Pfizer Inc, 10555 Science Center Dr, San Diego, CA, 92121, USA,
Cancer Chemother Pharmacol. 2014 Aug;74(2):411-8. doi: 10.1007/s00280-014-2502-0. Epub 2014 Jun 19.
To evaluate the effect of a potent cytochrome P450 3A4 (CYP3A4) inhibitor, ketoconazole, and separately the effect of food on PF-04449913 pharmacokinetics in healthy volunteers.
This was an open-label, two-sequence, three-period, three-treatment, single-dose, crossover study. Subjects were randomized to receive single doses of 200 mg PF-04449913 after an overnight fast or after consuming a high-fat meal during Period 1 or 2, with a washout period of at least 8 days. In Period 3, all subjects received ketoconazole (400 mg/day) (days 1-7) and a co-administered single 200-mg PF-04449913 dose (day 4).
Geometric mean ratio of PF-04449913 in the presence of ketoconazole versus PF-04449913 alone was 2.40 [90% confidence interval (CI) 2.15, 2.68] for area under the plasma concentration-time curve from time zero to infinity (AUC(0-inf)) and 1.40 (90% CI 1.24, 1.58) for peak plasma concentration (C max). The geometric mean ratio for fed state compared with fasted state for AUC(0-inf) was 0.87 (90% CI 0.78, 0.97) and for C max was 0.66 (90% CI 0.56, 0.78). PF-04449913 was well tolerated, and all adverse events were mild to moderate.
PF-04449913 plasma exposures and peak concentrations were increased following concurrent administration of ketoconazole in healthy volunteers. These findings provide the upper limit for expected PF-04449913 exposures after co-administration of a strong CYP3A4 inhibitor in patients with cancer who routinely receive antifungal azoles. While a high-fat meal decreased PF-04449913 exposure, the differences in plasma exposure under the two conditions were not considered clinically meaningful.
评估强效细胞色素 P450 3A4（CYP3A4）抑制剂酮康唑对 PF-04449913 药代动力学的影响，并分别评估食物对 PF-04449913 药代动力学的影响在健康志愿者中。
这是一项开放标签、两序列、三周期、三处理、单剂量、交叉研究。受试者随机分为三组，分别在第一或第二周期接受单剂量 200mg PF-04449913，一种是禁食状态，另一种是进食高脂肪餐，洗脱期至少 8 天。在第三周期，所有受试者接受酮康唑（400mg/天）（第 1-7 天）和同时给予的单剂量 200mg PF-04449913（第 4 天）。
酮康唑存在时 PF-04449913 的几何均数比值与 PF-04449913 单独给药相比，AUC（0-无穷大）的比值为 2.40 [90%置信区间（CI）2.15, 2.68]，Cmax 的比值为 1.40（90%CI 1.24, 1.58）。与禁食状态相比，进食状态下 AUC（0-inf）的几何均数比值为 0.87（90%CI 0.78, 0.97），Cmax 的比值为 0.66（90%CI 0.56, 0.78）。PF-04449913 耐受性良好，所有不良事件均为轻度至中度。
在健康志愿者中同时给予酮康唑可增加 PF-04449913 的血浆暴露和峰浓度。这些发现为癌症患者同时给予强效 CYP3A4 抑制剂时 PF-04449913 暴露的上限提供了依据，这些患者通常接受抗真菌唑类药物治疗。高脂肪餐降低了 PF-04449913 的暴露，但两种情况下的血浆暴露差异没有临床意义。
