费拉替尼生理药代动力学建模的进展:更新CYP3A4和CYP2C19双重抑制剂情况下的剂量指导。

IF 2.7 4区 医学 Q3 ONCOLOGY Cancer Chemotherapy and Pharmacology Pub Date : 2024-10-01 Epub Date: 2024-08-07 DOI:10.1007/s00280-024-04696-y
Ming Chang, Yizhe Chen, Ken Ogasawara, Brian James Schmidt, Lu Gaohua
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引用次数: 0

摘要

目的:对基于生理学的费拉替尼药代动力学(PBPK)模型进行了更新和重新验证,以弥补在健康参与者中观察到的单次亚有效剂量的药物相互作用(DDI)与癌症患者在稳定状态下的潜在DDI之间的差距。该研究旨在确定联合使用CYP3A4和CYP2C19双重抑制剂的患者服用非瑞替尼的适当剂量,为用药指导提供定量证据:使用 Simcyp® Simulator v17 开发了最初的最小 PBPK 模型。模型更新后,用两个独立的速率(CLin/CLout)取代了单一的分布速率(Qsac),并过渡到 v20。模型参数的更新进一步参考了 3 项临床研究,另外 3 项研究作为独立的验证数据。经过验证的模型被用于模拟非瑞替尼与一种已知的CYP3A4和CYP2C19双重抑制剂(氟康唑)之间潜在的DDI:结果:根据预测,患者在服用非瑞替尼的同时服用氟康唑会增加非瑞替尼的暴露量:更新后的PBPK模型改进了对所观察到的药代动力学的描述,并预测非瑞替尼与氟康唑之间发生临床重大DDI的风险较低。定量证据是临床实践中为非瑞替尼与CYP3A4和CYP2C19双重抑制剂联合用药提供剂量指导的主要依据。
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Advancements in physiologically based pharmacokinetic modeling for fedratinib: updating dose guidance in the presence of a dual inhibitor of CYP3A4 and CYP2C19.

Purpose: A physiologically based pharmacokinetic (PBPK) model for fedratinib was updated and revalidated to bridge a gap between the observed drug-drug interaction (DDI) of a single sub-efficacious dose in healthy participants and the potential DDI in patients with cancer at steady state. The study aimed to establish an appropriate dose for fedratinib in patients coadministered with dual CYP3A4 and CYP2C19 inhibitors, providing quantitative evidence to inform dosing guidance.

Methods: The original minimal PBPK model was developed using Simcyp® Simulator v17. The model was updated by substituting a single distribution rate (Qsac) with 2 separate rates (CLin/CLout) and transitioning to v20. Model parameter updates were further informed with 3 clinical studies, and 3 more studies served as independent validation data. The validated model was applied to simulate potential DDIs between fedratinib and a known dual inhibitor of CYP3A4 and CYP2C19 (fluconazole).

Results: Coadministration of fedratinib with fluconazole in patients was predicted to increase fedratinib exposure by < 2-fold in all simulated scenarios. For patients with cancer receiving the approved dose of fedratinib 400 mg once daily along with fluconazole 200 mg daily, the model predicted an approximate 50% increase in fedratinib exposure at steady state.

Conclusions: The updated PBPK model improved description of the observed pharmacokinetics and predicted a low risk of clinically significant DDIs between fedratinib and fluconazole. The quantitative evidence serves as a primary foundation for providing dose guidance in clinical practice for the coadministration of fedratinib with dual CYP3A4 and CYP2C19 inhibitors.

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来源期刊
CiteScore
6.10
自引率
3.30%
发文量
116
审稿时长
2.5 months
期刊介绍: Addressing a wide range of pharmacologic and oncologic concerns on both experimental and clinical levels, Cancer Chemotherapy and Pharmacology is an eminent journal in the field. The primary focus in this rapid publication medium is on new anticancer agents, their experimental screening, preclinical toxicology and pharmacology, single and combined drug administration modalities, and clinical phase I, II and III trials. It is essential reading for pharmacologists and oncologists giving results recorded in the following areas: clinical toxicology, pharmacokinetics, pharmacodynamics, drug interactions, and indications for chemotherapy in cancer treatment strategy.
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