Clinical Pharmacology and Clinical Research, Novartis Pharmaceuticals, Basel, Switzerland.
Transplantation. 2011 Feb 15;91(3):317-22. doi: 10.1097/TP.0b013e318203860d.
Sotrastaurin is a protein kinase C inhibitor in the development for prevention of organ rejection after renal transplantation.
In a multicenter phase 2 trial, 216 de novo renal transplant recipients were randomized to mycophenolic acid (MPA) with standard-exposure tacrolimus (treatment A, n=74), 200 mg sotrastaurin twice daily with standard-exposure tacrolimus (treatment B, n=76), or 200 mg sotrastaurin twice daily with reduced-exposure tacrolimus (treatment C, n=66). After month 3, tacrolimus was replaced with MPA in arms B and C. The longitudinal pharmacokinetics of sotrastaurin and tacrolimus were prospectively evaluated through month 6.
Sotrastaurin predose drug concentration (C0) was 0.6±0.4 μg/mL and did not differ when combined with standard-exposure versus reduced-exposure tacrolimus (P=0.99) nor when tacrolimus was replaced by MPA (P=0.11). Sotrastaurin peak concentration was 1.6±0.6 μg/mL, and area under the drug concentration-time curve over a dosing interval (AUC) was 12.2±4.2 μg hr/mL. Intersubject variability in AUC was 27% and not significantly influenced by age (18-67 years), weight (47-121 kg), sex, or creatinine clearance (36-173 mL/min). Sotrastaurin C0 was positively correlated with AUC (r=0.62, P<0.0001). Sotrastaurin increased tacrolimus concentrations by a pharmacokinetic interaction inasmuch as the tacrolimus dose needed to achieve a given C0 was up to 47% lower when combined with sotrastaurin versus with MPA.
Sotrastaurin pharmacokinetics were similar when combined with reduced-exposure or standard-exposure tacrolimus or with MPA. Tacrolimus exposure was significantly increased by sotrastaurin in the initial weeks posttransplant by a pharmacokinetic interaction.
索他司他汀是一种蛋白激酶 C 抑制剂，目前处于研发阶段，用于预防肾移植后的器官排斥。
在一项多中心 2 期临床试验中，216 名新诊断的肾移植受者被随机分为他克莫司标准暴露组（治疗 A，n=74）、他克莫司标准暴露+索他司他汀 200mg 每日 2 次组（治疗 B，n=76）和他克莫司低暴露+索他司他汀 200mg 每日 2 次组（治疗 C，n=66）。第 3 个月时，B 组和 C 组的他克莫司被换成麦考酚酸。通过第 6 个月，前瞻性地评估了索他司他汀和他克莫司的纵向药代动力学。
索他司他汀的预剂量药物浓度（C0）为 0.6±0.4μg/mL，与标准暴露或低暴露他克莫司联合使用时（P=0.99）或在他克莫司被麦考酚酸取代时（P=0.11）并无差异。索他司他汀的峰浓度为 1.6±0.6μg/mL，给药间隔内药物浓度-时间曲线下面积（AUC）为 12.2±4.2μg·hr/mL。AUC 的个体间变异性为 27%，不受年龄（18-67 岁）、体重（47-121kg）、性别或肌酐清除率（36-173mL/min）的影响。索他司他汀的 C0 与 AUC 呈正相关（r=0.62，P<0.0001）。由于与索他司他汀合用，达到特定 C0 所需的他克莫司剂量降低了多达 47%，因此索他司他汀通过药代动力学相互作用增加了他克莫司的浓度。
索他司他汀与低暴露或标准暴露的他克莫司或麦考酚酸合用时，药代动力学相似。在移植后的最初几周内，由于药代动力学相互作用，索他司他汀显著增加了他克莫司的暴露量。
