The Effect of Food on the Pharmacokinetics of Unesbulin in Patients with Advanced Leiomyosarcoma

Unesbulin is an orally bioavailable small molecule binding to the colchicine-binding site of tubulin and impeding tubulin polymerization and microtubule formation. It has been investigated as a monotherapy and in combination with other medications for the treatment of cancer, including leiomyosarcoma. This study investigated the effect of food on the pharmacokinetics of unesbulin. In total, eight leiomyosarcoma (LMS) patients (four males and four females) were enrolled in the food effect study during the phase 1b clinical study (NCT03761095). Patients received dacarbazine 1000 mg/m2 intravenously once every 21 days (Q21D) and unesbulin 300 mg orally twice weekly (BIW) starting the day after dacarbazine infusion in each 21-day cycle. The effect of food was assessed during the first week of a cycle that was most convenient for the patient. During this week, participants received the first unesbulin dose on Day 2 after a 10-hour overnight fast, and the second dose on Day 5 with a low-fat diet following another 10-hour overnight fast. There were no restrictions on food intake for the remainder of the trial. Blood samples were collected up to 72 hours post unesbulin administration, and plasma concentration was measured using a validated HPLC-MS method. Comparable unesbulin exposures were observed under both fed and fasted conditions with the geometric mean ratios of fed to fasted being 1.18 (90% CI: 0.976, 1.43) for Cmax, 0.934 (0.730, 1.20) for AUC0–48h, and 0.965 (0.711, 1.31) for AUC0–inf. Notably, the inter-subject variability was greatly reduced when unesbulin was administered with food, decreasing from 43.7% to 28.2% for Cmax and from 53.3% to 19.0% for AUC0–48h. The results indicate that food does not affect the mean oral bioavailability of unesbulin, allowing it to be administered regardless of food intake. However, administering unesbulin with food is encouraged to maintain consistent exposure levels.