Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.
Current affiliation: Clinical Pharmacology, Genentech Research and Early Development, South San Francisco, California, USA.
Clin Pharmacol Ther. 2018 May;103(5):854-867. doi: 10.1002/cpt.807. Epub 2017 Oct 9.
Our recent studies have shown that chronic kidney disease (CKD) affects the pharmacokinetics (PKs) of cytochrome P450 (CYP)2D6-metabolized drugs, whereas effects were less evident on CYP3A4/5. Therefore, the effect of CKD on the disposition of CYP1A2-metabolized, CYP2C8-metabolized, CYP2C9-metabolized, CYP2C19-metabolized, and organic anion-transporting polypeptide (OATP)-transported drugs was investigated. We identified dedicated CKD studies with 6, 5, 6, 4, and 12 "model" substrates for CYP1A2, CYP2C8, CYP2C9, CYP2C19, and OATP, respectively. Our analyses suggest that clearance of OATP substrates decreases as kidney function declines. Similar trends were seen for CYP2C8; but overlap between some CYP2C8 and OATP substrates highlights that their interplay needs further investigation. In contrast, the effect of CKD on CYP1A2, CYP2C9, and CYP2C19 was variable and modest compared to CYP2C8 and OATP. This improved understanding of elimination-pathway-dependency in CKD is important to inform the need and conduct of PK studies in these patients for nonrenally eliminated drugs.
我们最近的研究表明，慢性肾病（CKD）会影响细胞色素 P450（CYP）2D6 代谢药物的药代动力学（PKs），而对 CYP3A4/5 的影响则不那么明显。因此，研究了 CKD 对 CYP1A2 代谢、CYP2C8 代谢、CYP2C9 代谢、CYP2C19 代谢和有机阴离子转运多肽（OATP）转运药物处置的影响。我们确定了 6 项、5 项、6 项、4 项和 12 项分别针对 CYP1A2、CYP2C8、CYP2C9、CYP2C19 和 OATP 的“模型”底物的专门 CKD 研究。我们的分析表明，随着肾功能下降，OATP 底物的清除率降低。CYP2C8 也呈现出类似的趋势；但 CYP2C8 和 OATP 底物之间存在一些重叠，这表明它们之间的相互作用需要进一步研究。相比之下，CKD 对 CYP1A2、CYP2C9 和 CYP2C19 的影响与 CYP2C8 和 OATP 相比是可变的且适度的。这一对于 CKD 中消除途径依赖性的理解的提高，对于告知这些患者中非肾清除药物进行 PK 研究的必要性和进行这些研究非常重要。
