An Open-Label Phase 1 Study To Evaluate The Pharmacokinetics Of Axitinib (Ag-013736) In Healthy Chinese Volunteers

Introduction: Axitinib is an oral, potent, and selective inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3. It is mainly metabolized by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP1A2, CYP2C19, and uridine glucuronyltransferase (UGT1A1). Axitinib currently is in Phase 3 development for renal cell carcinoma. As part of the global clinical development program for axitinib, studies are ongoing in cancer patients in China. A clinical assessment of axitinib pharmacokinetics in healthy Chinese subjects, including dose-proportionality, was conducted to support the regulatory submission in China. Methods: This was an open-label, fixed-sequence study conducted in mainland China in 14 healthy volunteers. All subjects received a single axitinib dose of 5 mg, 7 mg, and 10 mg under fed conditions in study periods 1, 2, and 3, respectively, followed by safety and pharmacokinetic monitoring. Each study period was separated by a washout period of at least 7 days between successive axitinib doses. Serial blood sampling for axitinib pharmacokinetics was performed up to 32 hours postdose in each period. Plasma concentrations of axitinib were measured using a validated LC/MS/MS (liquid chromatography coupled with mass spectrometry) method. Axitinib plasma pharmacokinetic parameters were estimated using standard noncompartmental methods. Results: Axitinib AUC 0-∞ (area under the curve from time zero to infinity) and C max (maximal plasma concentration) estimates in healthy Chinese volunteers in this study are reported here. The geometric mean estimate of AUC 0-∞ was 150, 251, and 321 ng[[Unable to Display Character: ∙]]h/mL for doses of 5 mg, 7 mg, and 10 mg, respectively. This represented AUC 0-∞ increments of 1:1.7:2.1 for dose increments of 1:1.4:2, respectively (ie, a proportional increase in AUC 0-∞ per dose increment). Similarly, the geometric mean estimate of C max was 33.5, 51.1, and 69.4 ng/mL for 5 mg, 7 mg, and 10 mg, respectively, representing C max increments of 1:1.5:2.1 for dose increments of 1:1.4:2, respectively (a proportional increase in C max per dose increment). Axitinib was well tolerated with no serious adverse events (AEs) or discontinuations; the only observed AE was mild abdominal distension in 1 subject. Conclusions:. Dose-proportional linear pharmacokinetics for axitinib were observed for the 5 mg to 10 mg dose range in this study. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2762.