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Background: Transient lower esophageal sphincter relaxations (TLESRs) have been identified as a primary cause of reflux events in patients with gastroesophageal reflux disease (GERD). GABAB receptor agonists such as lesogaberan (AZD3355) have been shown to inhibit TLESRs in healthy subjects and patients with GERD, and, therefore, offer a novel therapeutic add-on strategy to acid suppression for the management of GERD. As lesogaberan is being developed as an add-on treatment for the management of patients with GERD who have a partial response to proton pump inhibitor (PPI) therapy, it is important to rule out any clinically important pharmacokinetic drug-drug interaction between lesogaberan and PPIs. Objective: To evaluate the effect of esomeprazole on the pharmacokinetics and safety of lesogaberan and vice versa. Study Design: This was an open-label, randomized, three-way crossover study. The study was open to healthy adult male and female subjects. The study subjects received treatment with, in random order, lesogaberan (150mg twice daily [dose interval 12 hours]), esomeprazole (40 mg once daily), and a combination of both, during 7-day treatment periods. Main Outcome: The presence or absence of pharmacokinetic interactions between lesogaberan and esomeprazole was assessed by measuring the steady-state area under the plasma concentration-time curves during the dosing interval (AUCτ) and the maximum observed plasma concentration (Cmax) for lesogaberan and esomeprazole. Results: Thirty male subjects (mean age 23.2 years, 97% Caucasian) were randomized to treatment and 28 subjects completed the study (one subject was lost to follow-up, and one subject discontinued due to an adverse event). The 95% confidence intervals of the geometric mean ratios for AUCτ and Cmax of lesogaberan and esomeprazole administered alone and concomitantly were within the recognized boundaries of bioequivalence (0.8–1.25). No new safety concerns were raised during this study. The number of patients with adverse events during treatment with lesogaberan alone (n = 17) and concomitantly with esomeprazole (n = 18) were comparable but higher than with esomeprazole alone (n = 10). Paresthesia (episodic, mild, and transient), pharyngitis, and flatulence were the most frequently reported adverse events. Conclusions: There was no observed pharmacokinetic interaction between lesogaberan and esomeprazole when concomitantly administered to healthy subjects, and concomitant therapy was well tolerated. Trial registration number (clinicaltrials.gov): NCT00684190