Rabeprazole

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Rabeprazole

Rabeprazole

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  • 1. Acid Peptic Disorders The Lesser Known Truths
  • 2. Stomach – common complaints
    • Common complaints of the stomach include –
      • GERD
      • Gastric Ulcer
      • Duodenal Ulcer
      • Zollinger Ellison Syndrome
  • 3. Overlapping Upper GI Symptoms
    • Ulcer
    • Epigastric pain
    • Nocturnal pain
    • Fasting pain
    • Pain relieved by food/antacids
    • Nonulcer Dyspepsia
    • Postprandial bloating
    • Early satiety
    • Nausea
    • Pain unrelieved by food/antacids
    GERD Heartburn Regurgitation Belching Adapted from Talley NJ et al. Gastroenterology . 1993;105:1378-1386.
  • 4. Non-ulcer Dyspepsia - Symptoms Ulcer-like Dominant Dysmotility-like Dominant
    • Nocturnal pain
    • Localized epigastric burning
    • Better with food
    Heartburn Retrosternal burning
    • Nausea
    • Bloating
    • Early satiety
    • Worse with food
  • 5. Complications of GERD GERD complications Oesophageal erosion Oesophageal ulcer Oesophageal stricture Replacement of normal esophageal epithelium with abnormal (Barrett's) epithelium Pulmonary aspiration
  • 6. Goals of GERD Therapy
    • Goals of GERD treatment are:
    • Symptom relief,
    • Diminish the frequency and duration of esophageal reflux
    • Promote healing,
    • Prevention of complications and
    • Prevention of relapses.
  • 7. Currently Practised Therapy
  • 8. Which PPI Can Promise Rapid Symptom Relief With Disease Resolution? Omeprazole Lansoprazole Pantoprazole Esomeprazole
  • 9. PPIs Today
    • All PPIs are 2-(2-pyridylmethyl)sulfinyl benzimidizole derivatives
    • They are enteric coated Prodrugs that show Acid induced activation and inhibit the proton pump irreversibly
    • They exert their effect through the same basic MOA but they do not have the same pharmacologic and clinical properties.
    • All PPIs are effective in healing and maintenance of GU, DU and GERD but they differ in their ability to control symptoms rapidly and consistently
    Optimizing acid-suppression therapy, Manag Care 2001 Oct;10(10 Suppl):17-21
  • 10. PPI Variations OCH 3 3,5–(CH 3 ) 2 CH 3 Ome 3-CH 3 3-CH 3 R I CH 2 CH 2 CH 2 OCH 3 CH 2 CF 3 R H Rabe H Lanso R II PPI R I R R II
  • 11. Differences Between PPIs
    • Differences between the PPIs exist in their-
      • Pharmacokinetics,
      • Pharmacodynamics,
      • Influence by food and antacids,
      • Clinical efficacy, and
      • Potential for drug interactions.
    Are the orally administered proton pump inhibitors equivalent? a comparison of lansoprazole, omeprazole, pantoprazole, and rabeprazole. Curr Gastroenterol Rep 2000 Dec;2(6):482-93
  • 12. The Need of Today An Ideal PPI What Is That?
  • 13. Requirements of an Ideal PPI
    • Fast onset of action;
    • Consistent efficacy in the recommended dose with low relapse rates,
    • Reliable bioavailability and safety record,
    • Metabolism which does not give rise to drug interactions
    • Economy of therapy
  • 14. Rabeprazole
    • A New substituted benzimidazole proton pump inhibitor PPI with several differences compared with existing PPIs
    • Contains 2 enantiomers (R and S), both of which are pharmacologically active and lipophilic
    • Enteric-coated, acid-activated prodrug
  • 15. Rabeprazole – Milestones Launched in USA August 1999 Launched in India February 2002 Launched in 14 European countries September 1998 Launched in UK May 1998 Launched in Japan 1997
  • 16. Rabeprazole
    • Differs from other PPIs in–
      • The degree of accumulation in the parietal cell, and
      • The activation rates
    • This leads to quicker activation / conversion to the active moiety
    Faster onset of activity
  • 17. Rabeprazole – Onset of Activity
    • Due to its more rapid rate of activation, rabeprazole results in a faster onset of action and faster symptom control than other PPIs.
