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

Background: 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 D-2 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. Objective: 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. Methods: 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. Results: 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 Among them, 28 subjects completed revaprazan treatment, and 27 completed the study (3 subjects were withdrawn).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 C-max,C-ss, and AUC(T,ss) with revaprazan were 0.92 (0.84-1.00) and 0.96 (0.89-1.03), respectively. The GMRs of C-max,C-ss and AUC(T,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. Conclusion: 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. ClinicalTrials.gov identifier: NCT0133289. (Clin Ther. 2012;34:1999-2010) (C) 2012 Elsevier HS Journals, Inc. All rights reserved.