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A phase‐1, open‐label, single‐dose study of the pharmacokinetics of buparlisib in subjects with mild to severe hepatic impairment
Author(s) -
Csonka Denes,
Hazell Katharine,
Waldron Edward,
Lorenzo Sebastien,
Duval Vincent,
Trandafir Lucia,
Kobalava Zhanna D.
Publication year - 2016
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.590
Subject(s) - pharmacokinetics , medicine , open label , maximum tolerated dose , pharmacology , gastroenterology , adverse effect
Abstract 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 ∞ ] 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 ∞ ) was moderately increased in subjects with mild (geometric mean ratio [GMR] 1.16; 90%CI 0.81, 1.65), moderate (GMR 1.14; 90%CI 0.80, 1.63), or severe (GMR 1.20; 90%CI 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 ∞ 1.52; 90%CI 1.09, 2.13; C max 1.83; 90%CI 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.