为连续静脉灌注选择最佳稳态他克莫司浓度的指导:基于生理学的药代动力学模型的启示

Pharmaceuticals Pub Date : 2024-08-08 DOI:10.3390/ph17081047
Romain Martischang, Argyro Nikolaou, Youssef Daali, C. Samer, Jean Terrier
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引用次数: 0

摘要

介绍:他克莫司的剂量-反应关系主要通过间歇给药期间的谷浓度进行评估。在口服给药不可行的情况下,建议连续静脉给药。在这种情况下,只能测量血浆或血液的稳态浓度(Css),而没有明显的谷值浓度(Cmin)。因此,所测得的浓度经常被误认为是谷浓度,可能导致他克莫司的真实血药浓度低于治疗水平。本研究采用基于生理学的药代动力学模型(PBPK)来确定他克莫司在各种临床情况下的 Css/Cmin 比值。方法:使用经过验证的 PBPK 模型,估算了在不同条件下他克莫司的剂量(包括 PO 和 IV)和与剂量间隔期间血药浓度-时间曲线下面积(AUCτ)值相匹配的 Css/Cmin 比值,包括健康受试者和表现出细胞色素 P450 3A (CYP3A) 相互作用或 CYP3A5 多态性的个体,并演示了实际临床应用。结果在健康志愿者中,口服/静脉注射(PO/IV)剂量比为 4.25,Css/Cmin 比为 1.40。一个具体的临床病例证实了 PBPK 模拟的 Css/Cmin 比值的实际应用性,表明移植手术没有出现直接的临床并发症。当考虑到肝脏供体与表达 CYP3A5 的受体时,他克莫司的 AUCτ 会受到明显影响,PO/IV 剂量比为 4.00,Css/Cmin 比为 1.75。此外,同时服用 CYP3A 抑制剂伊曲康唑(itraconazole),PO/IV 剂量比为 1.75,Css/Cmin 比为 1.28。值得注意的是,静脉注射伊曲康唑时,其抑制作用会减弱。结论通过应用 PBPK 方法,本研究估算出了 PO/IV 剂量比和 Css/Cmin 比,可在移植患者静脉注射和 PO 给药切换期间加强剂量调整和治疗药物监测,最终指导临床医生做出实时决策。建议进一步利用体内数据进行验证,以支持这些发现。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Guidance on Selecting Optimal Steady-State Tacrolimus Concentrations for Continuous IV Perfusion: Insights from Physiologically Based Pharmacokinetic Modeling
Introduction: The dose–response relationships of tacrolimus have been primarily assessed through trough concentrations during intermittent administrations. In scenarios where oral administration (PO) is unfeasible, continuous intravenous (IV) administration is advised. Under these circumstances, only steady-state (Css) plasma or blood concentrations are measured, with the absence of distinct trough levels (Cmin). Consequently, the measured concentrations are frequently misinterpreted as trough concentrations, potentially resulting in sub-therapeutic true tacrolimus blood levels. This study employs physiologically based pharmacokinetic modeling (PBPK) to establish the Css/Cmin ratio for tacrolimus across various clinical scenarios. Method: Using a validated PBPK model, the tacrolimus dose (both PO and IV) and the Css/Cmin ratios corresponding to matching area under the blood concentration–time curve during a dosage interval (AUCτ) values were estimated under different conditions, including healthy subjects and individuals exhibiting cytochrome P450 3A (CYP3A) interactions or CYP3A5 polymorphisms, along with a demonstration of a real-life clinical application. Result: In healthy volunteers, the oral/intravenous (PO/IV) dose ratio was found to be 4.25, and the Css/Cmin ratio was 1.40. A specific clinical case substantiated the practical applicability of the Css/Cmin ratio as simulated by PBPK, demonstrating no immediate clinical complications related to the transplant. When considering liver donors versus recipients expressing CYP3A5, the tacrolimus AUCτ was notably affected, yielding a PO/IV dose ratio of 4.00 and a Css/Cmin ratio of 1.75. Furthermore, the concomitant administration of the CYP3A inhibitor itraconazole given PO resulted in a PO/IV ratio of 1.75 with and a Css/Cmin ratio of 1.28. Notably, the inhibitory effect of itraconazole was diminished when administered IV. Conclusions: Through the application of PBPK methodologies, this study estimates the PO/IV dose ratios and Css/Cmin ratios that can enhance dose adjustment and therapeutic drug monitoring during the switch between IV and PO administration of tacrolimus in transplant patients, ultimately guiding clinicians in real-time decision-making. Further validation with in vivo data is recommended to support these findings.
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