Clinical Pharmacology, Global Product Development, Pfizer Inc., 10555 Science Center Dr., San Diego, CA, 92121, USA.
Clinical Pharmacology, Global Product Development, Pfizer Inc., New York, NY, USA.
Clin Pharmacokinet. 2020 Jun;59(6):699-714. doi: 10.1007/s40262-020-00867-1.
Understanding transporter-mediated drug-drug interactions (DDIs) for investigational agents is important during drug development to assess DDI liability, its clinical relevance, and to determine appropriate DDI management strategies. P-glycoprotein (P-gp) is an efflux transporter that influences the pharmacokinetics (PK) of various compounds. Assessing transporter induction in vitro is challenging and is not always predictive of in vivo effects, and hence there is a need to consider clinical DDI studies; however, there is no clear guidance on when clinical evaluation of transporter induction is required. Furthermore, there is no proposed list of index transporter inducers to be used in clinical studies. This review evaluated DDI studies with known P-gp inducers to better understand the mechanism and site of P-gp induction, as well as the magnitude of induction effect on the exposure of P-gp substrates. Our review indicates that P-gp and cytochrome P450 (CYP450) enzymes are co-regulated via the pregnane xenobiotic receptor (PXR) and the constitutive androstane receptor (CAR). The magnitude of the decrease in substrate drug exposure by P-gp induction is generally less than that of CYP3A. Most P-gp inducers reduced total bioavailability with a minor impact on renal clearance, despite known expression of P-gp at the apical membrane of the kidney proximal tubules. Rifampin is the most potent P-gp inducer, resulting in an average reduction in substrate exposure ranging between 20 and 67%. For other inducers, the reduction in P-gp substrate exposure ranged from 12 to 42%. A lower reduction in exposure of the P-gp substrate was observed with a lower dose of the inducer and/or if the administration of the inducer and substrate was simultaneous, i.e. not staggered. These findings suggest that clinical evaluation of the impact of P-gp inducers on the PK of investigational agents that are substrates for P-gp might be warranted only for compounds with a relatively steep exposure-efficacy relationship.
了解研究药物的转运体介导的药物相互作用（DDI）在药物开发过程中很重要，可用于评估 DDI 的责任、其临床相关性，并确定适当的 DDI 管理策略。P-糖蛋白（P-gp）是一种外排转运体，可影响多种化合物的药代动力学（PK）。体外评估转运体诱导作用具有挑战性，且并不总是可预测体内作用，因此需要考虑临床 DDI 研究；然而，目前尚没有关于何时需要进行转运体诱导的临床评估的明确指导。此外，也没有提出用于临床研究的索引转运体诱导剂列表。本综述评估了具有已知 P-gp 诱导剂的 DDI 研究，以更好地了解 P-gp 诱导的机制和部位，以及对 P-gp 底物暴露的诱导作用的程度。我们的综述表明，P-gp 和细胞色素 P450（CYP450）酶通过孕烷 X 受体（PXR）和组成型雄烷受体（CAR）共同调节。P-gp 诱导降低底物药物暴露的程度通常小于 CYP3A。尽管已知 P-gp 在肾脏近端小管的顶膜表达，但大多数 P-gp 诱导剂会降低总生物利用度，对肾清除率的影响较小。利福平是最强的 P-gp 诱导剂，导致底物暴露平均降低 20%至 67%。对于其他诱导剂，P-gp 底物暴露的降低范围为 12%至 42%。在诱导剂剂量较低或同时给予诱导剂和底物（即不交错）时，观察到 P-gp 底物暴露的降低幅度较小。这些发现表明，只有对于具有相对陡峭的暴露-疗效关系的化合物，才可能需要对 P-gp 诱导剂对研究药物 PK 的影响进行临床评估。
