Dose- and time-dependent pharmacokinetics of midostaurin in patients with diabetes mellitus
Dose- and time-dependent pharmacokinetics of midostaurin in patients with diabetes mellitus
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DOI：
10.1177/0091270008318006
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发表时间：
2008-06-01
影响因子：
2.9
通讯作者：
Schran, Horst
中科院分区：
文献类型：
--
作者：
Wang, Yanfeng;Yin, Ophelia Q. R.;Schran, Horst
midoin是一种新型的有效的蛋白激酶C抑制剂和血管内皮生长因子的主要受体，参与血管生成，提出了其用于糖尿病视网膜病变的基本原理。在糖尿病患者中，本研究以4种剂量水平（25mg bid, 50mg bid, 75mg bid, 75mg tid）和单次口服100mg剂量（每个剂量队列n = 9-13），评估了米多舒林28天的安全性和药代动力学。根据米多斯汀及其代谢物CGP62221和CGP52421的血浆浓度测定第1天和第28天的药动学参数。在25 ~ 100 mg剂量范围内，midoschin及其代谢物的血浆暴露量（C-max和AUC(0-tau)）增加的比例较小，在首次给药后增加了2.2倍。在给药的前3 - 6天，midoin浓度增加，然后随着时间的推移下降（30%-50%），直到达到稳定状态，平均积累因子(R)为1.7。CGP62221的浓度-时间模式与midostoin相似（R = 2.5），但CGP52421的积累显著（R = 18.8）。研究发现，与禁食过夜相比，高脂肪膳食可使midosvin的C-max和AUC(0.12) (h)分别提高1.5倍（P = 0.04）和1.8倍（P = 0.01）。在这组患者中，给予50至225mg /天的米多斯平似乎是安全的。最常见的治疗相关不良事件（如稀便、恶心、呕吐和头痛）被发现与剂量相关，并且频率在150 mg/天剂量水平以上显著增加。
Midostaurin is a novel potent inhibitor of both protein kinase C and the major receptor for vascular endothelial growth factor involved in angiogenesis, presenting a rationale for its use in diabetic retinopathy. This study evaluated the safety and pharmacokinetics of midostaurin following multiple oral doses of midostaurin for 28 days at 4 dose levels (25 mg bid, 50 mg bid, 75 mg bid, 75 mg tid), as well as a single oral 100-mg dose in patients with diabetes mellitus (n = 9-13 per dose cohort). Pharmacokinetic parameters were determined on days 1 and 28 based on the plasma concentrations of midostaurin and its metabolites, CGP62221 and CGP52421. The plasma exposures (C-max and AUC(0-tau)) of midostaurin and metabolites increased less than proportionally over the dose range of 25 to 100 mg, showing a 2.2-fold increase after the first dose. Midostaurin concentrations increased during the first 3 to 6 days of dosing, then declined with time (by 30%-50%) until a steady state was achieved, representing an average accumulation factor (R) of 1.7. CGP62221 showed a similar concentration-time pattern as midostaurin (R = 2.5), but CGP52421 accumulated significantly (R = 18.8). A high-fat meal was found to significantly increase the C-max and AUC(0.12) (h) of midostaurin by 1.5-fold (P = .04) and 1.8-fold (P = .01), respectively, compared with taking the drug after an overnight fast. Midostaurin administered at 50 to 225 mg/day appeared to be generally safe in this group of patients. The most common treatment-related adverse events (eg, loose stools, nausea, vomiting, and headache) were found to be dose related, and the frequency increased markedly above the 150-mg/day dose level.