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Optimizing the therapeutic window of sirolimus by monitoring blood concentration for the treatment of immune thrombocytopenia

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journal contribution
posted on 2023-11-21, 08:00 authored by Yun Zhang, Yao Quan, Dan Wang, Kaniel Cassady, Wenhang Zou, Jingkang Xiong, Han Yao, Xiaojuan Deng, Ping Wang, Shijie Yang, Xi Zhang, Yimei Feng

Previous studies have demonstrated that sirolimus (SRL) is an effective agent for the treatment of refractory/relapsed (R/R) ITP. However, the therapeutic window of sirolimus in the treatment of ITP has not been established. As the toxicity of sirolimus increases with higher blood concentrations, it is crucial to determine the optimal therapeutic concentration of SRL for the treatment of ITP. Thus, in this study, we used a retrospective cohort of ITP patients treated with sirolimus to propose the therapeutic dosage window for sirolimus. A total of 275 laboratory results of SRL blood concentration from 63 ITP patients treated with SRL were analyzed retrospectively. The ITP patients were divided into five groups based on their SRL blood concentration: 0−4 ng/ml, 4−8 ng/ml, 8−12 ng/ml, 12−16 ng/ml and ≥16 ng/ml. In addition to the SRL blood concentration, platelet counts and adverse events that occurred during the first 6 weeks of SRL treatment were analyzed. These findings were then used to establish the decision matrix tables and ROC curves, which helped identify the therapeutic window of SRL. Based on the values and trends of true-positive rate (TPR) and false-positive rate (FPR) in the ROC curve, patients who achieved a SRL blood concentration of 4−12 ng/ml displayed a higher response rate compared to those with a SRL concentration of 0−4 ng/ml or ≥16ng/ml. Additionally, the response rate was better for patients with a SRL concentration of 8−12 ng/ml compared to 4−8 ng/ml. Adverse events were related to the concentration of SRL; however, there was no significant difference in the incidence of adverse events between the concentrations of 4–8 ng/ml and 8–12 ng/ml (P > .05). Regression analysis suggested that the concentration of SRL correlated with the patient’s age, PLT count at the start of SRL administration, and the dose of SRL. It is suggested that the optimal blood concentration of SRL monotherapy for managing ITP is 8–12 ng/ml. This range may achieve a favorable balance between clinical efficacy and the severity of adverse events.

Although sirolimus (SRL) has been proven to be an effective alternative agent for refractory/relapsed immune thrombocytopenia (R/R ITP), there is currently no recommended optimal blood concentration during its administration. We collected data on SRL drug concentration, platelet response, and drug side effects in ITP patients, constructed ROC curves to evaluate the relationship between the SRL concentration and both efficacy and side effects, and finally suggested a most appropriate SRL blood concentration (8–12ng/ml). This concentration window ensured optimal efficacy of SRL in the treatment of ITP while maintaining tolerable side effects. Additionally, we conducted a multivariate analysis to explore factors that may influence SRL blood concentration. The present study made an important contribution to the precision therapy of ITP with sirolimus by clarifying the optimal blood concentration range.


This work was supported by the National Natural Science Foundation of China [No. 82020108004; No. 82270231], Chongqing Natural Science Foundation Innovative Group Program [cstc2021jcyj-cxttX0001], General Project of Chongqing Natural Science [cstc2019jcyj-msxmX0273; cstc2020jcyj-msxmX1086], and Chongqing Science and Health Joint Medical Research Program [2021MSXM140].