A phase‐1, open‐label, single‐dose study of the pharmacokinetics of buparlisib in subjects with mild to severe hepatic impairment. (14th September 2015)

• Record Type: Journal Article
• Authors: Csonka, Denes; Hazell, Katharine; Waldron, Edward; Lorenzo, Sebastien; Duval, Vincent; Trandafir, Lucia; Kobalava, Zhanna D.
• Is Part Of: Journal of clinical pharmacology. Volume 56:Number 3(2016)
• Page Start: 316
• Page End: 323
• Publication Date: 2015-09-14
• Subjects: buparlisib -- hepatic impairment -- pharmacokinetics -- PI3K inhibitor; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Pharmacology, Clinical -- Periodicals; 615.1
• DOI: 10.1002/jcph.590
• Languages: English
• ISSNs: 0091-2700

Abstract

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 Cmax ) were derived using noncompartmental analysis. Buparlisib was rapidly absorbed in all groups (median Tmax 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; Cmax 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.