Pharmacokinetic profiles of pemafibrate with virtual drug and/or disease interactions were assessed by creating a detailed physiologically based pharmacokinetic (PBPK) model.

Passive diffusion clearance in liver was experimentally determined as 0.013 mL/min/10⁶ human hepatocytes. In vitro intrinsic clearance values for pemafibrate by cytochromes P450 2C8, 2C9, and 3A4 were 54, 26, and 16 μL/min/mg protein, respectively. Values for the effective permeability and the intrinsic clearance of hepatic uptake by organic anion transporting polypeptide (OATP) 1B1 were optimized in a simulator platform.

This PBPK model was subsequently validated using reported maximum pemafibrate plasma concentration and area under the curve values in reported interaction studies in healthy subjects co-administered with rifampicin.

For subjects with Child-Pugh A and B liver cirrhosis, the intrinsic clearance of hepatic uptake of pemafibrate by OATP1B1 were modeled using 53% and 31% of that of healthy subjects, respectively. Virtual co-administrations of rifampicin and sacubitril (OATP1B inhibitors) in subjects with renal impairment and liver cirrhosis resulted in 11- to 13-folds (rifampicin) and 1.1- to 1.3-folds (sacubitril) increased plasma exposures of pemafibrate.

The current PBPK model and simulations revealed different pharmacokinetic profiles for pemafibrate following co-administration of rifampicin or sacubitril in virtual subjects with or without renal/hepatic impairment.

通过建立详细的基于生理的药代动力学（PBPK）模型，可以评估假性纤维蛋白与虚拟药物和/或疾病相互作用的药代动力学概况。

通过实验确定肝脏中的被动扩散清除率为0.013 mL / min / 10 ⁶个人肝细胞。细胞色素P450 2C8、2C9和3A4对血纤维蛋白的体外固有清除率分别为54、26和16μL/ min / mg蛋白。在模拟器平台中优化了有效渗透率和有机阴离子转运多肽（OATP）1B1对肝脏吸收的固有清除率的值。

随后在报道的与利福平共同治疗的健康受试者的相互作用研究中，使用报道的最大血浆纤维蛋白血浆浓度和曲线值下的面积验证了该PBPK模型。

对于患有Child-Pugh A和B肝硬化的受试者，分别以健康受试者的53％和31％为模型来模拟OATP1B1吸收肝内摄取的pemafibrate的内在清除率。在患有肾功能不全和肝硬化的受试者中，利福平和沙奎特利（OATP1B抑制剂）的虚拟联合给药导致血浆中的油酸马来酸暴露增加11至13倍（利福平）和1.1至1.3倍（沙奎特利）。

当前的PBPK模型和模拟结果显示，在有或没有肾/肝功能不全的虚拟受试者中，联合使用利福平或沙比特利后，血浆脂肪蛋白的药代动力学特征有所不同。