Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia.
Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia.
Cancer Chemother Pharmacol. 2024 Nov;94(5):747-761. doi: 10.1007/s00280-024-04715-y. Epub 2024 Sep 11.
Ruxolitinib (RUX), a Janus kinase 2 (JAK2) inhibitor, and lenalidomide (LEN), an immunomodulatory agent, have recently been proposed as a combined treatment for myelofibrosis (MF). This combination has demonstrated improved efficacy, safety, and tolerability compared to monotherapy. To further refine these findings, an efficient analytical tool is needed to simultaneously determine RUX and LEN concentrations in blood plasma. This tool would enable the study of their pharmacokinetics, drug-drug interactions, and therapeutic monitoring during MF therapy. Unfortunately, such a method has not been existed in the literature. This study presents the first HPLC method with UV detection for the simultaneous quantitation of RUX and LEN in plasma. The method was validated according to the ICH guidelines for bioanalytical method validation. It exhibited linearity in the concentration ranges of 10 to 3150 ng mL for RUX and 80 to 5200 ng mL for LEN. The limits of quantitation were determined to be 25 and 90 ng mL for RUX and LEN, respectively. All other validation parameters were satisfactory. The HPLC-UV method was successfully employed to study the pharmacokinetics and drug-drug interactions of RUX and LEN in rats following oral administration of single doses. The results demonstrated that the pharmacokinetics of both drugs were changed substantially by their coadministration. LEN exhibited synergistic effects on the maximum plasma concentration (C) and total bioavailability of RUX, meanwhile it exhibited diminishing effect on the values of volume of distribution (Vd) and clearance (CL). Additionally, RUX decreased the C and total bioavailability of LEN, meanwhile it increased its Vd and CL. These data suggest that the use of RUX, as a combination with LEN, is a better therapeutic approach for MF, compared with RUX as a monotherapy. The effects of LEN on the pharmacokinetics of RUX should be considered and can be useful in determining the appropriate RUX dosage and dosing regimen to achieve the desired therapeutic effect when used as a combination therapy with LEN. The method's environmental friendliness was confirmed through three comprehensive tools. This method represents a valuable tool for determining the appropriate dosage and dosing regimen of RUX in combination therapy with LEN to achieve the desired therapeutic effect. Furthermore, it can aid in predicting drug distribution in different patients and assessing the drug accumulation or insufficient drug levels in specific body compartments.
芦可替尼（RUX）是一种 Janus 激酶 2（JAK2）抑制剂，来那度胺（LEN）是一种免疫调节剂，最近被提议联合用于治疗骨髓纤维化（MF）。与单药治疗相比，这种联合治疗显示出更好的疗效、安全性和耐受性。为了进一步完善这些发现，需要一种有效的分析工具来同时测定血浆中 RUX 和 LEN 的浓度。该工具将能够研究它们在 MF 治疗期间的药代动力学、药物相互作用和治疗监测。不幸的是，这种方法在文献中尚未存在。本研究首次提出了一种 HPLC 方法，并用 UV 检测法同时定量血浆中的 RUX 和 LEN。该方法根据 ICH 生物分析方法验证指南进行了验证。它在 RUX 的浓度范围为 10 至 3150ng mL 和 LEN 的浓度范围为 80 至 5200ng mL 时表现出线性。RUX 和 LEN 的定量限分别确定为 25 和 90ng mL。所有其他验证参数均令人满意。HPLC-UV 方法成功地用于研究大鼠单次口服给予 RUX 和 LEN 后它们的药代动力学和药物相互作用。结果表明，两种药物的药代动力学均因联合用药而发生显著变化。LEN 对 RUX 的最大血浆浓度（C）和总生物利用度表现出协同作用，同时对分布容积（Vd）和清除率（CL）的值表现出减弱作用。此外，RUX 降低了 LEN 的 C 和总生物利用度，同时增加了其 Vd 和 CL。这些数据表明，与 RUX 单药治疗相比，RUX 与 LEN 联合使用是 MF 的更好治疗方法。应该考虑 LEN 对 RUX 药代动力学的影响，这对于确定与 LEN 联合治疗时适当的 RUX 剂量和给药方案以达到所需的治疗效果可能会很有用。该方法的环保性通过三种综合工具得到了确认。该方法代表了一种有价值的工具，可用于确定与 LEN 联合治疗时 RUX 的适当剂量和给药方案，以达到所需的治疗效果。此外，它可以帮助预测不同患者体内的药物分布，并评估特定身体部位的药物蓄积或药物水平不足。