    Optimizing acid-suppression therapy, Manag Care 2001 Oct;10(10 Suppl):17-21
    • Rabeprazole has a more rapid onset of H+,K+-ATPase inhibition than the other PPIs and compared with omeprazole, a greater effect on intragastric pH after the first dose.
    Clin Ther 2000 Mar;22(3):266-80; discussion 265
  • 18. Rabeprazole - Pharmacokinetics
    • Absorption
      • food does not affect the degree of absorption.
    • Bioavailability
      • 52%
    • Metabolic effects
      • exhibits extensive, stereoselective, hepatic metabolism, involving CYP 3A and CYP 2C19.
    • Elimination
      • Elimination as urinary metabolites and in the faeces
    • Timing of effect
      • Reach a steady state for optimum acid suppression in about 3 days
  • 19. Rabeprazole – Comparative Pharmacokinetics 1 97% 1-2 Esome-prazole 1.3 98% 2.4 Panto-prazole 0.85-2 0.5-1 1.6 Half-life (hours) 94.8-97.5% 95% 97% Protein binding (%) 2-5 0.5-3.5 1.7 Time to peak plasma concentration (hours) Rabe-prazole Ome-prazole Lanso-prazole Pharmaco-kinetic Parameter
  • 20. Rabeprazole – Comparative Pharmacodynamics Percent inhibition of the H+/K+-ATPase 100% 47% 66% At 10 minutes Activation time (minutes) 100% 83% 100% At 45 minutes 7.2 84 90 At a pH of 5.1 1.3 2.8 2.0 At a pH of 1.2 Rabeprazole Omeprazole Lansoprazole Pharmaco-dynamic Parameter Pharmacodynamic Parameters of the PPIs
  • 21. Rabeprazole – Increased Acid suppression * Barnett JL et al, Managed Care 2001
  • 22. Rabeprazole – Faster symptom relief * Barnett JL et al, Managed Care 2001
  • 23. Rabeprazole / Esomeprazole
    • Rabeprazole and esomeprazole achieve more rapid and profound inhibition of acid secretion than do older agents (omeprazole, lansoprazole and pantoprazole).
    • They sustain this suppression to provide acid control and symptom relief over 24 h.
    • The balanced hepatic metabolism of rabeprazole, involving both cytochrome P450 (CYP)-mediated reactions in the liver and nonenzymatic reactions, appears to confer an advantage over other PPIs including esomeprazole.
    Eur J Gastroenterol Hepatol 2001 May;13 Suppl 1:S43-7
  • 24. Rabeprazole – Adverse effects
    • Low incidence (8%) of mild, transient adverse events 1 .
    2 The benefit / risk profile of rabeprazole, a new proton-pump inhibitor. Eur J Gastroenterol Hepatol 2000 Jul;12(7):799-806
    • Overall rate of discontinuations due to adverse events = approximately 3% 2 .
    1 Latin American open-label study with rabeprazole in patients with functional dyspepsia. Mexican Rabeprazole Investigators Group.Adv Ther 2000 Jul-Aug;17(4):190-4
  • 25. Rabeprazole – Adverse effects
    • Side effects [Short term & Long term]
      • Common adverse events assigned to rabeprazole have been headache [ 7%] , diarrhoea [ 3%] , rhinitis, nausea, pharyngitis and abdominal pain.
      • Histological changes, increases in serum gastrin levels are unremarkable and seen as a direct result of acid inhibition but return to pretreatment levels within 1 week of discontinuing the drug .
