FP390MODERATE HEPATIC IMPAIRMENT HAS ONLY A MINOR IMPACT ON THE PHARMACOKINETICS OF ROXADUSTAT, AN ORAL HYPOXIA-INDUCIBLE FACTOR PROLYL-HYDROXYLASE INHIBITOR

Abstract

Introduction and Aims: roxadustat (FG-4592/ASP1517) is a hypoxia-inducible factor prolyl hydroxylase inhibitor, which is currently in phase III development for the treatment of anaemia associated with chronic kidney disease. This study was designed to evaluate the effects of moderate hepatic impairment on the pharmacokinetics (PKs) of roxadustat. Method(s): this was an open-label study, in which eight subjects with moderate hepatic impairment (Child-Pugh Score between 7 and 9) and eight healthy subjects with normal hepatic function (matched for body mass index, age and sex) received a single dose of 100 mg roxadustat under fasted conditions. Plasma samples were collected until 144 h post-dose in subjects with moderate hepatic impairment and until 96 h post-dose in subjects with normal hepatic function to assess the roxadustat concentrations and to determine the non-compartmental PK parameters. Result(s): the PK results of total roxadustat in subjects with moderate hepatic impairment and subjects with normal hepatic function are shown in the table below. In subjects with moderate hepatic impairment, the exposure parameters AUCinf and Cmax were 23% higher (GMR%:123 [90% CI: 86.1, 175]) and 16% lower (GMR%: 83.6 [90% CI: 67.5, 104]), respectively than in subjects with normal hepatic function. However, these differences do not appear to be of clinical significance, since the 90% confidence intervals are overlapping. Mean t1/2 appeared to be longer (17.7 vs 12.8 h) in subjects with moderate hepatic impairment. However, the intersubject variability on CL/F, Vz/F and t1/2 was approximately twofold higher. A single oral dose of roxadustat 100 mg was generally well tolerated in subjects with moderate hepatic impairment and in their matching normal healthy control subjects. Conclusion(s): only small differences in roxadustat exposure were observed in subjects with moderate hepatic impairment relative to healthy subjects with normal hepatic function. These small differences in Cmax and AUCinf are not expected to be of clinical significance. (Table Presented).