Effect of OATP1B1/1B3 Inhibitor GDC-0810 on the Pharmacokinetics of Pravastatin and Coproporphyrin I/III in Healthy Female Subjects
Effect of OATP1B1/1B3 Inhibitor GDC-0810 on the Pharmacokinetics of Pravastatin and Coproporphyrin I/III in Healthy Female Subjects
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DOI：
10.1002/jcph.1261
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发表时间：
2018-11-01
影响因子：
2.9
通讯作者：
Sahasranaman, Srikumar
中科院分区：
文献类型：
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作者：
Liu, Lichuan;Cheeti, Sravanthi;Sahasranaman, Srikumar
GDC-0810 是一种口服抗癌药物，用于治疗雌激素受体阳性乳腺癌，体外试验显示，GDC-0810 是有机阴离子转运多肽 1B1 和 1B3 (OATP1B1/1B3) 的有效抑制剂。进行了一项临床研究来评估 GDC-0810 和普伐他汀之间的药物相互作用潜力，普伐他汀是一种相对选择性和敏感的 OATP1B1/1B3 底物。十五名具有非生育能力的健康女性受试者参加了这项研究。在第 1 阶段的第 1 天，向所有受试者施用单次 10 毫克剂量的普伐他汀。经过 4 天的清除期后，在第 2 阶段的第 5 至 8 天每天施用一次 600 毫克 GDC-0810，以达到稳态浓度。第 7 天，单剂量 10 mg 普伐他汀与 600 mg GDC-0810 剂量共同给药。对血液样本中普伐他汀（第 1 期和第 2 期）和 GDC-0810（仅第 2 期）的浓度进行定量，随后用于计算药代动力学 (PK) 参数。与单独使用普伐他汀相比，普伐他汀与 GDC-0810 联合给药后的普伐他汀平均最大浓度和曲线下面积值分别高出约 20% 和 41%。根据这项药物-药物相互作用研究中的变化幅度，与 GDC-0810 一起给药时，认为没有必要调整普伐他汀（和其他 OATP1B1/1B3 底物）的剂量。回顾性地，还测量了 OATP1B1/1B3 的内源性生物标志物粪卟啉 I 和 III，并显示出与普伐他汀相当的变化，表明它们在临床环境中检测 OATP1B1/1B3 的弱抑制方面的实用性。
Developed as an oral anticancer drug to treat estrogen receptor-positive breast cancer, GDC-0810 was shown to be a potent inhibitor of organic anion-transporting polypeptide 1B1 and 1B3 (OATP1B1/1B3) from an in vitro assay. A clinical study was conducted to assess the drug-drug interaction potential between GDC-0810 and pravastatin, which is a relatively selective and sensitive OATP1B1/1B3 substrate. Fifteen healthy female subjects of non-childbearing potential were enrolled in the study. On day 1 in period 1, a single 10-mg dose of pravastatin was administered to all subjects. Following a 4-day washout period, 600 mg of GDC-0810 was administered once daily on days 5 through 8 in period 2 to achieve steady-state concentrations. On day 7, a single dose of 10-mg pravastatin was coadministered with the 600-mg GDC-0810 dose. Concentrations of pravastatin (periods 1 and 2) and GDC-0810 (period 2 only) were quantified in blood samples and subsequently used to calculate the pharmacokinetics (PK) parameters. The pravastatin mean maximal concentration and area under the curve values were approximately 20% and 41% higher, respectively, following pravastatin coadministration with GDC-0810 compared to pravastatin alone. Based on the magnitude of change in this drug-drug interaction study, dose adjustments for pravastatin (and other OATP1B1/1B3 substrates) were not considered necessary when administered with GDC-0810. Retrospectively, the endogenous biomarkers of OATP1B1/1B3, coproporphyrin I and III, were also measured and showed changes comparable to those of pravastatin, indicating their utility in detecting weak inhibition of OATP1B1/1B3 in the clinical setting.