50. 50.
    Appel-Dingemanse S, Hubert M, Alladina L, et al. Pharmacokinetics and safety of SDZ HTF 919, a new propotile drug, in healthy subjects and patients with hepatic cirrhosis. World Congress Gastroenterology; 1998 Sep 6–11; Vienna, Austria. Digestion 1998; 59 Suppl. 3: 736–7Google Scholar
  51. 51.
    Zhou H, McLeod J, Alladina L, et al. Pharmacokinetics (PK) of SDZ HTF 919 (HTF) not altered in subjects with severe renal insufficiency requiring hemodialysis [abstract]. Clin Pharm Ther 1999; 65: 203Google Scholar
  52. 52.
    Lemaire M. SDZ HTF 919: blood-brain barrier permeability [data on file]. Document 303-205. Basel, Switzerland: Novartis Pharma AG, 1995Google Scholar
  53. 53.
    Fioramonti J, Million M, Bueno L. Investigations on a 5-HT4 agonist (SDZ HTF 919) and its main metabolite in conscious dogs: effects on gastrointestinal motility and impaired gastric emptying [abstract]. Gastroenterology 1998; 114: A752–(G3103)CrossRefGoogle Scholar
  54. 54.
    Thévenin J-P. Stability of SDZ HTF 919 in acidic solutions [data on file]. Basel, Switzerland: Novartis Pharma AG, 1992Google Scholar
  55. 55.
    Zhou H, Kalilieh S, Campestrini J, et al. Effect of gastric pH on plasma concentrations of tegaserod (HTF 919) and its major metabolite in healthy subjects [abstract A1206]. Gastroenterology 2000; 118: 5538Google Scholar
  56. 56.
    Gwynne JT, Kumle A, Appel S, et al. A study on the safety and tolerability of single rising intravenous doses of SDZ HTF 919 in healthy subjects [data on file]. Document 303-223. Basel, Switzerland: Novartis Pharma AG, 1993Google Scholar
  57. 57.
    Schmitt C, Krumholz S, Tanghe J, et al. Tegaserod, a partial 5-HT4 receptor agonist, improves abdominal discomfort/pain and altered bowel function in irritable bowel syndrome (IBS) [abstract]. Gut 1999; 45 Suppl. V: A258 (P0960)Google Scholar
  58. 58.
    Krumholz S, Tanghe J, Schmitt C, et al. The 5-HT4 partial agonist tegaserod improves abdominal bloating and altered stool consistency in irritable bowel syndrome (IBS) [abstract]. Gut 1999; 45 Suppl. V: A260 (P0965)Google Scholar
  59. 59.
    Appel-Dingemanse S, Rawls J, Campestrini J, et al. Similar pharmacokinetics of tegaserod (HTF 919) in patients with constipation- and diarrhea-predominant irritable bowel syndrome [abstract Al 160]. Gastroenterology 2000; 118: 5340CrossRefGoogle Scholar
  60. 60.
    Rawls J, Lefkowitz M, Shi Y, et al. Tegaserod is well tolerated in diarrhea-predominant irritable bowel syndrome [abstract]. Gut 2000; 47 Suppl. III: A217Google Scholar
  61. 61.
    Appel-Dingemanse S, Horowitz A, Campestrini J, et al. The pharmacokinetics of the novel promotile drug tegaserod are similar in healthy subjects male and female, elderly and young. Aliment Pharmacol Ther 2001; 15(7): 937–44PubMedCrossRefGoogle Scholar
  62. 62.
    Osborne S. Effect of demographic characteristics (body weight, age, gender, race) on HTF 919 pharmacokinetic parameters (AUC0-∞, Cmax) [data on file]. Document BS7335. Basel, Switzerland: Novartis Pharma AG, 1999Google Scholar
  63. 63.
    Schweitzer A, Dannecker R. Embryo-fetal transfer in pregnant rats on day 13 and day 17 of gestation after oral administration of [14C]HTF919-hml [data on file]. DMPK (CH) R98-263 and DMPK(CH) R98-263-01. Basel, Switzerland: Novartis Pharma AG, 1999Google Scholar
  64. 64.
    Wiegand HJ, Schweitzer A, Dannecker R. Placental transfer of radioactive substance(s) in rabbits after peroral administration of 14C-labeled HTF919-hml [data on file]. DMPK (CH) R98-023. Basel, Switzerland: Novartis Pharma AG, 1999Google Scholar
  65. 65.
    Guntz P, Dannecker R, Keller B, et al. Passage of [14C]SDZ HTF 919 into rat milk after single oral administration (60mg/kg) [data on file]. Document 304-210. Basel, Switzerland: Novartis Pharma AG, 1995Google Scholar
  66. 66.
    Zhou H, Khalilieh S, Svendsen K, et al. Tegaserod coadmini-stration does not alter the pharmacokinetics of theophylline in healthy subjects. J Clin Pharmacol 2001; 41(9): 987–95PubMedCrossRefGoogle Scholar
  67. 67.
    Kalbag J, Migoya E, Osborne S, et al. Tegaserod does not significantly affect the pharmacokinetics of dextromethorphan in healthy subjects [abstract Al 179]. Gastroenterology 2000; 118: 5422CrossRefGoogle Scholar
  68. 68.
    Zhou H, Horowitz A, Ledford PC, et al. The effects of tegaserod (HTF 919) on the pharmacokinetics and pharmacodynamics of digoxin in healthy subjects. J Clin Pharmacol 2001; 41(10): 1131–9PubMedCrossRefGoogle Scholar
  69. 69.
    Ledford P, On N, Lingueros-Saylan M, et al. Tegaserod does not significantly affect the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects [abstract A1184]. Gastroenterology 2000; 18: 5445Google Scholar
  70. 70.
    Zhou H, Walter Y, Hubert M, et al. Tegaserod (HTF 919) does not decrease the effectiveness of an oral contraceptive when co-administered to healthy female subjects [abstract A1207]. Gastroenterology 2000; 118: 5539Google Scholar
  71. 71.
    Appel S, Kumle A, Meier R. Clinical pharmacodynamics of SDZ HTF 919, a new 5-HT4 receptor agonist, in a model of slow colonic transit. Clin Pharmacol Ther 1997; 62: 546–55PubMedCrossRefGoogle Scholar
  72. 72.
    Prather CM, Camilleri M, Zinsmeister AR, et al. Tegaserod accelerates orocecal transit in patients with constipation-predominant irritable bowel syndrome. Gastroenterology 2000; 118: 463–8PubMedCrossRefGoogle Scholar
  73. 73.
    Morganroth J, Rüegg PC, Dunger-Baldauf C, et al. Tegaserod, a 5-HT4 receptor partial agonist is devoid of significant elec-trocardiographic side effects. Am J Gastroenterol 2002. In pressGoogle Scholar

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© Adis International Limited 2002

Authors and Affiliations

  1. 1.Department of Clinical PharmacologyNovartis Pharma AGBaselSwitzerland

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