Effects of a proton pump inhibitor (lansoprazole) and food on the bioavailability of enzastaurin administered as single oral doses to healthy subjects

Abstract

14076 Background: Enzastaurin (ENZ) targets the PKCβ and PI3K/AKT pathways to induce tumor cell apoptosis, reduce proliferation, and suppress tumor-induced angiogenesis. In vitro studies show ENZ solubility is highest at pH 2.0 and decreases with increasing pH. This study examined the effect of increased gastric pH by a proton pump inhibitor (lansoprazole) and the effect of food on the bioavailability of a single oral dose of ENZ in healthy subjects. Methods: In this open-label, three-period, fixed sequence, crossover study, healthy subjects received an oral, 500-mg single dose of ENZ in the fed state, alone (A) and with lansoprazole (B), and in the fasted state alone (C). Lansoprazole was dosed for 5 days, with ENZ administered 2 hours after the 5th dose. A two-week washout occurred between each period. Plasma samples were collected at predose and scheduled timepoints for up to 168 hours post-ENZ dose for pharmacokinetic (PK) characterization of ENZ and its active metabolites. Results: 22 subjects were enrolled in the study with 19 subjects completing all treatment periods. The table summarizes the PK results for enzastaurin and total analytes (enzastaurin + metabolites). ENZ Cmax and AUC(0–8) were unaffected by the administration of lansoprazole, when ENZ was then given in the fed state. Enzastaurin Cmax and AUC(0–8) increased significantly, respectively by 6.8 and 2.8 fold, when ENZ was administered after a standardized breakfast, compared to the fasted state. Median tmax increased from approximately 3 hours in the fed state to 6 hours in the fasted state, indicating slower absorption when ENZ was administered in the fasted state. Conclusions: No significant alterations in ENZ exposures were seen in the presence of lansoprazole, indicating that increased gastric pH did not decrease exposures of ENZ, when ENZ is administered in the fed state. Exposures of ENZ and its active metabolites were significantly enhanced by administration of ENZ after a meal. [Table: see text] No significant financial relationships to disclose.