A phase‐1, open‐label, single‐dose study of the pharmacokinetics of buparlisib in subjects with mild to severe hepatic impairment

The pharmacokinetics (PK) and safety of single-dose buparlisib (30 mg) were assessed in subjects with mild to severe hepatic impairment (n = 6 each) relative to healthy controls (n = 13). Blood samples were collected until 336 hours postdose and evaluated by liquid chromatography tandem mass spectrometry. PK parameters (including area under the curve [AUC(infinity)] and C-max) were derived using noncompartmental analysis. Buparlisib was rapidly absorbed in all groups (median T-max 1.0-1.3 h). Buparlisib exposure (AUC(infinity)) was moderately increased in subjects with mild (geometric mean ratio [GMR] 1.16; 90%Cl 0.81, 1.65), moderate (GMR 1.14; 90%Cl 0.80, 1.63), or severe (GMR 1.20; 90%Cl 0.84, 1.72) hepatic impairment, relative to healthy controls. Apparent oral clearance was similar across groups. Due to a higher unbound fraction in the severe group (0.21) than all other groups (0.17), subjects with severe hepatic impairment had greater exposure to unbound buparlisib (GMR relative to healthy controls: AUC(infinity) 1.52; 90%Cl 1.09, 2.13; C-max 1.83; 90%Cl 1.42, 2.36). The results indicate that a buparlisib dose adjustment may not be necessary for patients with mild to moderate hepatic impairment. The safety and therapeutic indices should be considered before determining if a dose adjustment is appropriate for patients with severe hepatic impairment.