      • The incidence of high gastrin levels, defined as >400 pmol/L, is approximately 11%
  • 26. Rabeprazole - Drug Interactions
    • Rabeprazole does not interact with the cytochrome P450 system and therefore are not expected to interact with other drugs metabolized via this pathway.
    • Antacids have no influence on the pharmaco-kinetics of rabeprazole*
    • Binding of rabeprazole to the proton pump has been shown in vitro to be partially reversible
    * Int J Clin Pharmacol Ther 1999 May;37(5):249-53
  • 27. Rabeprazole – Dosing Information
    • Dosing - 20 mg od – Because PPIs inhibit only actively secreting proton pumps, gastric acid suppression is optimal when the PPI is taken about 30 minutes before a meal ;
    • Instructions - Patients should not crush, chew or split the tablets.
    • Special - No dosage adjustment is necessary in renal and mild to moderate hepatic impairment, elderly subjects. Even in severe liver disease, drug accumulation is unlikely with rabeprazole but dose adjustments have not been assessed.*
    * Aliment pharmacology ther. 1999,13(suppl 3):11-17
  • 28. Potential effects of Rabeprazole
    • Cytoprotective effect of rabeprazole, a new proton pump inhibitor, against ethanol-induced gastric mucosal damage was investigated in rats.
    • Repeated administration of rabeprazole significantly inhibited ethanol-induced gastric mucosal damage, although single administration of this drug did not.
    • Results suggest that rabeprazole has a cytoprotective effect against ethanol-induced gastric mucosal damage and that this effect may be mediated via nitric oxide but not via prostaglandins.
    Drugs Exp Clin Res 2000;26(2):41-5
  • 29. Rabeprazole Clinical Studies
  • 30. Patients' Perceptions of GERD: Evidence From the Trenches* Most persons with heartburn, experience night attacks - Nocturnal acid breakthrough [NAB]
  • 31. Nocturnal Heartburn Grades in GERD: Evidence From the Trenches*
  • 32. Patients' Perceptions of GERD: Evidence From the Trenches*
    • Amongst Nocturnal Heartburn patients,
      • 50% reported that nighttime symptoms had a greater impact on their life than daytime symptoms
      • 60% reported one to four attacks per week
      • 40% had moderate to severe impairment in sleep
      • 35% could not sleep when they wanted
      • 30% reported serious impairment of functioning, with regard to mood and general well-being, a finding closely correlated with the severity of esophagitis.
  • 33. Problems in GERD Therapy
    • Despite the revolution in treatment brought about by the use of proton pump inhibitor (PPI) therapy, Some issues in GERD remain particularly challenging even today –
      • Rapidity and consistency of acid suppression that translate clinically into faster symptom relief
      • Control of nocturnal symptoms,
      • Injurious effects of nocturnal reflux,
      • Maintenance of healing and
      • Prevention of symptoms in patients with healed GERD
    Optimizing acid-suppression therapy, Manag Care 2001 Oct;10(10 Suppl):17-21
  • 34. Rabeprazole In GERD
  • 35. Rabeprazole in Erosive or Ulcerative GERD
    • >2500 patients with endoscopically confirmed GERD who were studied in an 8 week trial on Rabeprazole were observed for significant symptom relief on 1 st day :
    • 91.2% reported satisfactory symptom relief for daytime heartburn;
    • 91.7% reported satisfactory symptom relief for nighttime heartburn;
    • 85% reported reduction in day time symptom severity;
    • 88% reported reduction in night time symptom severity.
