Abstract

1. Oral antidyslipidaemic drug pemafibrate is cleared from human plasma via hepatic uptake by organic anion transporting polypeptide (OATP) 1B1 and oxidation by cytochromes P450 (P450) 2C8, 2C9 and 3A4. The pharmacokinetic profiles of pemafibrate with virtual administrations of P450 inhibitors and/or disease interactions were generated using a physiologically based pharmacokinetic (PBPK) model previously established for co-administration of pemafibrate with OATP1B1 inhibitors.

2. This PBPK model was validated in the current study using reported maximum pemafibrate plasma concentrations and areas under the curve from interaction studies in healthy subjects co-administered with clopidogrel (P450 2C8 inhibitor), fluconazole (P450 2C9/3A4 inhibitor) or clarithromycin (P450 3A4 inhibitor).

3. Virtual co-administrations of pemafibrate with clopidogrel, fluconazole or clarithromycin increased the predicted plasma exposures of pemafibrate 1.4–1.7-fold, 1.2–1.4-fold and 2.9–11-fold, respectively, in subjects with or without moderate or severe renal impairment or Child-Pugh A or B liver cirrhosis. Some of the exposure-enhancing effects of clarithromycin may originate from its inhibitory potential toward OATP1B1, because the estimated effects of itraconazole (a P450 3A4 inhibitor) were only minor.

4. Simulations using the current PBPK model in groups of virtual subjects with or without renal or hepatic impairment revealed modified pharmacokinetic profiles for pemafibrate following co-administration of typical P450 inhibitors.

摘要

1. 口服抗血脂异常药物匹马贝特可通过有机阴离子转运多肽（OATP）1B1的肝吸收和细胞色素P450（P450）2C8、2C9和3A4的氧化从人血浆中清除。使用先前建立的将匹马贝特与OATP1B1抑制剂共同给药的基于生理的药代动力学（PBPK）模型，可以生成虚拟给药的P450抑制剂和/或疾病相互作用时的匹马贝特的药代动力学概况。

2. 在当前研究中使用与氯吡格雷（P450 2C8抑制剂），氟康唑（P450 2C9 / 3A4抑制剂）或克拉霉素（P450 3A4）并用的健康受试者的相互作用研究中报告的最大血浆纤维化血浆浓度和曲线下面积验证了PBPK模型抑制剂）。

3. 在有或没有中度或重度肾功能不全或无肾功能不全或肾功能不全的受试者中，虚拟联合使用匹马贝特与氯吡格雷，氟康唑或克拉霉素的血浆血浆暴露分别为匹马贝特的1.4–1.7倍，1.2–1.4倍和2.9–11倍。 Child-Pugh A或B型肝硬化。克拉霉素的某些增强暴露效果可能源自其对OATP1B1的抑制潜力，因为估计的伊曲康唑（一种P450 3A4抑制剂）的作用很小。

4. 在有或没有肾或肝功能不全的虚拟受试者组中使用当前的PBPK模型进行的模拟显示，在共同使用典型的P450抑制剂后，pemafibrate的药代动力学特征有所改变。