系统开发和验证利伐沙班的基于生理学的药代动力学模型。
Systematic Development and Verification of a Physiologically Based Pharmacokinetic Model of Rivaroxaban.
机构信息
Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore (E.J.Y.C., D.W.X.T., D.X.Y.C., E.C.Y.C.); and National University Cancer Institute, National University Hospital Medical Centre, Singapore, Singapore (E.C.Y.C.).
Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore (E.J.Y.C., D.W.X.T., D.X.Y.C., E.C.Y.C.); and National University Cancer Institute, National University Hospital Medical Centre, Singapore, Singapore (E.C.Y.C.)
出版信息
Drug Metab Dispos. 2019 Nov;47(11):1291-1306. doi: 10.1124/dmd.119.086918. Epub 2019 Sep 10.
Rivaroxaban is indicated for stroke prevention in nonvalvular atrial fibrillation (AF). Its elimination is mediated by both hepatic metabolism and renal excretion. Consequently, its clearance is susceptible to both intrinsic (pathophysiological) and extrinsic (concomitant drugs) variabilities that in turn implicate bleeding risks. Upon systematic model verification, physiologically based pharmacokinetic (PBPK) models are qualified for the quantitative rationalization of complex drug-drug-disease interactions (DDDIs). Hence, this study aimed to develop and verify a PBPK model of rivaroxaban systematically. Key parameters required to define rivaroxaban's disposition were either obtained from in vivo data or generated via in vitro metabolism and transport kinetic assays. Our developed PBPK model successfully predicted rivaroxaban's clinical pharmacokinetic parameters within predefined success metrics. Consideration of basolateral organic anion transporter 3 (OAT3)-mediated proximal tubular uptake in tandem with apical P-glycoprotein (P-gp)-mediated efflux facilitated mechanistic characterization of the renal elimination of rivaroxaban in both healthy and renal impaired patients. Retrospective drug-drug interaction (DDI) simulations, incorporating in vitro metabolic inhibitory parameters, accurately recapitulated clinically observed attenuation of rivaroxaban's hepatic clearance due to enzyme-mediated DDIs with CYP3A4/2J2 inhibitors (verapamil and ketoconazole). Notably, transporter-mediated DDI simulations between rivaroxaban and the P-gp inhibitor ketoconazole yielded minimal increases in rivaroxaban's systemic exposure when P-gp-mediated efflux was solely inhibited, but were successfully characterized when concomitant basolateral uptake inhibition was incorporated in the simulation. In conclusion, our developed PBPK model of rivaroxaban is systematically verified for prospective interrogation and management of untested yet clinically relevant DDDIs pertinent to AF management using rivaroxaban. SIGNIFICANCE STATEMENT: Rivaroxaban is susceptible to DDDIs comprising renal impairment and P-gp and CYP3A4/2J2 inhibition. Here, systematic construction and verification of a PBPK model of rivaroxaban, with the inclusion of a mechanistic kidney component, provided insight into the previously arcane role of OAT3-mediated basolateral uptake in influencing both clinically observed renal elimination of rivaroxaban and differential extents of transporter-mediated DDIs. The verified model holds potential for investigating clinically relevant DDDIs involving rivaroxaban and designing dosing adjustments to optimize its pharmacotherapy in atrial fibrillation.
利伐沙班用于预防非瓣膜性心房颤动（AF）的中风。其消除受肝代谢和肾排泄的双重介导。因此，其清除易受内在（生理病理）和外在（伴随药物）变异性的影响，进而暗示出血风险。经过系统的模型验证，基于生理学的药代动力学（PBPK）模型能够对复杂的药物-药物-疾病相互作用（DDDIs）进行定量合理化。因此，本研究旨在系统地开发和验证利伐沙班的 PBPK 模型。定义利伐沙班处置所需的关键参数要么从体内数据中获得，要么通过体外代谢和转运动力学测定产生。我们开发的 PBPK 模型成功地在预定的成功指标内预测了利伐沙班的临床药代动力学参数。考虑到基底外侧有机阴离子转运蛋白 3（OAT3）介导的近端肾小管摄取与顶端 P-糖蛋白（P-gp）介导的外排相结合，有助于对健康和肾功能受损患者中利伐沙班的肾脏消除进行机制描述。回顾性药物相互作用（DDI）模拟，纳入体外代谢抑制参数，准确再现了由于酶介导的与 CYP3A4/2J2 抑制剂（维拉帕米和酮康唑）的 DDI 导致的利伐沙班肝清除率的临床观察到的衰减。值得注意的是，当仅抑制 P-gp 介导的外排时，利伐沙班与 P-gp 抑制剂酮康唑之间的转运体介导的 DDI 模拟导致利伐沙班的全身暴露增加最小，但当在模拟中纳入共基底外侧摄取抑制时，成功地对其进行了特征描述。总之，我们开发的利伐沙班 PBPK 模型经过系统验证，可用于前瞻性探究和管理与使用利伐沙班治疗 AF 相关的未测试但具有临床相关性的 DDDI。意义陈述：利伐沙班易受包括肾功能不全、P-gp 和 CYP3A4/2J2 抑制在内的 DDDI 的影响。在这里，利伐沙班的 PBPK 模型的系统构建和验证，包括一个机制性的肾脏组件，深入了解了 OAT3 介导的基底外侧摄取对影响利伐沙班的临床观察到的肾脏消除和不同程度的转运体介导的 DDI 的以前未知的作用。经验证的模型有可能用于研究涉及利伐沙班的临床相关 DDDI，并设计剂量调整以优化其在心房颤动中的药物治疗。
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