Pharmacokinetics, bioavailability, & bioequivalence Original research| Volume 34, ISSUE 9, P1999-2010, September 2012

Bioavailability and Tolerability of Combination Treatment With Revaprazan 200 mg + Itopride 150 mg: A Randomized Crossover Study in Healthy Male Korean Volunteers



      To date, no definitive treatment of functional dyspepsia (FD) has been proven to be effective and reasonably well-tolerated. Proton pump inhibitors (PPIs) combined with prokinetic agents are considered an effective option. Revaprazan is a selective potassium-competitive acid blocker that reversibly inhibits gastric H+/K+-ATPase and shows effective acid suppression comparable to PPIs. Itopride is a prokinetic agent that has anticholinesterase activity as well as dopamine D2 receptor antagonistic activity. For this reason, revaprazan and itopride have been prescribed for FD; however, no available studies have reported the pharmacokinetic interactions of these 2 drugs.


      The objective of this study was to compare the bioavailability and tolerability of revaprazan and itopride combination therapy to those of equally dosed monotherapies to acquire basic drug–drug interaction information about revaprazan.


      This multiple-dose, randomized crossover study was conducted in healthy male Korean subjects. Subjects received, in randomized sequence, a 7-day oral dose of revaprazan 200 mg once daily, itopride 50 mg TID, or both. Each treatment period was separated by a 7-day washout period. Blood samples were collected for up to 24 hours following the last dose at steady state, and drug concentrations were determined using validated LC/MS-MS. Pharmacokinetic properties were obtained using noncompartmental analysis. Drug tolerability was assessed throughout the study, using measurements of vital signs, clinical chemistry testing, and interviews.


      A total of 30 subjects were enrolled in the study. Among them, 28 subjects completed revaprazan treatment, and 27 completed the study (3 subjects were withdrawn). The geometric mean ratios (GMRs) (90% CI) of Cmax,ss, and AUCτ,ss with revaprazan were 0.92 (0.84–1.00) and 0.96 (0.89–1.03), respectively. The GMRs of Cmax,ss and AUCτ,ss with itopride were 1.07 (0.96–1.20) and 1.12 (1.06–1.18), respectively. A total of 15 adverse events (AEs) were reported in 8 subjects. All AEs were considered to be mild, and there were no clinically significant differences between treatment groups.


