Impact of Increased GastricpHon the Pharmacokinetics of Evacetrapib in Healthy Subjects

Abstract

Study ObjectiveTo 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.DesignOpen‐label, two‐treatment, two‐period, fixed‐sequence crossover study.SettingClinical research unit.SubjectsThirty‐four healthy subjects.InterventionIn 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 ResultsNoncompartmental 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/m2. 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 (Cmax) 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 Cmax 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.ConclusionThe 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.

Effect of Omeprazole Administration on the Pharmacokinetics of Oral Extended‐Release Nifedipine in Healthy Subjects

“…The population for PK analysis consisted of subjects with evaluable data for the comparison of interest without major protocol violations. PK analysis was also conducted in a subpopulation of subjects with gastric pH ≤ 3 in arms A and B (nifedipine alone) or gastric pH ≥ 4 in arms C and D (Co‐administration multiple‐dose of omeprazole) 4 . Intragastric pH of < 4 was found to be a strong predictor for increased GERD‐related symptoms and severity of mucosal injury as the analysis of this subpopulation may represent a so‐called worst case scenario for the effect of increased gastric pH 4,19–21 .…”

“…Although the product-specific bioequivalence (BE) between two products should be demonstrated in healthy volunteers to meet regulatory requirements, it is of interest of the US Food and Drug Administration (FDA) to assess risk of formulation changes for BE assessment under certain conditions, such as gastric pH change due to comedication with proton pump inhibitors (PPIs). [4][5][6] Nifedipine is a calcium channel blocker used to manage angina and hypertension and is mainly metabolized via the CYP3A4 system. 7 With its low solubility and high permeability, nifedipine is classified as a biopharmaceutical classification system class II drug.…”

“…PK analysis was also conducted in a subpopulation of subjects with gastric pH ≤ 3 in arms A and B (nifedipine alone) or gastric pH ≥ 4 in arms C and D (Co-administration multiple-dose of omeprazole). 4 Intragastric pH of < 4 was found to be a strong predictor for increased GERD-related symptoms and severity of mucosal injury as the analysis of this subpopulation may represent a so-called worst case scenario for the effect of increased gastric pH. 4,[19][20][21] PK analysis was performed using a noncompartmental approach with the linear trapezoidal rule (Phoenix WinNonlin version 6.4).…”

“…4 Intragastric pH of < 4 was found to be a strong predictor for increased GERD-related symptoms and severity of mucosal injury as the analysis of this subpopulation may represent a so-called worst case scenario for the effect of increased gastric pH. 4,[19][20][21] PK analysis was performed using a noncompartmental approach with the linear trapezoidal rule (Phoenix WinNonlin version 6.4). The following PK metrics were computed: maximum plasma concentration (C max ), time to C max (T max ), area under the concentration-time curve (AUC) from time zero to the last measurable time point (AUC 0-t ), AUC extrapolated to infinity (AUC 0-inf ), terminal rate constant (λ z ), and terminal elimination half-life (t 1/2 ).…”

“…Specifically, when a generic ER product uses a different release mechanism and/or critical excipients from those of the reference listed drugs (RLDs; e.g., osmotic pump RLD vs. matrix generic counterparts), difference in pH dependent release due to altered GI pH conditions can lead to potential PK differences. Although the product‐specific bioequivalence (BE) between two products should be demonstrated in healthy volunteers to meet regulatory requirements, it is of interest of the US Food and Drug Administration (FDA) to assess risk of formulation changes for BE assessment under certain conditions, such as gastric pH change due to comedication with proton pump inhibitors (PPIs) 4–6 …”