Abstract A193: Assessment of effect of low- and high-fat diet on E7050 pharmacokinetics and characterization of E7050 pharmacokinetics after 100 mg, 200 mg, and 400 mg single oral doses in healthy subjects.

Abstract

Abstract Purpose: E7050, an orally available c-MET tyrosyne kinase inhibitor is currently under evaluation for the treatment of advanced malignancies. The objectives of this study were to evaluate (1) effects of a standard high-fat and low-fat meal on the pharmacokinetics (PK) of 100 mg E7050; (2) E7050 PK following single doses of 100, 200 and 400 mg of E7050 in under fasted condition and (3) the safety of E7050 in healthy subjects. Methods: This open label study consisted of two parts: Part A (Food Effect) and Part B (Rising dose PK). Part A was a randomized, single-dose, three-way crossover study with a 2-week wash out between treatments. In Part A, 18 subjects received a single dose of E7050 (100 mg) in a fasting state, following a high-fat meal or a low-fat meal. In Part B, 12 and 10 subjects sequentially received 200 and 400 mg E7050 doses, respectively in fasted state. Serial blood samples for E7050 PK analysis were taken up to 196 h post-dosing. Subjects were evaluated for adverse events (AEs). Results: Study results are summarized in Table 1. Based on E7050 Cmax, AUC(0−t) and AUC(0−inf), the presence of food at the time of dosing reduces exposure by 21 to 28%. When administered with food (high-fat or low-fat), the lower 90% CI limit for E7050 is below 80% for Cmax and AUC. Thus the food effect is independent of the type of meal consumed. However, the magnitude of the observed food effect was modest and clinically insignificant. PK of E7050 was found to be linear following single doses of 100 to 400 mg E7050. In this study, a single dose of the 400-mg E7050 tablet was safe and well tolerated when administered under fed and fasted conditions. Most TEAEs were mild in severity; there were no treatment-related severe or serious AEs and no treatment-related AEs leading to study treatment withdrawal. There were no clinically significant changes in vital sign assessments, clinical laboratory analyzes or ECG parameters. Conclusion: Consumption of a low- or high-fat meal had no clinically significant effect on E7050 PK and E7050 can be administered without regards to food. PK of E7050 was found to be linear following single doses of 100 to 400 mg E7050. This study demonstrated an acceptable safety/tolerability profile of E7050 in healthy subjects. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A193.