Nilotinib population pharmacokinetics and exposure-response analysis in patients with imatinib-resistant or -intolerant chronic myeloid leukemia.
Eur J Clin Pharmacol
; 69(4): 813-23, 2013 Apr.
Article
em En
| MEDLINE
| ID: mdl-23052406
ABSTRACT
PURPOSE:
We evaluated the population pharmacokinetics (PK) and exposure-response relationship of nilotinib in patients with imatinib-resistant or -intolerant chronic myeloid leukemia (CML).METHODS:
Concentration data from 493 patients with CML in chronic phase (CML-CP), accelerated phase, or blast crisis were used to perform a population pharmacokinetic analysis using nonlinear mixed-effect modeling. Steady-state nilotinib trough concentrations (Cmin) in individual patients were estimated from the population PK model for correlation with the efficacy and safety variables. Exposure-efficacy analysis was performed in patients with CML-CP, whereas exposure-safety analysis was performed in all patients who had both nilotinib PK data and efficacy/safety measures available.RESULTS:
Baseline demographics and CML disease phase did not significantly affect nilotinib PK. Patients with a lower Cmin had significantly longer time to complete cytogenetic response (P = 0.010), longer time to major molecular response (P = 0.012), shorter time to progression (TTP; P = 0.009), and a trend toward lower response rates vs. patients with higher Cmin. A joint effect of prognostic risk score and Cmin on TTP was significant (P < 0.001). Nilotinib Cmin was also associated with the occurrence of all-grade elevations in total bilirubin (P < 0.001) and lipase (P = 0.002) levels.CONCLUSIONS:
When tolerability allows, adherence to the nilotinib dose (400 mg twice daily) in order to maintain sufficient Cmin is important in maximizing the efficacy of nilotinib in patients with imatinib-resistant or -intolerant CML.
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Base de dados:
MEDLINE
Assunto principal:
Piperazinas
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Pirimidinas
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Benzamidas
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Leucemia Mielogênica Crônica BCR-ABL Positiva
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Resistencia a Medicamentos Antineoplásicos
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Modelos Biológicos
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Antineoplásicos
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Irlanda