Effects of a High-fat Meal on the Pharmacokinetics of the VEGFR Inhibitor Fruquintinib: A Randomized Phase I Study in Healthy Subjects

Purpose: Fruquintinib is a potent and highly selective oral small-molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor and demonstrates promising activity against a broad spectrum of cancer types. The objective of the study was to investigate the tolerability and effect of high-fat food on the pharmacokinetic profile of a fruquintinib capsule in healthy Chinese subjects.

Methods: Healthy Chinese male subjects aged between 18 and 45 years were enrolled in the study. The study included 2 phases: a dose-escalation phase and a food effect-assessment phase. In the dose-escalation phase, subjects were administered a single dose of fruquintinib (2, 3, or 4 mg) in the fasted state. In the food effect-assessment phase, subjects were administered a 4-mg fruquintinib capsule in the fasted and fed states, respectively, in 2 cycles. Blood samples for pharmacokinetic analysis were collected at the designated time points. Tolerability was assessed throughout the study by physical examination including vital sign measurements, clinical laboratory tests, 12-lead ECG, clinical assessments, and monitoring for and spontaneous reporting of adverse events.

Findings: Twenty-nine eligible male subjects were enrolled in the study, including 9 in the dose-escalation phase and 20 in the food effect-assessment phase. In the food effect-assessment phase, the ratios (90% CI) of the geometric mean AUC_0-∞ and C_max values for fruquintinib in the fed state to those observed in the fasted state were 97.2% (94.0%-100.4%) and 82.9% (76.7%-89.5%), respectively. The mean (SD) T_max values of fruquintinib were 3.0 (1.0) and 5.6 (4.5) hours in the fasted and fed states, respectively. The most common adverse events possibly related to the study drug were elevated blood uric acid, diarrhea, and decreased white blood cell count.

Implications: The overall bioavailability of the evaluated formulation of fruquintinib was not affected by the consumption of a high-fat, high-calorie meal prior to dosing. However, the consumption of a high-fat, high-calorie meal prior to dosing prolonged the T_max. These results indicate that the fruquintinib capsule can be administered with or without food. ClinicalTrials.gov identifier: NCT01955304.