Li R, Barton H A, Maurer T S
Systems Modeling and Simulation, Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide R&D, Cambridge, Massachusetts, USA.
Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide R&D, Groton, Connecticut, USA.
CPT Pharmacometrics Syst Pharmacol. 2014 Dec 10;3(12):e151. doi: 10.1038/psp.2014.50.
Physiologically based pharmacokinetic (PBPK) models are increasingly being used to provide human pharmacokinetic (PK) predictions for organic anion-transporting polypeptide (OATP) substrates based on in vitro assay data. As a natural extension in the application of these models, in this study, we incorporated in vitro information of three major OATP1B1 genetic variants into a previously reported PBPK model to predict the impact of OATP1B1 polymorphisms on human PK. Using pravastatin and rosuvastatin as examples, we showed that the predicted plasma concentration-time profiles in groups carrying different OATP1B1 genetic variants reasonably matched the clinical observations from multiple studies. This modeling and simulation approach may aid decision making in early pharmaceutical research and development as well as patient-specific dose adjustment in clinical practice.
基于生理的药代动力学（PBPK）模型越来越多地被用于根据体外试验数据提供有机阴离子转运多肽（OATP）底物的人体药代动力学（PK）预测。作为这些模型应用的自然延伸，在本研究中，我们将三种主要OATP1B1基因变体的体外信息纳入先前报道的PBPK模型，以预测OATP1B1多态性对人体PK的影响。以普伐他汀和瑞舒伐他汀为例，我们表明，携带不同OATP1B1基因变体的组中预测的血浆浓度-时间曲线与多项研究的临床观察结果合理匹配。这种建模和模拟方法可能有助于早期药物研发中的决策以及临床实践中针对患者的剂量调整。
