Abstract:
Dabigatran etexilate (DABE) is a clinical probe substrate for studying drug-drug interaction (DDI) through an intestinal P-glycoprotein (P-gp). A recent in vitro study, however, has suggested a potentially significant involvement of CYP3A-mediated oxidative metabolism of DABE and its intermediate monoester BIBR0951 in DDI following microdose administration of DABE. In this study, the relative significance of CYP3A- and P-gp-mediated pathways to the overall disposition of DABE has been explored using mechanistic physiologically based pharmacokinetic (PBPK) modeling approach. The developed PBPK model linked DABE with its 2 intermediate (BIBR0951 and BIBR1087) and active (dabigatran, DAB) metabolites, and with all relevant drug-specific properties known to date included. The model was successfully qualified against several datasets of DABE single/multiple dose pharmacokinetics and DDIs with CYP3A/P-gp inhibitors. Simulations using the qualified model supported that the intestinal CYP3A-mediated oxidation of BIBR0951, and not the gut P-gp-mediated efflux of DABE, was a key contributing factor to an observed difference in the DDI magnitude following the micro-versus therapeutic doses of DABE with clarithromycin. Both the saturable CYP3A-mediated metabolism of BIBR0951 and the solubility-limited DABE absorption contributed to the relatively modest nonlinearity in DAB exposure observed with increasing doses of DABE. Furthermore, the results suggested a limited role of the gut P-gp, but an appreciable, albeit small, contribution of gut CYP3A in mediating the DDIs following the therapeutic dose of DABE with dual CYP3A/P-gp inhibitors. Thus, a possibility exists for a varying extent of CYP3A involvement when using DABE as a clinical probe in the DDI assessment, across DABE dose levels.
摘要:
达比加群etexilate(DABE)是用于研究通过肠P-糖蛋白(P-gp)的药物-药物相互作用(DDI)的临床探针底物。最近的一项体外研究,然而,提示在微剂量施用DABE后,CYP3A介导的DABE及其中间体单酯BIBR0951在DDI中的氧化代谢可能具有重要意义。在这项研究中,CYP3A-和P-gp-介导的通路对DABE整体处置的相对意义已经使用基于机械生理学的药代动力学(PBPK)建模方法进行了探索。开发的PBPK模型将DABE与其2个中间体(BIBR0951和BIBR1087)和活性(达比加群,DAB)代谢物,以及迄今为止已知的所有相关药物特异性特性。该模型成功地针对DABE单/多剂量药代动力学和使用CYP3A/P-gp抑制剂的DDI的几个数据集进行了鉴定。使用合格模型的模拟支持肠道CYP3A介导的BIBR0951氧化,而不是肠道P-gp介导的DABE外排,是在使用克拉霉素的DABE的微剂量与治疗剂量之后观察到的DDI幅度差异的关键促成因素。BIBR0951的饱和CYP3A介导的代谢和溶解度受限的DABE吸收都导致DAB暴露中相对适度的非线性,DABE剂量增加时观察到。此外,结果表明肠道P-gp的作用有限,但是一个可观的,虽然很小,在使用CYP3A/P-gp双重抑制剂治疗剂量的DABE后,肠道CYP3A在介导DDI中的贡献。因此,当在DDI评估中使用DABE作为临床探针时,CYP3A的参与程度不同,跨越DABE剂量水平。