骨髓移植后他克莫司与 CYP3A4 抑制剂伏立康唑和克拉霉素联合用药的药物相互作用药代动力学模型

IF 1.9 4区医学 Q3 PHARMACOLOGY & PHARMACY European Journal of Drug Metabolism and Pharmacokinetics Pub Date : 2024-09-24 DOI:10.1007/s13318-024-00915-2

Toshinori Hirai, Takahiko Aoyama, Yasuhiro Tsuji, Kazuko Ino, Makoto Ikejiri, Isao Tawara, Takuya Iwamoto

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引用次数: 0

摘要

背景和目的：根据 CYP3A5 和 CYP2C19 基因型，建立了一个药代动力学模型来量化他克莫司与伏立康唑和克拉霉素对细胞色素 P450 (CYP) 3A4 浓度依赖性抑制的药物相互作用：这项回顾性研究招募了接受口服他克莫司同时服用伏立康唑和克拉霉素的非亲属骨髓移植受者。整合了已发表的人群药代动力学模型，该模型包含了 CYP3A5（他克莫司）和 CYP2C19（伏立康唑）的基因型。测试的 CYP3A4 抑制模型（Sigmoid 药效最大值[Emax]、Emax、对数线性和线性）是伏立康唑的竞争性抑制和克拉霉素在虚拟酶区的机制性抑制的函数：他克莫司的总谷浓度为 119 点，中位数为 4.3（范围：2.0-9.9）纳克/毫升（n = 3）。最终模型包括伏立康唑和克拉霉素的Sigmoid Emax模型，该模型描述了服用伏立康唑和克拉霉素时他克莫司浓度和清除率的时程变化：这些发现有助于在非亲缘骨髓移植后根据模型精确使用他克莫司。

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Pharmacokinetic Model of Drug Interaction of Tacrolimus with Combined Administration of CYP3A4 Inhibitors Voriconazole and Clarithromycin After Bone Marrow Transplantation.

Background and objectives: A pharmacokinetic model has been developed to quantify the drug-drug interactions of tacrolimus with concentration-dependent inhibition of cytochrome P450 (CYP) 3A4 from voriconazole and clarithromycin based on the CYP3A5 and CYP2C19 genotypes.

Methods: This retrospective study recruited unrelated bone marrow transplant recipients receiving oral tacrolimus concomitantly with voriconazole and clarithromycin. The published population pharmacokinetic model that implemented genotypes of CYP3A5 (tacrolimus) and CYP2C19 (voriconazole) was integrated. The tested CYP3A4 inhibition models (Sigmoid efficacy maximum [E_max], E_max, log-linear, and linear) were a function of competitive inhibition of voriconazole and mechanism-based inhibition of clarithromycin in a virtual enzyme compartment.

Results: The total tacrolimus trough concentrations were 119 points, with a median of 4.3 (range: 2.0-9.9) ng/mL (n = 3). The final model comprised the Sigmoid E_max model for voriconazole and clarithromycin, which depicted time-course alterations in tacrolimus concentration and clearance when given voriconazole and clarithromycin.

Conclusions: These findings could facilitate the model-informed precision dosing of tacrolimus after unrelated bone marrow transplant.

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来源期刊

European Journal of Drug Metabolism and Pharmacokinetics 医学-药学

CiteScore

3.70

自引率

0.00%

发文量

审稿时长

>12 weeks

期刊介绍： Hepatology International is a peer-reviewed journal featuring articles written by clinicians, clinical researchers and basic scientists is dedicated to research and patient care issues in hepatology. This journal focuses mainly on new and emerging diagnostic and treatment options, protocols and molecular and cellular basis of disease pathogenesis, new technologies, in liver and biliary sciences. Hepatology International publishes original research articles related to clinical care and basic research; review articles; consensus guidelines for diagnosis and treatment; invited editorials, and controversies in contemporary issues. The journal does not publish case reports.