Purpose: Arbaclofen placarbil (AP), a novel reflux inhibitor, is an actively transported prodrug of the R isomer of baclofen (RB). AP is currently under investigation as an adjunct to proton pump inhibitors (PPI) for the treatment of gastroesophageal reflux disease (GERD) in patients who remain symptomatic on PPIs. The purpose of this study was to assess the potential for pharmacokinetic (PK) drug-drug interaction between AP and esomeprazole.
Methods: In this open-label, 2-treatment, 2-period, sequential design study, 15 healthy adult subjects were treated with sustained-release AP 60 mg qd for 5 days, followed by AP 60 mg + esomeprazole 40 mg qd for 5 days. There was a 3-day titration period and a 5-day tapering period for AP. Steady-state AP and RB concentrations were determined on days 8 and 13, using LC/MS/MS methods. PK parameters were estimated using noncompartmental analysis and compared for AP and AP + esomaprazole (days 8 and 13) using ANOVA.
Results: Fifteen subjects completed the study. AP was well absorbed and rapidly converted to RB. Mean RB Css,max and AUCss,24 values were 144 ng/mL and 1480 ng*h/mL, respectively, for AP alone, and were 124 ng/mL and 1270 ng*h/mL, respectively, when AP was dosed with esomeprazole. Mean Css,max and AUCss,24 of RB were each decreased by approximately 14% when AP was coadministered with esomeprazole. Statistical analysis showed no significant treatment effect on the PK parameters at level α=0.05. The 90% confidence intervals of ratio of means included 1. Levels of the intact prodrug were low and transient for both treatments (Mean of % [AP AUClast to RB AUClast] of ≤ 10). There was no effect on AP exposure when AP was coadministered with esomeprazole. Both AP and AP+ esomaprazole treatments were generally safe and well tolerated. There were no clinically significant changes in laboratory values, vital signs, or ECG parameters.
Conclusion: There was no clinically relevant or statistically significant drug-drug interaction when AP was administered with esomeprazole. The results of this study suggest that no AP dose adjustment is needed with coadministration of PPIs.
Disclosure: All authors are employees of XenoPort, Inc.
The study was funded by XenoPort, Inc.