Results of a phase 1, randomized study evaluating the effects of food and diurnal variation on the pharmacokinetics of linifanib.

Purpose: The primary objectives of this study were to evaluate the effect of food on the oral bioavailability and to evaluate the effect of diurnal variation on the pharmacokinetics of linifanib, a novel tyrosine kinase (TK) inhibitor selective for vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors, in patients with advanced solid tumors. Adverse events were monitored.

Methods: This was a phase 1, open-label, randomized, crossover study. Thirty-four patients received dosing regimens to evaluate linifanib pharmacokinetic parameters under fasting and non-fasting conditions and with morning or evening dosing. Adverse events (AEs) were assessed according to National Cancer Institute Common Terminology Criteria for AEs (Version 3.0).

Results: The administration with food had a negligible effect on the AUC∞ of linifanib, but the Cmax of linifanib was decreased by 40 % compared to the fasting condition. Evening dosing after a 2-h fast had a negligible effect on AUC₂₄; however, the dose-normalized Cmax of linifanib after evening dosing was 64 % of that after morning dosing following a 10-h fast. Common Grade 3/4 AEs were fatigue (24 %), hypertension (21 %), and palmar-plantar erythrodysaesthesia syndrome (15 %).

Conclusions: Dosing with food or in the evening has a significant effect on the oral bioavailability of linifanib that should be taken into consideration when designing future clinical studies. The pattern of adverse advents reported in this study is similar to that seen in other studies of linifanib and other agents in the VEGF/PDGF TK receptor inhibitor class.