Assuntos
Células-Tronco Hematopoéticas/patologia , Proteínas de Homeodomínio/genética , Carioferinas/metabolismo , Leucemia Experimental/patologia , Proteínas de Fusão Oncogênica/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Ativação Transcricional , Transporte Ativo do Núcleo Celular , Animais , Apoptose , Proliferação de Células , Células Cultivadas , Regulação Leucêmica da Expressão Gênica , Células-Tronco Hematopoéticas/metabolismo , Proteínas de Homeodomínio/metabolismo , Carioferinas/genética , Leucemia Experimental/etiologia , Leucemia Experimental/metabolismo , Camundongos , Proteínas de Fusão Oncogênica/genética , Receptores Citoplasmáticos e Nucleares/genética , Fatores de Transcrição/genética , Proteína Exportina 1RESUMO
PURPOSE: To investigate any effect of a CYP3A4 inhibitor (ketoconazole) or inducer (rifampicin) on cediranib steady-state pharmacokinetics in patients with advanced solid tumours. METHODS: In two Phase I, open-label trials, patients received once-daily oral doses of cediranib alone [20 mg (ketoconazole study); 45 mg (rifampicin study)] for 7 days followed by cediranib at the same dose with ketoconazole 400 mg/day for 3 days or once-daily rifampicin 600 mg/day for 7 days, respectively. Patients then continued to receive once-daily cediranib. RESULTS: In the ketoconazole study, 46 patients were dosed; 38 were evaluable for C (ss,max), 36 for AUC(ss). gMean AUC(ss) and C (ss,max) for cediranib 20 mg increased by 21 % (94 % CI 9-35 %) and 26 % (94 % CI 10-43 %), respectively, in the presence of ketoconazole. In the rifampicin study, 64 patients were dosed; 44 were evaluable for C (ss,max) and 41 for AUC(ss). gMean AUC(ss) and C (ss,max) for cediranib 45 mg decreased by 39 % (90 % CI 34-43 %) and 23 % (90 % CI 16-30 %), respectively, in the presence of rifampicin. gMean ratios for AUC(ss) and C (ss,max) were >1 for ketoconazole and <1 for rifampicin and CIs were outside the pre-specified equivalence boundaries, indicating a statistically significant effect. Significant inter-patient variability in cediranib AUC(ss) and C (ss,max) was observed. The safety profile of cediranib was similar to that reported previously. CONCLUSIONS: Co-administration of ketoconazole or rifampicin had statistically significant effects on steady-state pharmacokinetics of cediranib in patients with advanced solid tumours. Therefore, caution is advised when administering cediranib with potent enzyme inhibitors or inducers.