Abstract:
Pitavastatin, a potent 3-hydroxymethylglutaryl coenzyme A reductase inhibitor, is indicated for the treatment of hypercholesterolemia and mixed dyslipidemia. Hepatic uptake of pitavastatin is predominantly occupied by the organic anion transporting polypeptide 1B1 (OATP1B1) and solute carrier organic anion transporter family member 1B1 (SLCO1B1) gene, which is a polymorphic gene that encodes OATP1B1. SLCO1B1 genetic polymorphism significantly alters the pharmacokinetics of pitavastatin. This study aimed to establish the physiologically based pharmacokinetic (PBPK) model to predict pitavastatin pharmacokinetics according to SLCO1B1 genetic polymorphism. PK-Sim® version 10.0 was used to establish the whole-body PBPK model of pitavastatin. Our pharmacogenomic data and a total of 27 clinical pharmacokinetic data with different dose administration and demographic properties were used to develop and validate the model, respectively. Physicochemical properties and disposition characteristics of pitavastatin were acquired from previously reported data or optimized to capture the plasma concentration-time profiles in different SLCO1B1 diplotypes. Model evaluation was performed by comparing the predicted pharmacokinetic parameters and profiles to the observed data. Predicted plasma concentration-time profiles were visually similar to the observed profiles in the non-genotyped populations and different SLCO1B1 diplotypes. All fold error values for AUC and Cmax were included in the two fold range of observed values. Thus, the PBPK model of pitavastatin in different SLCO1B1 diplotypes was properly established. The present study can be useful to individualize the dose administration strategy of pitavastatin in individuals with various ages, races, and SLCO1B1 diplotypes.
摘要:
匹伐他汀,一种有效的3-羟甲基戊二酰辅酶A还原酶抑制剂,用于治疗高胆固醇血症和混合性血脂异常。匹伐他汀的肝摄取主要由有机阴离子转运多肽1B1(OATP1B1)和溶质载体有机阴离子转运蛋白家族成员1B1(SLCO1B1)基因占据,它是编码OATP1B1的多态基因。SLCO1B1基因多态性显著改变匹伐他汀的药代动力学。本研究旨在建立基于生理的药代动力学(PBPK)模型,以根据SLCO1B1基因多态性预测匹伐他汀的药代动力学。采用PK-Sim®10.0版建立匹伐他汀的全身PBPK模型。我们的药物基因组学数据和总共27个具有不同剂量给药和人口统计学特性的临床药代动力学数据用于开发和验证模型。分别。匹伐他汀的理化性质和处置特征是从先前报道的数据中获得的,或经过优化以捕获不同SLCO1B1二倍体型中的血浆浓度-时间曲线。通过将预测的药代动力学参数和曲线与观察到的数据进行比较来进行模型评估。预测的血浆浓度-时间曲线在视觉上类似于在非基因型群体和不同SLCO1B1二倍体中观察到的曲线。AUC和Cmax的所有倍数误差值包括在观察值的两倍范围内。因此,正确建立了匹伐他汀在不同SLCO1B1复型中的PBPK模型。本研究可用于在不同年龄的个体中个体化匹伐他汀的剂量给药策略。种族,和SLCO1B1二倍体。