Pfizer Inc, 500 Arcola Rd, Collegeville, PA 19426, USA.
Eur J Clin Pharmacol. 2013 Apr;69(4):835-42. doi: 10.1007/s00228-012-1407-2. Epub 2012 Oct 4.
Sirolimus and tacrolimus are immunosuppressive compounds that have been used concomitantly in renal transplant patients. Both drugs are dosed orally and have common intestinal and hepatic metabolism and intestinal transport mechanisms. As such, there is a potential for pharmacokinetic drug interaction.
A single-dose, open-label, four-period, four-treatment, randomized crossover study was conducted in 27 healthy fasting volunteers. Each subject received a 15-mg oral dose of sirolimus alone, a 10-mg oral dose of tacrolimus alone, sirolimus and tacrolimus administered simultaneously, and tacrolimus administered 4 h before sirolimus. Whole blood and plasma samples for sirolimus and tacrolimus testing were analyzed by liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameters were assessed using noncompartmental methods and were compared using analysis of variance (ANOVA).
The geometric mean ratio and 90 % confidence interval (CI) area under the concentration-time curve from time 0 to infinity (AUCinf) for sirolimus administered simultaneously with tacrolimus versus sirolimus alone were 97 and 89-106, respectively, and, when administered in a staggered approach versus sirolimus alone, 107 and 98-117, respectively. The geometric mean ratio (%) and 90 % CI AUCinf for tacrolimus administered simultaneously with sirolimus versus tacrolimus alone were 92 and 82-102, respectively, and, when administered in a staggered approach versus tacrolimus alone, 94 and 84-105, respectively.
The results of this study demonstrate a lack of any clinically important drug interaction between sirolimus and tacrolimus in healthy subjects after single-dose administration. However, due to the complexity of anti-rejection immunosuppressive therapy dosing, we suggest that sirolimus and tacrolimus concentration monitoring be performed when changes in dosing are made for either drug regimen.
西罗莫司和他克莫司是免疫抑制化合物，已在肾移植患者中联合使用。两种药物均口服给药，具有共同的肠内和肝内代谢及肠内转运机制。因此，存在药代动力学药物相互作用的潜力。
在 27 名健康禁食志愿者中进行了一项单剂量、开放标签、四期、四处理、随机交叉研究。每位受试者单独接受 15 毫克口服西罗莫司、10 毫克口服他克莫司、西罗莫司和他克莫司同时给药以及他克莫司在西罗莫司给药前 4 小时给药。通过液相色谱/串联质谱法分析西罗莫司和他克莫司检测的全血和血浆样本。使用非房室分析方法评估药代动力学参数，并使用方差分析（ANOVA）进行比较。
当与西罗莫司同时给予时，与单独给予西罗莫司相比，他克莫司的几何均数比值和 90%置信区间（CI）从时间 0 到无穷大（AUCinf）的西罗莫司的几何均数比值和 90%CI AUCinf 分别为 97 和 89-106，当以交错方式给予时，分别为 107 和 98-117。当与西罗莫司同时给予时，与单独给予他克莫司相比，他克莫司的几何均数比值（%）和 90%CI AUCinf 的几何均数比值（%）和 90%CI AUCinf 分别为 92 和 82-102，当以交错方式给予时，分别为 94 和 84-105。
这项研究的结果表明，在健康受试者中单剂量给药后，西罗莫司和他克莫司之间没有任何临床相关的药物相互作用。然而，由于抗排斥免疫抑制治疗剂量的复杂性，我们建议在改变任一药物方案的剂量时，监测西罗莫司和他克莫司的浓度。
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