Darwish Ibrahim A, Alzoman Nourah Z, Almomen Aliyah, Almehizia Abdulrahman A, Attwa Mohamed W, Darwish Hany W, Sayed Ahmed Y
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University P.O. Box 2457 Riyadh 11451 Saudi Arabia
RSC Adv. 2023 Mar 10;13(12):7929-7938. doi: 10.1039/d3ra00310h. eCollection 2023 Mar 8.
Duvelisib (DUV) is a new oral phosphoinositide-3-kinase (PI3K)-δ and PI3K-γ inhibitor. It is used for the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). This study describes the development and validation of a new highly sensitive and efficient UPLC-ESI-MS/MS method for quantitation of DUV in plasma samples and its application to the pharmacokinetic study of DUV in rats. The method employed a very simple step for plasma sample pretreatment precipitation of protein using methanol. DUV and ceritinib (CRB) as an internal standard (IS) were separated on a porous Hypersil BDS-C18 column (125 mm × 2 mm, 3 μm) using a mobile phase consisting of ammonium formate (10 mM, pH 4.2):acetonitrile (42 : 58, v/v), pumped isocratically at a flow rate of 0.3 mL min. DUV and CRB were eluted at 0.58 and 1.10 min, respectively. The mass spectrometric analysis was performed using an ESI in positive mode with multiple reaction monitoring (MRM). The technique was validated in accordance with the standards for validating bioanalytical methods established by the International Conference on Harmonization (ICH). The method's linear range was 5-500 ng mL, and its correlation coefficient was satisfactory as it is almost unity (0.9999). The limit of quantitation (LOQ) was 5 ng mL, while the limit of detection (LOD) was 1.7 ng mL. The recovery of the spiking DUV was between 94.95 and 102.21%, and the relative standard deviation (RSD) was less than 2.70%, confirming the method's accuracy and precision. The specificity/carryover of the method was proved. The robustness and ruggedness of the method was proved as the recovery values were 97.6-101.96% (±01.17-2.20%) and 98.74-102.00 (±1.18-4.02%) for robustness and ruggedness, respectively. The stability of DUV under the different analytical conditions were documented as the recovery values were in the range of 95.89-103.28% and the RSD values did not exceed 7.36%. The method was efficiently used to analyze DUV in human plasma samples that had been spiked with DUV and to conduct pharmacokinetic investigations of DUV in rats after giving them a single oral dosage of 25 mg kg of the drug. The methodology is distinguished by excellent sensitivity, accuracy, and ease of sample pretreatment. Furthermore, it is efficient and has a short run time, which makes it high throughput and accordingly enables faster processing of many samples in clinical laboratories.
度维利塞（DUV）是一种新型口服磷酸肌醇-3-激酶（PI3K）-δ和PI3K-γ抑制剂。它用于治疗复发或难治性慢性淋巴细胞白血病（CLL）和小淋巴细胞淋巴瘤（SLL）。本研究描述了一种用于定量血浆样品中DUV的新型高灵敏度和高效超高效液相色谱-电喷雾串联质谱（UPLC-ESI-MS/MS）方法的开发和验证及其在大鼠体内DUV药代动力学研究中的应用。该方法采用非常简单的血浆样品预处理步骤——用甲醇沉淀蛋白质。使用由甲酸铵（10 mM，pH 4.2）：乙腈（42 : 58，v/v）组成的流动相，以0.3 mL/min的流速等度泵入，在多孔Hypersil BDS-C18柱（125 mm×2 mm，3 μm）上分离DUV和作为内标（IS）的色瑞替尼（CRB）。DUV和CRB分别在0.58和1.10分钟洗脱。使用电喷雾正离子模式和多反应监测（MRM）进行质谱分析。该技术根据国际协调会议（ICH）制定的生物分析方法验证标准进行了验证。该方法的线性范围为5-500 ng/mL，其相关系数令人满意，几乎为1（0.9999）。定量限（LOQ）为5 ng/mL，而检测限（LOD）为1.7 ng/mL。加标DUV的回收率在94.95%至102.21%之间，相对标准偏差（RSD）小于2.70%，证实了该方法的准确性和精密度。证明了该方法的特异性/残留。该方法的稳健性和耐用性得到了证明，稳健性和耐用性的回收率分别为97.6-101.96%（±01.17-2.20%）和98.74-102.（±1.18-4.02%）。记录了DUV在不同分析条件下的稳定性，回收率在95.89-103.28%范围内，RSD值不超过7.36%。该方法有效地用于分析添加了DUV的人血浆样品，并在给大鼠单次口服25 mg/kg药物后进行DUV的药代动力学研究。该方法的特点是灵敏度高、准确性好且样品预处理简便。此外，它效率高且运行时间短，具有高通量，因此能够在临床实验室中更快地处理许多样品。
