Laboratoire de Pharmacologie Toxicologie, University Hospital of Saint-Etienne, Saint-Etienne, France.
Br J Clin Pharmacol. 2013 Jul;76(1):107-13. doi: 10.1111/bcp.12055.
The aim of this study was to develop a PK/PD model to assess drug-drug interactions between dabigatran and P-gp modulators, using the example of clarithromycin, a strong inhibitor of P-gp.
Ten healthy male volunteers were randomized to receive in the first treatment period a single 300 mg dose of dabigatran etexilate (DE) and in the second treatment period 500 mg clarithromycin twice daily during 3 days and then 300 mg DE plus 500 mg clarithromycin on the fourth day, or the same treatments in the reverse sequence. Dabigatran plasma concentration and ecarin clotting time (ECT) were measured on 11 blood samples. Models were built using a non-linear mixed effect modelling approach.
The best PK model was based on an inverse Gaussian absorption process with two compartments. The relationship between dabigatran concentration and ECT was implemented as a linear function. No continuous covariate was associated with a significant decrease in the objective function. The concomitant administration of clarithromycin induced a significant change only in DE bioavailability, which increased from 6.5% to 10.1% in the presence of clarithromycin. Clarithromycin increased peak concentration and AUC by 60.2% and 49.1% respectively.
The model proposed effectively describes the complex PK of dabigatran and takes into account drug-drug interactions with P-gp activity modulators, such as clarithromycin.
本研究旨在开发一种药代动力学/药效学（PK/PD）模型，以评估达比加群与 P 糖蛋白（P-gp）调节剂之间的药物相互作用，以克拉霉素为例，克拉霉素是 P-gp 的强抑制剂。
10 名健康男性志愿者随机分为两组，第一组在第一个治疗期内单次服用 300mg 达比加群酯（DE），第二组在第二个治疗期内连续 3 天每日服用 500mg 克拉霉素两次，然后第四天服用 300mg DE 和 500mg 克拉霉素，或者以相反的顺序接受相同的治疗。在 11 个血样中测量达比加群血浆浓度和蝰蛇凝血时间（ECT）。使用非线性混合效应建模方法构建模型。
最好的 PK 模型基于一个具有两个隔室的逆高斯吸收过程。达比加群浓度与 ECT 之间的关系采用线性函数实现。没有连续的协变量与客观功能的显著降低有关。克拉霉素的同时给药仅显著改变 DE 的生物利用度，克拉霉素存在时，DE 的生物利用度从 6.5%增加到 10.1%。克拉霉素分别使峰浓度和 AUC 增加 60.2%和 49.1%。
所提出的模型有效地描述了达比加群的复杂 PK，并考虑了药物与 P-gp 活性调节剂（如克拉霉素）的相互作用。
