Lack of food eVect on single-dose pharmacokinetics of brivanib, and safety and eYcacy following multiple doses in subjects with advanced or metastatic solid tumors

Abstract

Purpose Brivanib alaninate, an orally available prodrug of brivanib, is currently under evaluation for the treatment of several malignancies. This study aimed to (1) investigate eVects of a high-fat meal on single-dose pharmacokinetics of brivanib in subjects with advanced/metastatic solid tumors and (2) assess the safety and preliminary eYcacy of single and multiple doses of brivanib alaninate in this population. Methods A two-part study was conducted consisting of a single-dose phase (Part A) and a multiple-dose phase (Part B). In Part A, subjects received a single dose of brivanib alaninate (800 mg) either in a fasting state or following ingestion of a high-fat meal (approximately 951 kcal [15% protein, 33% carbohydrate, 52% fat]); serial blood samples were collected for pharmacokinetic analysis up to 48 h post-dosing. In Part B, subjects received brivanib alaninate (800 mg) once daily until discontinuation. Throughout both phases, subjects were evaluated for adverse events (AEs) and best clinical response. Results No clinically signiWcant diVerences in brivanib exposure were observed between fed and fasting subjects in Part A; Cmax was unchanged and AUCINF decreased marginally when administered in a fed versus fasted state. In Part A, the incidence of treatment-emergent AEs was broadly similar in a fed or fasted state. Brivanib alaninate was generally well tolerated throughout the study and showed preliminary evidence of antitumor activity. Conclusions Consumption of a high-fat meal had no signiWcant eVect on brivanib pharmacokinetics. The study further demonstrates the acceptable safety/tolerability proWle and antitumor potential of brivanib in patients with advanced malignancies. Keywords Pharmacokinetics · Exposure · Food · Safety · Brivanib alaninate · Solid tumors