Background and Objective

Ruxolitinib is a tyrosine kinase inhibitor targeting the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways. Ruxolitinib is used to treat myelofibrosis, polycythemia vera and steroid-refractory graft-versus-host disease in the setting of allogeneic stem-cell transplantation. This review describes the pharmacokinetics and pharmacodynamics of ruxolitinib.

Methods

Pubmed, EMBASE, Cochrane Library and web of Science were searched from the time of database inception to march 15, 2021 and was repeated on November 16, 2021. Articles not written in English, animal or in vitro studies, letters to the editor, case reports, where ruxolitinib was not used for hematological diseases or not available as full text were excluded.

Results

Ruxolitinib is well absorbed, has 95% bio-availability, and is bound to albumin for 97%. Ruxolitinib pharmacokinetics can be described with a two-compartment model and linear elimination. Volume of distribution differs between men and women, likely related to bodyweight differences. Metabolism is mainly hepatic via CYP3A4 and can be altered by CYP3A4 inducers and inhibitors. The major metabolites of ruxolitinib are pharmacologically active. The main route of elimination of ruxolitinib metabolites is renal. Liver and renal dysfunction affect some of the pharmacokinetic variables and require dose reductions. Model-informed precision dosing might be a way to further optimize and individualize ruxolitinib treatment, but is not yet advised for routine care due to lack of information on target concentrations.

Conclusion

Further research is needed to explain the interindividual variability of the ruxolitinib pharmacokinetic variables and to optimize individual treatment.

中文翻译：

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Ruxolitinib 的药代动力学和药效学：综述

背景和目标

Ruxolitinib 是一种酪氨酸激酶抑制剂，靶向 Janus 激酶 (JAK) 和信号转导和转录激活因子 (STAT) 通路。Ruxolitinib 用于治疗同种异体干细胞移植中的骨髓纤维化、真性红细胞增多症和类固醇难治性移植物抗宿主病。本综述描述了 ruxolitinib 的药代动力学和药效学。

方法

Pubmed、EMBASE、Cochrane Library 和 web of Science 从数据库创建到 2021 年 3 月 15 日进行了检索，并于 2021 年 11 月 16 日重复检索。非英文文章、动物或体外研究、致编辑的信、案例ruxolitinib 未用于血液病或无法获得全文的报告被排除在外。

结果

Ruxolitinib 吸收良好，生物利用度为 95%，与白蛋白的结合率为 97%。Ruxolitinib 的药代动力学可以用二室模型和线性消除来描述。分布容积在男性和女性之间不同，可能与体重差异有关。代谢主要通过 CYP3A4 在肝脏进行，并且可被 CYP3A4 诱导剂和抑制剂改变。ruxolitinib 的主要代谢物具有药理活性。ruxolitinib 代谢物消除的主要途径是肾脏。肝肾功能障碍会影响一些药代动力学变量，需要减少剂量。基于模型的精确剂量可能是进一步优化和个体化 ruxolitinib 治疗的一种方法，但由于缺乏有关目标浓度的信息，尚不建议用于常规护理。

结论

需要进一步的研究来解释 ruxolitinib 药代动力学变量的个体差异并优化个体治疗。