A phase-1, open-label, single-dose study of the pharmacokinetics of buparlisib in subjects with mild to severe hepatic impairment
| Autor: | Katharine Hazell, Sebastien Lorenzo, Denes Csonka, Zhanna Kobalava, Vincent Duval, Lucia Trandafir, Edward Waldron |
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| Rok vydání: | 2015 |
| Předmět: |
Adult
Male 0301 basic medicine buparlisib medicine.medical_specialty hepatic impairment Adolescent Morpholines Buparlisib Cmax Administration Oral Aminopyridines Antineoplastic Agents PI3K inhibitor Severity of Illness Index Gastroenterology Young Adult 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Pharmacokinetics Dose adjustment Internal medicine medicine Humans Pharmacology (medical) Aged Pharmacology business.industry Liver Diseases Hepatic impairment Area under the curve PK Parameters Middle Aged 030104 developmental biology chemistry Case-Control Studies 030220 oncology & carcinogenesis Anesthesia Female Open label business |
| Zdroj: | Journal of Clinical Pharmacology |
| ISSN: | 0091-2700 |
| DOI: | 10.1002/jcph.590 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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