Evaluation of Absolute Oral Bioavailability and Bioequivalence of Ribociclib, a Cyclin-Dependent Kinase 4/6 Inhibitor, in Healthy Subjects.
Clin Pharmacol Drug Dev
; 9(7): 855-866, 2020 10.
Article
em En
| MEDLINE
| ID: mdl-32706937
ABSTRACT
Ribociclib, a selective and potent cyclin-dependent kinase 4/6 inhibitor, has demonstrated safety and efficacy in combination with endocrine therapy in hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer. In 2 open-label crossover studies in healthy participants, the absolute bioavailability of a single oral dose of a ribociclib 600-mg tablet (n = 16) was compared with a single intravenous ribociclib infusion of 150 mg (n = 16), and the bioequivalence of a ribociclib 600-mg tablet (n = 31) and a ribociclib 600-mg capsule (n = 31) was evaluated. The pharmacokinetics of ribociclib and its major metabolite, LEQ803, were assessed in both studies. The oral bioavailability of the 600-mg ribociclib tablet was 65.8% (90% confidence interval [CI], 59.1-73.2%). The geometric mean systemic clearance of ribociclib was moderate (40.2 L/h; 27.4% intersubject variability [CV%]) compared with hepatic blood flow, and the geometric mean volume of distribution was high (979 L; 25.2 CV%). LEQ803-to-ribociclib metabolic ratios were 0.198 for the oral administration and 0.125 for intravenous infusion. Bioequivalence of the tablet and capsule formulations was demonstrated for ribociclib. The geometric mean ratios of maximum concentration and area under the curve from time 0 to last quantifiable concentration and to infinity were 1.01, 1.00, and 0.937, respectively, within the predefined bioequivalence range of 0.80 to 1.25. The median time to reach maximum concentration was 3 hours with both formulations. No serious adverse events were observed in either study.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Purinas
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Neoplasias da Mama
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Quinase 4 Dependente de Ciclina
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Quinase 6 Dependente de Ciclina
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Aminopiridinas
Tipo de estudo:
Clinical_trials
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Prognostic_studies
Limite:
Adult
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Clin Pharmacol Drug Dev
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Estados Unidos