Kovarik J M, Bartlett M, Rordorf C, Antunes M C, Winter S, Marbach P, van Marle S
Novartis Pharmaceuticals, 4002 Basel, Switzerland.
Int J Clin Pharmacol Ther. 2010 Feb;48(2):103-8. doi: 10.5414/cpp48103.
Sotrastaurin is an immunosuppressant that blocks T-lymphocyte activation via protein kinase C inhibition. The authors determined whether a pharmacokinetic interaction occurs between sotrastaurin and everolimus, both of which are substrates and inhibitors of CYP3A4.
This was a randomized, three-period, crossover study in 18 healthy subjects. They received single oral doses of (1) 100 mg sotrastaurin, (2) 2 mg everolimus, and (3) the drug combination. Clinical and pharmacokinetic data were collected to Day 5 after each treatment.
Coadministration of everolimus decreased sotrastaurin C(max) from 638 +/- 295 to 539 +/- 211 ng/ml yielding a combination/ monotherapy ratio (90% confidence interval) of 0.87 (0.76 - 1.00). Sotrastaurin total AUC was not altered by everolimus with values of 3660 +/- 1853 versus 3630 +/- 2006 ngh/ml and a ratio of 1.00 (0.88 - 1.13). Sotrastaurin increased everolimus C(max) from 15 +/- 6 to 16 +/- 6 ng/ml yielding a ratio of 1.15 (0.99 - 1.33) and increased everolimus total AUC from 114 +/- 50 to 137 +/- 56 ngh/ml yielding a ratio of 1.20 (1.05 - 1.37). The possibility that a higher dose of sotrastaurin than used in this study might further increase everolimus blood levels cannot be excluded.
Coadministration of a single 100 mg dose sotrastaurin with a single 2 mg dose everolimus did not alter sotrastaurin pharmacokinetics to a clinically relevant extent. Everolimus AUC was increased 20% by sotrastaurin.
索拉司他丁是一种免疫抑制剂，通过抑制蛋白激酶C来阻断T淋巴细胞激活。作者研究了索拉司他丁和依维莫司之间是否存在药代动力学相互作用，这两种药物均为CYP3A4的底物和抑制剂。
这是一项针对18名健康受试者的随机、三阶段、交叉研究。他们分别接受单次口服剂量的：（1）100毫克索拉司他丁；（2）2毫克依维莫司；（3）两种药物的组合。在每次治疗后的第5天收集临床和药代动力学数据。
依维莫司与索拉司他丁合用时，索拉司他丁的C(max)从638±295降至539±211纳克/毫升，联合治疗/单药治疗的比值（90%置信区间）为0.87（0.76 - 1.00）。依维莫司未改变索拉司他丁的总AUC，其值分别为3660±1853和3630±2006纳克·小时/毫升，比值为1.00（0.88 - 1.13）。索拉司他丁使依维莫司的C(max)从15±6升至16±6纳克/毫升，比值为1.15（0.99 - 1.33），并使依维莫司的总AUC从114±50升至137±56纳克·小时/毫升，比值为1.20（1.05 - 1.37）。不能排除使用比本研究中更高剂量的索拉司他丁可能会进一步提高依维莫司血药浓度的可能性。
单次口服100毫克索拉司他丁与单次口服2毫克依维莫司合用时，索拉司他丁的药代动力学在临床上未发生相关改变。索拉司他丁使依维莫司的AUC增加了20%。
