Kirigaya Yoshiaki, Shiramoto Masanari, Ishizuka Tomoko, Uchimaru Hinako, Irie Shin, Kato Manabu, Shimizu Takako, Nakatsu Takafumi, Nishikawa Yasuhiro, Ishizuka Hitoshi
Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan.
SOUSEIKAI Hakata Clinic, 6-18, Tenyamachi, Hakata-ku, Fukuoka, 812-0025, Japan.
Br J Clin Pharmacol. 2020 Oct;86(10):2070-2079. doi: 10.1111/bcp.14302. Epub 2020 May 13.
To investigate the effects of the strong cytochrome P450 (CYP) 3A inhibitor itraconazole and the strong CYP3A inducer rifampicin on the pharmacokinetics of single-dose esaxerenone, a nonsteroidal mineralocorticoid receptor blocker, in healthy Japanese subjects.
Two open-label, single-sequence, crossover studies were conducted in healthy Japanese males aged 20-45 years. In Study 1 (n = 20), subjects received a single oral 2.5 mg dose of esaxerenone (Days 1, 13), with itraconazole 200 mg twice daily (Day 8) and once daily (Days 9-16). In Study 2 (n = 12), subjects received a single oral 5 mg dose of esaxerenone (Days 1, 13), with rifampicin 600 mg once daily (Days 8-16). The plasma concentration of esaxerenone and esaxerenone metabolites were measured using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated using noncompartmental analysis, and safety was assessed.
Esaxerenone exposure increased when coadministered with itraconazole. Geometric least-square mean ratios (90% confidence interval) of peak plasma esaxerenone concentration (C ), area under the plasma concentration-time curve (AUC) from zero until the last measurable concentration (AUC ) and AUC from zero until infinity (AUC ) were 1.13 (1.05, 1.20) ng mL , 1.47 (1.40, 1.54) ng h mL and 1.53 (1.45, 1.62) ng h mL , respectively. Esaxerenone exposure decreased when coadministered with rifampicin. Geometric least-squares mean ratios (90% confidence interval) of esaxerenone C , AUC and AUC were 0.659 (0.599, 0.724), 0.315 (0.300, 0.332) and 0.312 (0.297, 0.328), respectively.
Itraconazole increased esaxerenone AUC by 53.1%, and rifampicin decreased esaxerenone AUC by 68.8%. These results suggest that caution is recommended when coadministering esaxerenone with strong inhibitors and inducers of CYP3A.
在健康日本受试者中，研究强效细胞色素P450（CYP）3A抑制剂伊曲康唑和强效CYP3A诱导剂利福平对单剂量非甾体盐皮质激素受体阻滞剂依沙芦酮药代动力学的影响。
对20至45岁的健康日本男性进行了两项开放标签、单序列、交叉研究。在研究1（n = 20）中，受试者接受单次口服2.5 mg依沙芦酮（第1天、第13天），同时伊曲康唑200 mg每日两次（第8天）及每日一次（第9 - 16天）。在研究2（n = 12）中，受试者接受单次口服5 mg依沙芦酮（第1天、第13天），同时利福平600 mg每日一次（第8 - 16天）。使用液相色谱 - 串联质谱法测量依沙芦酮及其代谢产物的血浆浓度。采用非房室分析计算药代动力学参数，并评估安全性。
与伊曲康唑合用时，依沙芦酮的暴露量增加。血浆依沙芦酮峰浓度（C）、从零至最后可测量浓度的血浆浓度 - 时间曲线下面积（AUC）以及从零至无穷大的AUC的几何最小二乘均值比（90%置信区间）分别为1.13（1.05，1.20）ng/mL、1.47（1.40，1.54）ng·h/mL和1.53（1.45，1.62）ng·h/mL。与利福平合用时，依沙芦酮的暴露量减少。依沙芦酮C、AUC和AUC的几何最小二乘均值比（90%置信区间）分别为0.659（0.599，0.724）、0.315（0.300，0.332）和0.312（0.297，0.328）。
伊曲康唑使依沙芦酮的AUC增加了53.1%，利福平使依沙芦酮的AUC降低了68.8%。这些结果表明，依沙芦酮与强效CYP3A抑制剂和诱导剂合用时建议谨慎。
