A Phase I study to evaluate the pharmacokinetics of axitinib (AG-13736) in healthy Chinese volunteers

Abstract

To assess axitinib plasma pharmacokinetics and safety of single oral doses of axitinib under fed conditions in healthy Chinese volunteers. This Phase I, open-label study evaluated single dosing of axitinib in 14 healthy Chinese volunteers. Axitinib was administered as 5-, 7-, and 10-mg doses under fed conditions in study periods 1, 2, and 3, respectively, followed by pharmacokinetic assessments and safety monitoring. A washout period ≥ 7 days was provided between successive axitinib doses. Blood samples were collected during each period up to 32 h post-dose for pharmacokinetic analysis. Axitinib plasma pharmacokinetic parameters were estimated using standard noncompartmental methods. Estimates (geometric mean) of axitinib AUC(inf) were 150, 251, and 321 ng × h/ml for doses of 5, 7, and 10 mg, respectively, reflecting a dose-proportional increase in AUC(inf) (increments of 1 : 1.7 : 2.1 for dose increments of 1 : 1.4 : 2, respectively). Geometric mean estimates of maximum observed plasma concentration (Cmax) were 33.5, 51.1, and 69.4 ng/ml, respectively, which also showed dose proportionality. Axitinib plasma pharmacokinetics was similar to those previously observed in healthy Caucasians, with geometric mean values (% geometric coefficient of variation) for axitinib plasma AUC(inf) 150 ng × h/ml (62%) versus 125 ng × h/ml (60%), respectively. Axitinib was well tolerated, with no serious adverse events or discontinuations; one adverse event of mild abdominal distension was observed. In healthy Chinese subjects, single dosing of axitinib demonstrated dose-proportional pharmacokinetics. Axitinib pharmacokinetics in this population was similar to those previously observed in healthy Caucasians, suggesting a lack of ethnic differences.