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首页> 外文OA文献 >USING SEMIPHYSIOLOGICALLY-BASED PHARMACOKINETIC (SEMI-PBPK) MODELING TO EXPLORE THE IMPACT OF DIFFERENCES BETWEEN THE INTRAVENOUS (IV) AND ORAL (PO) ROUTE OF ADMINISTRATION ON THE MAGNITUDE AND TIME COURSE OF CYP3A-MEDIATED METABOLIC DRUG-DRUG INTERACTIONS (DDI) USING MIDAZOLAM (MDZ) AS PROTOTYPICAL SUBSTRATE AND FLUCONAZOLE (FLZ) AND ERYTHROMYCIN (ERY) AS PROTOTYPICAL INHIBITORS
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USING SEMIPHYSIOLOGICALLY-BASED PHARMACOKINETIC (SEMI-PBPK) MODELING TO EXPLORE THE IMPACT OF DIFFERENCES BETWEEN THE INTRAVENOUS (IV) AND ORAL (PO) ROUTE OF ADMINISTRATION ON THE MAGNITUDE AND TIME COURSE OF CYP3A-MEDIATED METABOLIC DRUG-DRUG INTERACTIONS (DDI) USING MIDAZOLAM (MDZ) AS PROTOTYPICAL SUBSTRATE AND FLUCONAZOLE (FLZ) AND ERYTHROMYCIN (ERY) AS PROTOTYPICAL INHIBITORS

机译：使用基于半生理学的药代动力学（SEMI-PBPK）模型来探讨静脉（IV）和口服（PO）给药途径对经CYP3A药物代谢药物治疗（药物）的幅度和时间过程的影响咪达唑仑（MDZ）作为原型基质，氟康唑（FLZ）和红霉素（ERY）作为原型抑制剂

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The purpose of the project was to investigate the impact of IV and PO routes difference for MDZ, a prototypical CYP3A substrate, and two CYP3A inhibitors (CYP3AI) -FLZ and ERY-, on the magnitude and time course of their inhibitory metabolic DDI.Individual semi-PBPK models for MDZ, FLZ and ERY were developed and validated separately, using pharmacokinetic (PK) parameters from clinical/in-vitro studies and published physiological parameters. Subsequently, DDI sub-models between MDZ and CYP3AIs incorporated non-competitive and mechanism-based inhibition (MBI) for FLZ and ERY, respectively, on hepatic and gut wall (GW) CYP3A metabolism of MDZ, using available in-vitro/in-vivo information. Model-simulated MDZ PK profiles were compared with observed data from available clinical PK and DDI studies, by visual predictive check and exposure metrics comparison. DDI magnitude and time course for CYP3AI (IV vs. PO) followed by MDZ (IV vs. PO) at various time points were predicted by the validated semi-PBPK-DDI models. Two hypothetical CYP3A substrates and four CYP3AI (derived from MDZ, FLZ and ERY, with GW metabolism removed, hepatic metabolism reduced, or oral bioavailability (Foral) and/or elimination half-life (t1/2) modified) were also simulated to generalize conclusions.The final semi-PBPK-DDI models predict well the PK profiles for IV/PO MDZ in absence/presence of IV/PO CYP3AI, with deviations between model-predicted and observed exposure metrics within 30%. Prospective simulations demonstrate that:1) CYP3A substrates, e.g., MDZ, are consistently more sensitive to metabolic inhibition after PO than after IV administration, due to pre-systemic hepatic and/or GW metabolism. For substrates without GW metabolism and limited hepatic metabolism, only a marginal route difference for substrate administration is observed.2) For high-Foral CYP3AIs, e.g., FLZ, no inhibitor IV-PO route DDI differences are expected, unless they are given simultaneously with PO MDZ.3) For low-Foral CYP3AIs, e.g., ERY, greater inhibition is expected after IV than after PO administration for IV MDZ, but is difficult to predict for PO MDZ.4) In addition to Foral and plasma t1/2 of CYP3AIs, the DDI onset, peak and duration are determined by their oral absorption rate and by the resulting hepatic and/or GW concentration profiles relative to Ki for noncompetitive CYP3AIs, but by CYP3A kinetics (synthesis, degradation rate) for MBI CYP3AIs.
机译：该项目的目的是研究IV和PO途径差异对MDZ（一种典型的CYP3A底物）和两种CYP3A抑制剂（CYP3AI）（FLZ和ERY-）的抑制作用及其对代谢DDI的影响。使用来自临床/体外研究的药代动力学（PK）参数以及已发布的生理参数，分别开发和验证了MDZ，FLZ和ERY的半PBPK模型。随后，使用可用的体外/体内/体外方法，MDZ和CYP3AI之间的DDI子模型分别对FLZ和ERY进行了非竞争性和基于机制的FLZ和ERY抑制（MBI），对MDZ的肝和肠壁（GW）CYP3A代谢进行了合并。体内信息。通过视觉预测检查和暴露指标比较，将模型模拟的MDZ PK配置文件与来自可用临床PK和DDI研究的观察数据进行比较。通过已验证的准PBPK-DDI模型预测了CYP3AI的DDI量级和时程（IV与PO），随后是MDZ（IV与PO）。还模拟了两种假设的CYP3A底物和四种CYP3AI（分别来自MDZ，FLZ和ERY，去除了GW代谢，降低了肝代谢，或修改了口服生物利用度（Foral）和/或消除了半衰期（t1 / 2））进行概括。结论。最终的半PBPK-DDI模型可以在不存在/存在IV / PO CYP3AI的情况下很好地预测IV / PO MDZ的PK曲线，模型预测的暴露指标与观察到的暴露指标之间的偏差在30％以内。前瞻性模拟表明：1）由于全身性肝和/或GW代谢，CYP3A底物（例如MDZ）始终比IV给药后对PO后的代谢抑制更敏感。对于没有GW代谢和肝代谢受限的底物，仅观察到底物给药的边际途径差异.2）对于高Foral CYP3AIs，例如FLZ，除非与CYP3AIs同时给予，否则预期没有抑制剂IV-PO途径DDI差异PO MDZ.3）对于低剂量的CYP3AIs，例如ERY，预期IV给药后静脉给药后比IV给药后给予更大的抑制作用，但难以预测PO MDZ.4）除Foral和血浆t1 / 2外CYP3AIs，DDI的起效，峰值和持续时间取决于口服吸收率以及非竞争性CYP3AIs相对于Ki的最终肝脏和/或GW浓度分布，但取决于MBI CYP3AIs的CYP3A动力学（合成，降解率）。

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    Li Mengyao;

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