Department of Oncology 5072, The Finsen Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Cancer Chemother Pharmacol. 2013 Feb;71(2):543-9. doi: 10.1007/s00280-012-2038-0. Epub 2012 Nov 30.
To investigate any effect of a CYP3A4 inhibitor (ketoconazole) or inducer (rifampicin) on cediranib steady-state pharmacokinetics in patients with advanced solid tumours.
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.
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.
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.
研究 CYP3A4 抑制剂（酮康唑）或诱导剂（利福平）对晚期实体瘤患者西地尼布稳态药代动力学的影响。
在两项 I 期、开放标签试验中，患者分别接受单剂量口服西地尼布（酮康唑研究为 20mg；利福平研究为 45mg），连续 7 天，随后分别给予酮康唑 400mg/天连续 3 天或利福平 600mg/天连续 7 天，随后继续给予单剂量西地尼布。
在酮康唑研究中，46 例患者接受了治疗；38 例患者可评估 C（ss，max），36 例患者可评估 AUC（ss）。酮康唑存在时，西地尼布 20mg 的 g 均数 AUC（ss）和 C（ss，max）分别增加 21%（94%CI 9-35%）和 26%（94%CI 10-43%）。在利福平研究中，64 例患者接受了治疗；44 例患者可评估 C（ss，max），41 例患者可评估 AUC（ss）。酮康唑存在时，西地尼布 45mg 的 g 均数 AUC（ss）和 C（ss，max）分别降低 39%（90%CI 34-43%）和 23%（90%CI 16-30%）。AUC（ss）和 C（ss，max）的 g 均值比值大于 1 表明酮康唑具有统计学意义的影响，小于 1 表明利福平具有统计学意义的影响，并且 CIs 超出了预设的等效性边界。观察到西地尼布 AUC（ss）和 C（ss，max）的个体间变异性很大。西地尼布的安全性与之前报道的相似。
酮康唑或利福平的联合应用对晚期实体瘤患者西地尼布的稳态药代动力学有统计学意义的影响。因此，在给予强效酶抑制剂或诱导剂时，应谨慎使用西地尼布。
