A Phase I Study of the Pharmacokinetic and Safety Profiles of Oral Pazopanib With a High-Fat or Low-Fat Meal in Patients With Advanced Solid Tumors

Abstract

Pazopanib is an oral angiogenesis inhibitor of vascular endothelial growth factor (VEGF) receptor, platelet-derived growth factor receptor, and cytokine receptor. This open-label, randomized, crossover, phase I study evaluated the effect of low- and high-fat meals on the pharmacokinetics (PK) of pazopanib in patients with advanced solid tumors. Patients participated in either the lead-in cohort or randomized food-effect cohort. Patients in the lead-in cohort were administered a single dose of pazopanib 400 mg with a high-fat meal. Patients in the food-effect cohort were randomized to receive single doses of pazopanib 800 mg in fed condition (high- or low-fat meal) or fasting condition, in random sequence 14 days apart. After completion of the study, patients were given the opportunity to continue treatment with daily pazopanib 800 mg. Administration of pazopanib with both low- and high-fat meals increased maximum observed plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC) by approximately twofold as compared with the corresponding values when administered to patients in the fasted condition. Therefore, pazopanib should be administered to patients in the fasted state so as to minimize within- and between-day variability in the systemic exposure to pazopanib in patients with cancer.

Preclinical Modeling of Tumor Growth and Angiogenesis Inhibition to Describe Pazopanib Clinical Effects in Renal Cell Carcinoma

“…To identify these mean exposure levels in the absence of pharmacokinetic data, we fitted an E max model to mean AUC values reported in previous clinical trials; this approach enabled us to account for the less‐than‐dose‐proportional increase in AUC. Data from five clinical trials that investigated pazopanib doses of 5 mg to 2,000 mg administered once daily were pooled for the analysis 28, 29, 30, 31, 32. According to the E max model, mean exposure was 771.6 μg·h/mL (range, 629.4–802.4 μg·h/mL) corresponding to a mean dose of 727 mg (range: 473–800 mg) through the population of 47 patients.…”

Phase I Study of Pazopanib in Combination with Weekly Paclitaxel in Patients with Advanced Solid Tumors

“…Pazopanib was administered orally once daily at least 1 hour before or 2 hours after a meal based on data showing that administration of food results in a twofold greater area under the curve (AUC) and maximal concentration (C max ) of pazopanib [13]. Pazopanib was started on day 2 during cycle 1 to allow assessment of paclitaxel pharmacokinetics alone on day 1, then pazopanib was continued throughout the duration of the study.…”

Drug Interactions in Palliative Cancer Care and Oncology

“…Axitinib and pazopanib are both TKIs that target vascular endothelial growth factor (VEGF) and indicated for the treatment of renal cell carcinoma (RCC), though pazopanib is also indicated for the treatment of advanced soft tissue sarcoma (Inlyta Concomitant administration of axitinib with food does not have a clinically meaningful impact on the absorption, while concomitant administration of pazopanib with food results in a twofold increase in serum concentrations (Pithavala et al 2012 ;Heath et al 2010 ).…”