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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.

Authors
  • Csonka, Denes1
  • Hazell, Katharine1
  • Waldron, Edward2
  • Lorenzo, Sebastien1
  • Duval, Vincent1
  • Trandafir, Lucia3
  • Kobalava, Zhanna D4
  • 1 Novartis Pharma AG, Basel, Switzerland. , (Switzerland)
  • 2 Novartis Pharmaceuticals, East Hanover, NJ, USA.
  • 3 Novartis Oncology, Paris, France. , (France)
  • 4 Peoples' Friendship University of Russia, Moscow, Russia.
Type
Published Article
Journal
Journal of clinical pharmacology
Publication Date
March 2016
Volume
56
Issue
3
Pages
316–323
Identifiers
DOI: 10.1002/jcph.590
PMID: 26183800
Source
Medline
Keywords
License
Unknown

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.

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