    Data presented at the American college of Gastroenterology 65 th annual scientific meeting, New York, October 2000
  • 36. Rabeprazole in GERD -0.81 -1.10 -0.65 -0.94 119  2 -1.05 -0.87 Ome-prazole 20mg. -0.84 -0.69 Ome-prazole 20mg.  5 -1.46 -1.27 48 Rabe-prazole 20mg. Rabe-prazole 20mg. -1.21 -1.02 92  3 Day 7 Day 3 Changes in heartburn score from baseline Number of patients Heartburn episodes during screening [per week] Comparison of Rabeprazole & Omeprazole in erosive GERD: heartburn relief after 3 & 7 days
  • 37. Rabeprazole for Healing of GERD Dig Dis Sci 2001 Mar;46(3):587-96 Treatment duration ranged from < or =8 weeks
  • 38. Rabeprazole in Long Term GERD Maintenance Dig Dis Sci 2000;45:845-853 Treatment duration = 52 weeks
  • 39. Rabeprazole In GU & DU
  • 40. Rabeprazole in GU Aliment. Phramacol ther. 1998, 12:789-795 Treatment rates verified in 227 patients at 3 & 6 weeks
  • 41. Rabeprazole / Omeprazole in Gastric Ulcer 86% 84% 6 80% 89% 6 67% 75% 6 83% 90% 6 44% 52% 6 65% 82% 6 59% 60% 3 Complete resolution Night time pain severity 75% 88% 3 Improvement Daytime pain severity 79% 82% 3 Improvement Frequency 61% 68% 3 Complete resolution 29% 34% 3 Complete resolution 61% 71% 3 Improvement Omeprazole 20mg Rabeprazole 20mg Week Pain Parameter Comparison of Rabeprazole & Omeprazole in GU symptom relief after 3 & 6 weeks
  • 42. Rabeprazole in DU Clin Ther 2000 Mar;22(3):266-80; discussion 265 Treatment duration ranged from  4 weeks for DU
  • 43. Rabeprazole In Helicobacter Pylori Infection
  • 44. Rabeprazole & Helicobacter Pylori
    • Rabeprazole has in vitro antibacterial activity against helicobacter pylori, with greater activity against this organism than either lansoprazole or omeprazole.
    • In addition to inhibiting bacterial urease activity, rabeprazole binds to several molecules on H. Pylori.
    Aliment Pharmacol Ther 1999 Aug;13 Suppl 3:3-10
  • 45. Rabeprazole and HP eradication
    • Efficacy rates of short course [4-day] triple therapy with Rabeprazole / Amoxycillin / Clarithromycin has revealed eradication rates of 90% at post treatment period of 5-6 weeks.
    • Approved, recommended dose of triple therapy in Europe is Rabeprazole 20 mg. Twice daily / Amoxycillin 1000 mg. Twice daily and Clarithromycin 500 mg. Twice daily .
    Gut 2000; 47 [ suppl]: A127
  • 46. Rabeprazole For Special Conditions
  • 47. Rabeprazole in ZE syndrome
    • Rabeprazole 60 mg / day has been succesfully used to reduce gastric acid secretion to target levels in patients with ZE-syndrome;
    • In study done with this dosage, no recurrence was seen.
    Gut 1999: 44 [suppl. 1] A125
  • 48. Rabeprazole - SUMMARY
    • Rabeprazole effectively and reversibly inhibits the proton pump in the canaliculi of the parietal cells of the stomach affecting acid output.
    • Efficacy and safety profiles of rabeprazole have been demonstrated in various clinical trials.
    • Rabeprazole was shown to be significantly faster acting than other PPIs.
    • Once-daily dosing of rabeprazole is effective and well tolerated.
  • 49. Rabeprazole - SUMMARY
    • Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD)
    • Maintenance of Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD)
    • Healing of Duodenal Ulcers
    • Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome.
  • 50. Rabeprazole
    • GU & DU
    Effective in GERD ZE syndrome H. Pylori eradication
  • 51. Summary
    • Fastest symptom relief from Day 1
    • 93% healing rates in GERD
    • 98% healing rates in Peptic Ulcers
    • Least chances of resistance
    • 2 times higher acid suppression than omeprazole
    • Covenient OD dosage, absorption unaffected by food
    • Excellent safety profile
    • Least Drug-Drug interactions