Effect of an Antacid (Aluminum Hydroxide/Magnesium Hydroxide/Simethicone) or a Proton Pump Inhibitor (Omeprazole) on the Pharmacokinetics of Tebipenem Pivoxil Hydrobromide (TBP-PI-HBr) in Healthy Adult Subjects

Abstract

Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is a novel oral carbapenem prodrug being developed for the treatment of serious bacterial infections. This open-label, 3-period, fixed sequence study evaluated the effect of gastric acid-reducing agents, aluminum hydroxide/magnesium hydroxide/simethicone, and omeprazole on the pharmacokinetics (PK) of tebipenem (TBP), the active moiety, following coadministration with immediate release TBP-PI-HBr during fasting. In Period 1, subjects received a single oral dose of TBP-PI-HBr 600 mg (2 × 300 mg tablets). In Period 2, subjects received a single oral dose of aluminum hydroxide 800 mg/magnesium hydroxide 800 mg/simethicone 80 mg suspension co-administered with a single dose of TBP-PI-HBr 600 mg. In Period 3, subjects received a single oral dose of omeprazole 40 mg once daily over 5 days, followed by single dose administration of TBP-PI-HBr 600 mg on day 5. In each period, whole blood samples were obtained prior to, and up to 24 h, following TBP-PI-HBr dose administration in order to characterize TBP PK. A 7-day washout was required between periods. Twenty subjects were enrolled and completed the study. Following co-administration of TBP-PI-HBr with either aluminum hydroxide/magnesium hydroxide/simethicone or omeprazole, total TBP exposure (area under the curve [AUC]) was approximately 11% (geometric mean ratio 89.2, 90% confidence interval: 83,2, 95.7) lower, and Cmax was 22% (geometric mean ratio 78.4, 90% confidence interval: 67.9, 90.6) and 43% (geometric mean ratio 56.9, 90% confidence interval: 49.2, 65.8) lower, respectively, compared to administration of TBP-PI-HBr alone. Mean TBP elimination half-life (t_1/2) was generally comparable across treatments (range: 1.0 to 1.5 h). Concomitant administration of TBP-PI-HBr with omeprazole or aluminum hydroxide/magnesium hydroxide/simethicone is not expected to impact the efficacy of TBP-PI-HBr, as there is minimal impact on TBP plasma AUC, which is the pharmacodynamic driver of efficacy. Co-administration was generally safe and well tolerated.

Keywords: aluminum hydroxide/magnesium hydroxide/simethicone; drug interaction; omeprazole; pharmacokinetics; tebipenem.