Abstract:
Warfarin is a widely used anticoagulant, and its S-enantiomer has higher potency compared to the R-enantiomer. S-warfarin is mainly metabolized by cytochrome P450 (CYP) 2C9, and its pharmacological target is vitamin K epoxide reductase complex subunit 1 (VKORC1). Both CYP2C9 and VKORC1 have genetic polymorphisms, leading to large variations in the pharmacokinetics (PKs) and pharmacodynamics (PDs) of warfarin in the population. This makes dosage management of warfarin difficult, especially in the case of drug-drug interactions (DDIs). This study provides a whole-body physiologically-based pharmacokinetic/PD (PBPK/PD) model of S-warfarin for predicting the effects of drug-drug-gene interactions on S-warfarin PKs and PDs. The PBPK/PD model of S-warfarin was developed in PK-Sim and MoBi. Drug-dependent parameters were obtained from the literature or optimized. Of the 34 S-warfarin plasma concentration-time profiles used, 96% predicted plasma concentrations within twofold range compared to observed data. For S-warfarin plasma concentration-time profiles with CYP2C9 genotype, 364 of 386 predicted plasma concentration values (~94%) fell within the twofold of the observed values. This model was tested in DDI predictions with fluconazole as CYP2C9 perpetrators, with all predicted DDI area under the plasma concentration-time curve to the last measurable timepoint (AUClast) ratio within twofold of the observed values. The anticoagulant effect of S-warfarin was described using an indirect response model, with all predicted international normalized ratio (INR) within twofold of the observed values. This model also incorporates a dose-adjustment method that can be used for dose adjustment and predict INR when warfarin is used in combination with CYP2C9 perpetrators.
摘要:
华法林是一种广泛使用的抗凝剂,并且其S-对映体与R-对映体相比具有更高的效力。S-华法林主要由细胞色素P450(CYP)2C9代谢,其药理靶标是维生素K环氧化物还原酶复合物亚基1(VKORC1)。CYP2C9和VKORC1均具有遗传多态性,导致人群中华法林的药代动力学(PKs)和药效学(PDs)差异很大。这使得华法林的剂量管理变得困难,特别是在药物-药物相互作用(DDI)的情况下。本研究提供了S-华法林的基于生理的全身药代动力学/PD(PBPK/PD)模型,用于预测药物-药物-基因相互作用对S-华法林PKs和PDs的影响。在PK-Sim和MoBi中建立了S-华法林的PBPK/PD模型。药物依赖性参数从文献中获得或优化。在使用的34个S-华法林血浆浓度-时间曲线中,与观察到的数据相比,96%的预测血浆浓度在两倍范围内。对于具有CYP2C9基因型的S-华法林血浆浓度-时间曲线,386个预测血浆浓度值中的364个(〜94%)落在观察值的两倍之内。该模型在DDI预测中进行了测试,以氟康唑为CYP2C9肇事者,血浆浓度-时间曲线下所有预测的DDI面积与最后可测量时间点(AUClast)的比率在观察值的两倍内。使用间接反应模型描述S-华法林的抗凝血作用,所有预测的国际标准化比率(INR)都在观测值的两倍以内。该模型还结合了剂量调整方法,该方法可用于剂量调整,并在华法林与CYP2C9肇事者联合使用时预测INR。