title: A phase-1, open-label, single-dose study of the pharmacokinetics of buparlisib in subjects with mild to severe hepatic impairment.
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.
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Denes
authors.initials: D
authors.lastname: Csonka
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Katharine
authors.initials: K
authors.lastname: Hazell
authors.affiliation: Novartis Pharmaceuticals, East Hanover, NJ, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Waldron
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Lorenzo
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Vincent
authors.initials: V
authors.lastname: Duval
authors.affiliation: Novartis Oncology, Paris, France.
authors.forename: Lucia
authors.initials: L
authors.lastname: Trandafir
authors.affiliation: Peoples' Friendship University of Russia, Moscow, Russia.
authors.forename: Zhanna D
authors.initials: ZD
authors.lastname: Kobalava
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000631:Aminopyridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D008107:Liver Diseases / Q000097:blood* / Q000175:diagnosis*; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D009025:Morpholines; C571178:NVP-BKM120
keywords: PI3K inhibitor; buparlisib; hepatic impairment; pharmacokinetics