Wang Q, Zheng M, Leil T
Quantitative Clinical Pharmacology, Clinical Pharmacology and Pharmacometrics, Bristol-Myers Squibb, Princeton, New Jersey, USA.
CPT Pharmacometrics Syst Pharmacol. 2017 Apr;6(4):228-238. doi: 10.1002/psp4.12168. Epub 2017 Mar 13.
Rosuvastatin is a frequently used probe in transporter-mediated drug-drug interaction (DDI) studies. This report describes the development of a physiologically based pharmacokinetic (PBPK) model of rosuvastatin for prediction of pharmacokinetic (PK) DDIs. The rosuvastatin model predicted the observed single (i.v. and oral) and multiple dose PK profiles, as well as the impact of coadministration with transporter inhibitors. The predicted effects of rifampin and cyclosporine (6.58-fold and 5.07-fold increase in rosuvastatin area under the curve (AUC), respectively) were mediated primarily via inhibition of hepatic organic anion-transporting polypeptide (OATP)1B1 (Inhibition constant (K ) ∼1.1 and 0.014 µM, respectively) and OATP1B3 (K ∼0.3 and 0.007 µM, respectively), with cyclosporine also inhibiting intestinal breast cancer resistance protein (BCRP; K ∼0.07 µM). The predicted effects of gemfibrozil and its metabolite were moderate (1.88-fold increase in rosuvastatin AUC) and mediated primarily via inhibition of hepatic OATP1B1 and renal organic cation transporter 3. This model of rosuvastatin will be useful in prospectively predicting transporter-mediated DDIs with novel pharmaceutical agents in development.
瑞舒伐他汀是转运体介导的药物相互作用（DDI）研究中常用的探针。本报告描述了用于预测药代动力学（PK）DDI的瑞舒伐他汀的基于生理学的药代动力学（PBPK）模型的开发。瑞舒伐他汀模型预测了观察到的单次（静脉注射和口服）和多次给药的PK曲线，以及与转运体抑制剂合用的影响。利福平（分别使瑞舒伐他汀曲线下面积（AUC）增加6.58倍和5.07倍）和环孢素的预测效应主要通过抑制肝脏有机阴离子转运多肽（OATP）1B1（抑制常数（K）分别约为1.1和0.014 μM）和OATP1B3（K分别约为0.3和0.007 μM）介导，环孢素还抑制肠道乳腺癌耐药蛋白（BCRP；K约为0.07 μM）。吉非贝齐及其代谢物的预测效应中等（瑞舒伐他汀AUC增加1.88倍），主要通过抑制肝脏OATP1B1和肾脏有机阳离子转运体3介导。这种瑞舒伐他汀模型将有助于前瞻性地预测与正在开发的新型药物的转运体介导的DDI。
