Establishment and Validation of a UPLC-MS/MS Method for Quantitative Determination of Zanubrutinib and Posaconazole in Rat Plasma: Application in Drug-Drug Interaction Studies.

IF 5.1 2区医学 Q1 CHEMISTRY, MEDICINAL

Drug Design, Development and Therapy Pub Date : 2025-09-09 eCollection Date: 2025-01-01 DOI:10.2147/DDDT.S531381

Hailun Xia, Yuxin Shen, Xinhao Xu, Jun Wu, Guanyang Lin, Xiaoxiang Du

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引用次数: 0

Abstract

Purpose: Zanubrutinib, a second-generation Bruton's tyrosine kinase (BTK) inhibitor, has been demonstrated to treat multiple B-cell malignancies, which include Waldenström's macroglobulinemia, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma and mantle cell lymphoma (MCL). There have been very few studies of drug-drug interactions (DDI) between zanubrutinib and other medications.

Methods: The current study validated a sensitive and reliable quantitative detection of zanubrutinib and posaconazole in rat plasma using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The plasma samples were prepared by protein precipitation with the addition of acetonitrile, using orelabrutinib and fluconazole as internal standards (IS). Fifteen male Sprague-Dawley (SD) rats were randomly and equally divided into three groups: posaconazole (40 mg/kg) administered orally alone, zanubrutinib (16 mg/kg) received orally alone, co-administered orally zanubrutinib (16 mg/kg) and posaconazole (40 mg/kg).

Results: The methodology was validated, and the precision, stability, accuracy, matrix effect and extraction recovery were within the permissible values. This method was successfully applied to evaluate the potential DDI between zanubrutinib and posaconazole, and the results showed a significant 0.98-fold increase in both AUC_0-t and AUC_0-∞ of zanubrutinib when zanubrutinib was administered concomitantly with posaconazole. In addition, posaconazole significantly increased AUC_0-t, AUC_0-∞, T_max, and C_max of zanubrutinib by 2.31-, 4.78-, 2.93-, and 0.86-fold, respectively, while CL_z/F significantly decreased by 83.5%.

Conclusion: These data suggested that when zanubrutinib was co-administered with posaconazole, there are increased exposures to both zanubrutinib and posaconazole. The current results contributed to a better understanding of the metabolism and DDI of zanubrutinib and posaconazole, and it is necessary to further investigate and validate the results in humans.

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大鼠血浆中扎鲁替尼和泊沙康唑的UPLC-MS/MS定量测定方法的建立与验证：在药物相互作用研究中的应用

目的：Zanubrutinib是第二代布鲁顿酪氨酸激酶（BTK）抑制剂，已被证明可治疗多种b细胞恶性肿瘤，包括Waldenström的巨球蛋白血症、慢性淋巴细胞白血病（CLL）、小淋巴细胞淋巴瘤和套细胞淋巴瘤（MCL）。很少有关于扎鲁替尼和其他药物之间药物相互作用（DDI）的研究。方法：采用超高效液相色谱-串联质谱法（UPLC-MS/MS）对大鼠血浆中扎鲁替尼和泊沙康唑进行了灵敏、可靠的定量检测。血浆样品以奥瑞布替尼和氟康唑为内标，加入乙腈进行蛋白沉淀制备。选取雄性SD大鼠15只，随机等分3组：泊沙康唑（40 mg/kg）单独口服，扎鲁替尼（16 mg/kg）单独口服，扎鲁替尼（16 mg/kg）和泊沙康唑（40 mg/kg）联合口服。结果：方法经验证，精密度、稳定性、准确度、基质效应、提取回收率均在允许范围内。该方法成功地评价了扎鲁替尼与泊沙康唑之间的潜在DDI，结果表明，扎鲁替尼与泊沙康唑合用时，扎鲁替尼的AUC0-t和AUC0-∞均显著增加0.98倍。泊沙康唑显著提高zanubrutinib的AUC0-t、AUC0-∞、Tmax和Cmax分别提高2.31倍、4.78倍、2.93倍和0.86倍，CLz/F显著降低83.5%。结论：这些数据表明，当扎鲁替尼与泊沙康唑合用时，扎鲁替尼和泊沙康唑的暴露量均增加。目前的结果有助于更好地了解扎鲁替尼和泊沙康唑的代谢和DDI，有必要进一步研究和验证人体结果。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.