Impact of Increased Gastric pH on the Pharmacokinetics of Evacetrapib in Healthy Subjects

STUDY OBJECTIVE: To examine the effect of increased gastric pH on exposure to evacetrapib, a cholesteryl ester transfer protein inhibitor evaluated for the treatment of atherosclerotic heart disease. DESIGN: Open‐label, two‐treatment, two‐period, fixed‐sequence crossover study. SETTING: Clinical research unit. SUBJECTS: Thirty‐four healthy subjects. INTERVENTION: In period 1, subjects received a single oral dose of evacetrapib 130 mg on day 1, followed by 7 days of analysis for evacetrapib plasma concentrations. In period 2, subjects received a once/day oral dose of omeprazole 40 mg on days 8–20, with a single oral dose of evacetrapib 130 mg administered 2 hours after the omeprazole dose on day 14, followed by 7 days of pharmacokinetic sampling. Subjects were discharged on day 21 and returned for a follow‐up visit at least 14 days after the last dose of evacetrapib in period 2. Gastric pH was measured before subjects received each evacetrapib dose. MEASUREMENTS AND MAIN RESULTS: Noncompartmental pharmacokinetic parameters were estimated from plasma concentration–time data and compared between periods 1 and 2. Geometric mean ratios with 90% confidence intervals (CIs) were reported. Safety and tolerability were also assessed. The mean age of the 34 subjects was 40.9 years; mean body mass index was 27.2 kg/m(2). Omeprazole treatment increased mean gastric pH across all subjects by 2.80 and increased evacetrapib area under the concentration versus time curve from time zero extrapolated to infinity (AUC (0–∞)) and maximum observed drug concentration (C(max)) by 15% (90% CI −2 to 35) and 30% (90% CI 3–63), respectively. For both parameters, the upper bound of the 90% CI of the ratio of geometric least‐squares means exceeded 1.25 but was less than 2, indicating a weak interaction. To assess the effect of gastric pH on subjects who responded best to omeprazole treatment, the analyses were repeated to include only the 22 subjects whose predose gastric pH was 3.0 or lower in period 1 and 4.0 or higher in period 2. In this subpopulation, mean gastric pH increased by 4.15 during omeprazole treatment, and evacetrapib AUC (0–∞) and C(max) increased by 22% (90% CI 4–42) and 35% (90% CI 1–80), respectively. Despite the small mathematical differences between the analyses, the overall effect in both was a minimal increase in evacetrapib exposure. Of 35 adverse events reported during the study, 4 (11.4%) were considered to be treatment‐related, and most were mild in severity. CONCLUSION: The impact of increased gastric pH on evacetrapib pharmacokinetics would not be expected to be clinically relevant. The magnitude of change in pH did not affect the degree of the interaction.