      The findings from this study suggest bioequivalence between revaprazan given as monotherapy and in combination with itopride in these healthy Korean male volunteers, with no clinical significant drug–drug interaction. All treatments in this study was generally well tolerated. identifier: NCT0133289.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Clinical Therapeutics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Brook R.A.
        • Kleinman N.L.
        • Choung R.S.
        • et al.
        Functional dyspepsia impacts absenteeism and direct and indirect costs.
        Clin Gastroenterol Hepatol. 2010; 8: 498-503
        • Drossman D.A.
        The functional gastrointestinal disorders and the Rome III process.
        Gastroenterology. 2006; 130: 1377-1390
        • Talley N.J.
        • McNeil D.
        • Hayden A.
        • Piper D.W.
        Randomized, double-blind, placebo-controlled crossover trial of cimetidine and pirenzepine in nonulcer dyspepsia.
        Gastroenterology. 1986; 91: 149-156
        • Talley N.J.
        • Janssens J.
        • Lauritsen K.
        • et al.
        • Optimal Regimen Cures Helicobacter Induced Dyspepsia (ORCHID) Study Group
        Eradication of Helicobacter pylori in functional dyspepsia: randomised double blind placebo controlled trial with 12 months' follow up.
        BMJ. 1999; 318: 833-837
        • Hammett D.C.
        • Evans M.F.
        Functional (non-ulcer) dyspepsia and Helicobacter pylori infection.
        Can Fam Physician. 1999; 45: 2323-2326
        • Ghoshal U.C.
        • Singh R.
        • Chang F.Y.
        • et al.
        Epidemiology of uninvestigated and functional dyspepsia in Asia: facts and fiction.
        J Neurogastroenterol Motil. 2011; 17: 235-244
        • Drossman D.A.
        • Corazziari E.
        • Delvaux M.
        • et al.
        Appendix B: Rome III diagnostic criteria for functional gastrointestinal disorders [in Spanish].
        Rev Gastroenterol Mex. 2010; 75: 511-516
        • Galligan J.J.
        • Vanner S.
        Basic and clinical pharmacology of new motility promoting agents.
        Neurogastroenterol Motil. 2005; 17: 643-653
        • Giurcan R.
        • Voiosu T.A.
        Functional dyspepsia: a pragmatic approach.
        Rom J Intern Med. 2010; 48: 9-15
        • Moayyedi P.
        • Delaney B.C.
        • Vakil N.
        • et al.
        The efficacy of proton pump inhibitors in nonulcer dyspepsia: a systematic review and economic analysis.
        Gastroenterology. 2004; 127: 1329-1337
        • Peura D.A.
        • Kovacs T.O.
        • Metz D.C.
        • et al.
        Lansoprazole in the treatment of functional dyspepsia: two double-blind, randomized, placebo-controlled trials.
        Am J Med. 2004; 116: 740-748
        • Mundo-Gallardo F.
        • De Mezerville-Cantillo L.
        • Burgos-Quiroz H.
        • et al.
        • Mexican Rabeprazole Investigators Group
        Latin American open-label study with rabeprazole in patients with functional dyspepsia.
        Adv Ther. 2000; 17: 190-194
        • Talley N.J.
        • Meineche-Schmidt V.
        • Pare P.
        • et al.
        Efficacy of omeprazole in functional dyspepsia: double-blind, randomized, placebo-controlled trials (the Bond and Opera studies).
        Aliment Pharmacol Ther. 1998; 12: 1055-1065
        • Schwartz M.P.
        • Samsom M.
        • Van Berge Henegouwen G.P.
        • Smout A.J.
        Effect of inhibition of gastric acid secretion on antropyloroduodenal motor activity and duodenal acid hypersensitivity in functional dyspepsia.
        Aliment Pharmacol Ther. 2001; 15: 1921-1928
        • Lee K.J.
        • Vos R.
        • Janssens J.
        • Tack J.
        Influence of duodenal acidification on the sensorimotor function of the proximal stomach in humans.
        Am J Physiol Gastrointest Liver Physiol. 2004; 286: G278-G284
        • Son H.J.
        • Rhee P.L.
        • Kim J.J.
        • et al.
        Hypersensitivity to acid in ulcer-like functional dyspepsia.
        Korean J Intern Med. 1997; 12: 188-192
        • Bolling-Sternevald E.
        • Lauritsen K.
        • Talley N.J.
        • et al.
        Is it possible to predict treatment response to a proton pump inhibitor in functional dyspepsia?.
        Aliment Pharmacol Ther. 2003; 18: 117-124
        • Oshima T.
        • Okugawa T.
        • Tomita T.
        • et al.
        Generation of dyspeptic symptoms by direct acid and water infusion into the stomachs of functional dyspepsia patients and healthy subjects.
        Aliment Pharmacol Ther. 2012; 35: 175-182
        • Kindt S.
        • Tack J.
        Impaired gastric accommodation and its role in dyspepsia.
        Gut. 2006; 55: 1685-1691
        • Thumshirn M.
        • Camilleri M.
        • Saslow S.B.
        • et al.
        Gastric accommodation in non-ulcer dyspepsia and the roles of Helicobacter pylori infection and vagal function.
        Gut. 1999; 44: 55-64
        • Sarnelli G.
        • Caenepeel P.
        • Geypens B.
        • et al.
        Symptoms associated with impaired gastric emptying of solids and liquids in functional dyspepsia.
        Am J Gastroenterol. 2003; 98: 783-788
        • Tack J.
        Prokinetics and fundic relaxants in upper functional GI disorders.
        Curr Opin Pharmacol. 2008; 8: 690-696
        • Hiyama T.
        • Yoshihara M.
        • Matsuo K.
        • et al.
        Meta-analysis of the effects of prokinetic agents in patients with functional dyspepsia.
        J Gastroenterol Hepatol. 2007; 22: 304-310
        • Tack J.
        • Masclee A.
        • Heading R.
        • et al.
        A dose-ranging, placebo-controlled, pilot trial of Acotiamide in patients with functional dyspepsia.
        Neurogastroenterol Motil. 2009; 21: 272-280
        • Jee S.R.
        • Jung H.K.
        • Min B.H.
        • et al.
        Guidelines for the treatment of functional dyspepsia.
        Korean J Gastroenterol. 2011; 57 ([in Korean]): 67-81
        • Futagami S.
        • Iwakiri K.
        • Shindo T.
        • et al.
        The prokinetic effect of mosapride citrate combined with omeprazole therapy improves clinical symptoms and gastric emptying in PPI-resistant NERD patients with delayed gastric emptying.
