Abstract：
Physiologically-based pharmacokinetic (PBPK) models have an important role in drug discovery/development and decision making in regulatory submissions. This is facilitated by predefined PBPK platforms with user-friendly graphical interface, such as Simcyp and PK-Sim. However, evaluations of platform differences and the potential implications for disposition-related applications are still lacking. The aim of this study was to assess how PBPK model development, input parameters, and model output are affected by the selection of PBPK platform. This is exemplified via the establishment of simvastatin PBPK models (workflow, final models, and output) in PK-Sim and Simcyp as representatives of established whole-body PBPK platforms. The major finding was that the choice of PBPK platform influenced the model development strategy and the final model input parameters, however, the predictive performance of the simvastatin models was still comparable between the platforms. The main differences between the structure and implementation of Simcyp and PK-Sim were found in the absorption and distribution models. Both platforms predicted equally well the observed simvastatin (lactone and acid) pharmacokinetics (20-80 mg), BCRP and OATP1B1 drug-gene interactions (DGIs), and drug-drug interactions (DDIs) when co-administered with CYP3A4 and OATP1B1 inhibitors/inducers. This study illustrates that in-depth knowledge of established PBPK platforms is needed to enable an assessment of the consequences of PBPK platform selection. Specifically, this work provides insights on software differences and potential implications when bridging PBPK knowledge between Simcyp and PK-Sim users. Finally, it provides a simvastatin model implemented in both platforms for risk assessment of metabolism- and transporter-mediated DGIs and DDIs.
摘要：
基于生理的药代动力学（PBPK）模型在药物发现/开发和监管提交决策中具有重要作用。这是促进预定义的PBPK平台与用户友好的图形界面，如Simcyp和PK-Sim。然而,仍然缺乏对平台差异和对处置相关应用程序的潜在影响的评估。这项研究的目的是评估PBPK模型的开发，输入参数，和模型输出受PBPK平台选择的影响。这是通过建立辛伐他汀PBPK模型(工作流程，最终模型，和输出）在PK-Sim和Simcyp中作为已建立的全身PBPK平台的代表。主要发现PBPK平台的选择影响了模型开发策略和最终模型输入参数,然而,辛伐他汀模型的预测性能在两个平台之间仍具有可比性.Simcyp和PK-Sim的结构和实现之间的主要区别在于吸收和分布模型。两个平台同样预测观察到的辛伐他汀（内酯和酸）药代动力学（20-80毫克），BCRP和OATP1B1药物-基因相互作用（DGI），以及与CYP3A4和OATP1B1抑制剂/诱导剂共同施用时的药物-药物相互作用（DDI）。这项研究表明，需要深入了解已建立的PBPK平台，以评估PBPK平台选择的后果。具体来说,这项工作提供了有关在Simcyp和PK-Sim用户之间桥接PBPK知识时的软件差异和潜在含义的见解。最后,它提供了在两个平台中实施的辛伐他汀模型,用于代谢和转运蛋白介导的DGI和DDI的风险评估.
