Clinical Pharmacokinetics and Drug-Drug Interaction Potential for Coadministered SCY-078, an Oral Fungicidal Glucan Synthase Inhibitor, and Tacrolimus
Clinical Pharmacokinetics and Drug-Drug Interaction Potential for Coadministered SCY-078, an Oral Fungicidal Glucan Synthase Inhibitor, and Tacrolimus
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DOI：
10.1002/cpdd.588
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发表时间：
2019-01-01
影响因子：
2
通讯作者：
Angulo, David
中科院分区：
文献类型：
--
作者：
Wring, Stephen;Murphy, Gail;Angulo, David
SCY-078是一种口服生物可利用的三萜类葡聚糖合成酶抑制剂，临床开发用于静脉和口服治疗念珠菌和曲霉属真菌引起的真菌感染。这是一项序贯、单中心、开放标签、I期研究，旨在评估健康受试者中SCY-078和他克莫司伴随给药期间的药物间相互作用潜力。在队列1阶段1中，受试者在空腹状态下接受他克莫司2 mg单次口服给药。在>= 15天洗脱后的第2阶段，受试者在第1天接受单次负荷剂量的SCY-078 1250 mg，随后在第2天至第8天接受维持剂量的SCY-780 750 mg。在第2阶段第3天，受试者还接受了他克莫司2 mg单次给药，同时接受SCY-078。在队列2中，受试者在第1天接受负荷剂量的SCY-078 1250 mg，随后在第2天和第3天接受维持剂量的SCY-780 750 mg。比较药代动力学（PK）参数以评估稳态SCY-078对他克莫司的影响和他克莫司对稳态SCY-078的PK的影响。他克莫司和SCY-078同时联合给药对他克莫司的最大血药浓度没有影响，这可以通过血浆中药物的最大浓度没有变化和血浆药物浓度-时间曲线下总面积增加1.4倍来证明。他克莫司和SCY-078同时给药导致的相互作用比唑类抗真菌药通常观察到的相互作用弱。目前的数据表明，当与SCY-078联合使用时，可能不需要调整他克莫司的初始剂量，因为暴露量的适度增加小于治疗窗口，尽管建议对他克莫司进行监测，如添加任何新药一样。这些结果支持SCY-078和他克莫司的联合给药。
SCY-078 is an orally bioavailable triterpenoid glucan synthase inhibitor in clinical development as an intravenous and oral treatment of fungal infections caused by Candida and Aspergillus species. This was a sequential, single-center, open-label phase 1 study to assess the drug-drug interaction potential between SCY-078 and tacrolimus during concomitant administration in healthy subjects. In cohort 1, period 1, subjects received a single oral dose of tacrolimus 2 mg in the fasted state. In period 2 after a >= 15 day washout, subjects received a single loading dose of SCY-078 1250 mg on day 1 followed by maintenance doses of SCY-780 750 mg on days 2 through 8. On day 3 of period 2, subjects also received a single dose of tacrolimus 2 mg concurrent with SCY-078. In cohort 2, subjects received a loading dose of SCY-078 1250 mg on day 1 followed by maintenance doses of SCY-780 750 mg on days 2 and 3. Pharmacokinetic (PK) parameters were compared to assess both the impact of steady-state SCY-078 on tacrolimus and the impact of tacrolimus on the PK of steady-state SCY-078. The concurrent coadministration of tacrolimus and SCY-078 had no effect on the maximum blood levels of tacrolimus, as evidenced by no change in maximum concentration of drug in blood plasma and a 1.4-fold increase in total area under the plasma drug concentration-time curve. The concurrent coadministration of tacrolimus and SCY-078 resulted in a weaker interaction than typically observed with the azole class of antifungals. The current data indicate that an initial dose adjustment for tacrolimus may not be warranted when combined with SCY-078, as the modest increase in exposure is less than the therapeutic window, although tacrolimus monitoring, as with addition of any new medication, is recommended. These results support the coadministration of SCY-078 and tacrolimus.