        J Gastroenterol. 2010; 45: 413-421
        • Stanghellini V.
        • Poluzzi E.
        • De Ponti F.
        • et al.
        Idiopathic dyspepsia.
        Curr Treat Options Gastroenterol. 2005; 8: 175-183
        • Kim H.K.
        • Park S.H.
        • Cheung D.Y.
        • et al.
        Clinical trial: inhibitory effect of revaprazan on gastric acid secretion in healthy male subjects.
        J Gastroenterol Hepatol. 2010; 25: 1618-1625
        • Yu K.S.
        • Bae K.S.
        • Shon J.H.
        • et al.
        Pharmacokinetic and pharmacodynamic evaluation of a novel proton pump inhibitor, YH1885, in healthy volunteers.
        J Clin Pharmacol. 2004; 44: 73-82
        • Chung I.S.
        • Park S.H.
        Revaprazan (Revanex), a novel acid pump antagonist, for duodenal ulcer: results of a double-blind, randomized, parallel, multi-center phase III clinical trial [in Korean].
        Korean J. Gastrointest Endosc. 2005; 31 (CM): 17-24
        • Talley N.J.
        • Tack J.
        • Ptak T.
        • et al.
        Itopride in functional dyspepsia: results of two phase III multicentre, randomised, double-blind, placebo-controlled trials.
        Gut. 2008; 57: 740-746
        • Sun J.
        • Yuan Y.Z.
        • Holtmann G.
        Itopride in the treatment of functional dyspepsia in chinese patients: a prospective, multicentre, post-marketing observational study.
        Clin Drug Investig. 2011; 31: 865-875
        • Holtmann G.
        • Talley N.J.
        • Liebregts T.
        • et al.
        A placebo-controlled trial of itopride in functional dyspepsia.
        N Engl J Med. 2006; 354: 832-840
        • Loyd R.A.
        • McClellan D.A.
        Update on the evaluation and management of functional dyspepsia.
        Am Fam Physician. 2011; 83: 547-552
      1. ICH harmonized tripartite guideline: Guideline for Good Clinical Practice.
        J Postgrad Med. 2001; 47: 45-50
      2. [The Helsinki Declaration].
        Assist Inferm Ric. 2010; 29: 41-44
        • Food and Drug Administration, US Dept of Health and Human Services
        Guidance for Industry: Bioanalytical Method Validation.
        (Accessed March 5, 2012)
        • Lee H.W.
        • Seo J.H.
        • Choi S.K.
        • Lee K.T.
        Determination of itopride in human plasma by liquid chromatography coupled to tandem mass spectrometric detection: application to a bioequivalence study.
        Anal Chim Acta. 2007; 583: 118-123
        • Rowland M.
        • Tozer T.
        Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications.
        4th ed. Lippincott Williams & Wilkins, Philadalphia, Pa2011
        • Huang S.M.
        • Temple R.
        • Throckmorton D.C.
        • Lesko L.J.
        Drug interaction studies: study design, data analysis, and implications for dosing and labeling.
        Clin Pharmacol Ther. 2007; 81: 298-304
        • Quigley E.M.
        • Keohane J.
        Curr Opin Gastroenterol. 2008; 24: 692-697
        • Stanghellini V.
        Three-month prevalence rates of gastrointestinal symptoms and the influence of demographic factors: results from the Domestic/International Gastroenterology Surveillance Study (DIGEST).
        Scand J Gastroenterol Suppl. 1999; 231: 20-28
        • Stanghellini V.
        • De Ponti F.
        • De Giorgio R.
        • et al.
        New developments in the treatment of functional dyspepsia.
        Drugs. 2003; 63: 869-892
        • McCarthy D.M.
        Adverse effects of proton pump inhibitor drugs: clues and conclusions.
        Curr Opin Gastroenterol. 2010; 26: 624-631
        • Choudhry U.
        • Boyce Jr, H.W.
        • Coppola D.
        Proton pump inhibitor-associated gastric polyps: a retrospective analysis of their frequency, and endoscopic, histologic, and ultrastructural characteristics.
        Am J Clin Pathol. 1998; 110: 615-621
        • Laine L.
        • Ahnen D.
        • McClain C.
        • et al.
        Review article: potential gastrointestinal effects of long-term acid suppression with proton pump inhibitors.
        Aliment Pharmacol Ther. 2000; 14: 651-668
        • Mathieu N.
        [Risk of long-term treatment with proton pump inhibitors].
        Rev Prat. 2008; 58: 1451-1454
        • Kim Y.G.
        • Jang B.I.
        • Kim T.N.
        A matched case-control study of a novel Acid-pump antagonist and proton-pump inhibitor for the treatment of iatrogenic ulcers caused by endoscopic submucosal dissection.
        Gut Liver. 2010; 4: 25-30
        • Mushiroda T.
        • Douya R.
        • Takahara E.
        • Nagata O.
        The involvement of flavin-containing monooxygenase but not CYP3A4 in metabolism of itopride hydrochloride, a gastroprokinetic agent: comparison with cisapride and mosapride citrate.
        Drug Metab Dispos. 2000; 28: 1231-1237
        • Jung J.W.
        • Kang H.R.
        • Kwon J.W.
        • et al.
        The potential inhibitory effect of revaprazan, an acid pump antagonist, on anticoagulation with warfarin.
        Tohoku J Exp Med. 2011; 224: 293-300
        • Tomilo D.L.
        • Smith P.F.
        • Ogundele A.B.
        • et al.
        Inhibition of atazanavir oral absorption by lansoprazole gastric acid suppression in healthy volunteers.
        Pharmacotherapy. 2006; 26: 341-346
        • Cohen A.F.
        • Kroon R.
        • Schoemaker R.
        • et al.
        Influence of gastric acidity on the bioavailability of digoxin.
        Ann Intern Med. 1991; 115: 540-545
        • Beorlegui B.
        • Aldaz A.
        • Ortega A.
        • et al.
        Potential interaction between methotrexate and omeprazole.
        Ann Pharmacother. 2000; 34: 1024-1027
        • Gabello M.
        • Valenzano M.C.
        • Barr M.
        • et al.
        Omeprazole induces gastric permeability to digoxin.
        Dig Dis Sci. 2010; 55: 1255-1263
        • Ma J.
        • Yuan L.H.
        • Ding M.J.
        • et al.
        Determination of itopride hydrochloride in human plasma by RP-HPLC with fluorescence detection and its use in bioequivalence study.
        Pharmacol Res. 2009; 59: 189-193