Pharmacokinetics and Tolerability of Vandetanib in Chinese Patients With Solid, Malignant Tumors: An Open-Label, Phase I, Rising Multiple-Dose Study

Abstract: Background: Vandetanib (ZD6474) is an orally available inhibitor of 3 signaling pathways important in tumor progression: vascular endothelial growth factor receptor, epidermal growth factor receptor, and rearranged during transfection tyrosine kinase activity. Current development of vandetanib is focused on the treatment of non–small-cell lung cancer and other tumor types, including thyroid cancer. This study was conducted as a requirement for regulatory submission for vandetanib in China. Objective: To determine the pharmacokinetics of vandetanib in Chinese patients with advanced, solid, malignant tumors and to compare these with data obtained in Japanese and Western populations. Methods: Phase I consisted of a nonrandomized, open-label, single-center study conducted in Guangzhou, China. Adult patients (12 per treatment) who had tumors refractory to standard treatments or for whom no appropriate therapies existed received oral vandetanib (100 mg every other day, 100 mg once daily, or 300 mg once daily) until disease progression or discontinuation in the study. The initial cohort was dosed at 100 mg every other day. Once at least 3 patients had received this dose of vandetanib for 28 days without experiencing dose-limiting toxicity, a second cohort at 100 mg once daily was started. Following the same criteria, the third cohort received 300 mg once daily. Pharmacokinetics, tolerability, and tumor response were assessed. The pharmacokinetics of vandetanib in Chinese, Western, and Japanese patients were compared through a combined population pharmacokinetic model. Tolerability was assessed by recording adverse events and monitoring physical examination, body weight, performance status, vital signs, urinalysis, biochemistry, hematology, and 12-lead electrocardiogram. Results: Thirty-six patients were enrolled (age range 21−82 years, 56% male, body mass index range 17.6−33.0 kg/m2). Thirty-three of 36 patients (92%) were World Health Organization performance status 0−1. Vandetanib pharmacokinetics were linear over the dose range studied with AUCss for the 300 mg once daily group (38611 ng/h/mL) being 3.6-fold higher than that for the 100 mg once daily group (10826 ng/h/mL). Absorption was relatively slow following a single 100- or 300-mg dose, with Tmax ranging from 2 to 10 hours. Interpatient variability in Cmax SS and AUCSS was relatively high, with the coefficient of variation ranging from 29.1% to 40.6%. Vandetanib plasma clearance was slow (7.8–9.2 L/h) and was independent of dose. The most common drug-related adverse events were rash (42%) and diarrhea (39%). No QTC prolongation was observed. Hypertension was reported as an adverse event in 3 patients. There were no clinically relevant changes in hematology, urinalysis, or World Health Organization performance status. Elevation of alanine aminotransferase was reported as an adverse event in 1 patient. One patient with medullary thyroid cancer showed a partial tumor response. Population pharmacokinetic analysis suggests that vandetanib pharmacokinetics appear to be comparable in Chinese, Western, and Japanese patients. Conclusions: The pharmacokinetic properties of vandetanib in these Chinese patients were characterized by low plasma clearance of approximately 8 L/h, a long half-life of approximately 8 to10 days, and an accumulation of approximately 8−fold to 15-fold on multiple dosing. In these Chinese patients, the pharmacokinetic profile of vandetanib appeared to be comparable with that observed in Japanese and Western populations. Oral doses up to 300 mg once daily appeared to be well tolerated. [Copyright &y& Elsevier]