Novartis Pharmaceuticals, Basel, Switzerland and East Hanover, NJ, USA.
Transpl Int. 2011 Mar;24(3):276-83. doi: 10.1111/j.1432-2277.2010.01196.x. Epub 2010 Dec 7.
Sotrastaurin is a protein kinase C inhibitor in development for prevention of rejection after liver transplantation. In a pharmacokinetic study, 13 de novo liver transplant recipients received 100 mg sotrastaurin once between days 1-3 and once between days 5-8 post-transplant. Sotrastaurin absorption based on the area under the concentration-time curve (AUC) of total drug in blood (3544 ± 1434 ng·h/ml) was similar to that of healthy subjects in a previous study (4531 ± 1650 ng·h/ml). However, the sotrastaurin binding protein, α1-acid glycoprotein, was nominally higher in patients (1.07 ± 0.28 vs. 0.87 ± 0.16 g/l, P = 0.13) yielding a 60% lower AUC based on free drug versus that in healthy subjects (27 ± 13 vs. 62 ± 15 ng·h/ml, P < 0.0001). There was minor excretion of sotrastaurin in drained bile (1% of dose) consistent with the fact that sotrastaurin is extensively metabolized leaving little unchanged drug to excrete. In the first week after liver transplantation, sotrastaurin is bioavailable after oral administration. However, patients with elevated α1-acid glycoprotein levels may have lower free drug concentrations. Whether a higher dose of sotrastaurin is needed to compensate for this in the short-term after surgery will be addressed in future clinical trials.
索他拉唑是一种蛋白激酶 C 抑制剂，目前正在开发用于预防肝移植后的排斥反应。在一项药代动力学研究中，13 例新诊断的肝移植受者在移植后第 1-3 天和第 5-8 天之间各接受 100mg 索他拉唑一次。索他拉唑的血药浓度时间曲线下面积（AUC）的吸收（3544 ± 1434ng·h/ml）与先前一项研究中的健康受试者相似（4531 ± 1650ng·h/ml）。然而，患者的索他拉唑结合蛋白，α1-酸性糖蛋白，名义上较高（1.07 ± 0.28 vs. 0.87 ± 0.16g/l，P = 0.13），导致游离药物的 AUC 比健康受试者低 60%（27 ± 13 vs. 62 ± 15ng·h/ml，P < 0.0001）。索他拉唑在胆汁中的排泄量很少（占剂量的 1%），这与索他拉唑广泛代谢，几乎没有未改变的药物排泄的事实一致。肝移植后第一周，索他拉唑经口服给药后具有生物利用度。然而，α1-酸性糖蛋白水平升高的患者可能具有较低的游离药物浓度。术后短期内是否需要更高剂量的索他拉唑来补偿这一点，将在未来的临床试验中解决。
