Exposure-Response Relationships for Isavuconazole in Patients with Invasive Aspergillosis and Other Filamentous Fungi.
Exposure-Response Relationships for Isavuconazole in Patients with Invasive Aspergillosis and Other Filamentous Fungi.
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DOI：
10.1128/aac.01034-17
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发表时间：
2017-12
影响因子：
4.9
通讯作者：
Bonate PL
中科院分区：
文献类型：
--
作者：
Desai AV;Kovanda LL;Hope WW;Andes D;Mouton JW;Kowalski DL;Townsend RW;Mujais S;Bonate PL
异武康唑是一种用于治疗侵袭性真菌感染的三氮唑类抗真菌药，是水溶性前体药物硫酸异武康唑的活性部分。这项分析的目的是描述安全临床试验中侵袭性曲霉病患者和其他丝状真菌感染患者的异武康唑暴露-反应关系，以衡量其有效性和安全性。231名接受临床给药方案并有暴露参数的患者被纳入分析。主要药物暴露参数包括通过稳态血药浓度预测谷值，在给药7天和14天预测谷值浓度，以及稳态曲线下面积估计(AUCss)。根据疗效终点分析暴露参数，包括意向治疗(ITT)和改良ITT人群中42天的全因死亡率、数据审查委员会(DRC)判定的治疗结束时的总体反应(EOT)以及DRC判定的EOT临床反应。分析的安全终点是丙氨酸氨基转移酶升高或异常，天冬氨酸转氨酶升高，以及两者的组合。终点采用Logistic回归模型进行分析。未发现异武康唑暴露与疗效或安全终点之间有统计学意义的关系(P>；0.05)。暴露与疗效之间没有关联，这表明通过临床剂量获得的异武康唑暴露在安全研究中用于治疗感染生物是合适的，丙氨酸或天冬氨酸转氨酶的增加与暴露的增加无关。在没有明确关系的情况下，目前没有临床证据建议对异武康唑进行常规治疗药物监测。
Isavuconazole, the active moiety of the water-soluble prodrug isavuconazonium sulfate, is a triazole antifungal agent for the treatment of invasive fungal infections. The purpose of this analysis was to characterize the isavuconazole exposure-response relationship for measures of efficacy and safety in patients with invasive aspergillosis and infections by other filamentous fungi from the SECURE clinical trial. Two hundred thirty-one patients who received the clinical dosing regimen and had exposure parameters were included in the analysis. The primary drug exposure parameters included were predicted trough steady-state plasma concentrations, predicted trough concentrations after 7 and 14 days of drug administration, and area under the curve estimated at steady state (AUCss). The exposure parameters were analyzed against efficacy endpoints that included all-cause mortality through day 42 in the intent-to-treat (ITT) and modified ITT populations, data review committee (DRC)-adjudicated overall response at end of treatment (EOT), and DRC-adjudicated clinical response at EOT. The safety endpoints analyzed were elevated or abnormal alanine aminotransferase, increased aspartate aminotransferase, and a combination of the two. The endpoints were analyzed using logistic regression models. No statistically significant relationship (P > 0.05) was found between isavuconazole exposure and either efficacy or safety endpoints. The lack of association between exposure and efficacy indicates that the isavuconazole exposures achieved by clinical dosing were appropriate for treating the infecting organisms in the SECURE study and that increases in alanine or aspartate aminotransferase were not related to increase in exposures. Without a clear relationship, there is no current clinical evidence for recommending routine therapeutic drug monitoring for isavuconazole.