Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington, USA.
Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, Washington, USA.
Clin Transl Sci. 2017 Sep;10(5):395-403. doi: 10.1111/cts.12481. Epub 2017 Jul 4.
Drug-dose modification in chronic kidney disease (CKD) utilizes glomerular filtration rate (GFR) with the implicit assumption that multiple renal excretory processes decline in parallel as CKD progresses. We compiled published pharmacokinetic data to evaluate if GFR predicts renal clearance changes as a function of CKD severity. For each drug, we calculated ratio of renal clearance to filtration clearance (Rnf). Of 21 drugs with Rnf >0.74 in subjects with GFR >90 mL/min (implying filtration and secretion), 13 displayed significant change in Rnf vs. GFR (slope of linear regression statistically different from zero), which indicates failure of GFR to predict changes in secretory clearance. The dependence was positive (n = 3; group A) or negative (n = 10; group B). Eight drugs showed no correlation (group C). Investigated drugs were small molecules, mostly hydrophilic, and ionizable, with some characterized as renal transporter substrates. In conclusion, dosing adjustments in CKD require refinement; in addition to GFR, biomarkers of tubular function are needed for secreted drugs.
在慢性肾脏病 (CKD) 中，药物剂量调整利用肾小球滤过率 (GFR)，其隐含假设是随着 CKD 的进展，多种肾脏排泄过程呈平行下降。我们编译了已发表的药代动力学数据，以评估 GFR 是否可以预测 CKD 严重程度相关的肾清除率变化。对于每个药物，我们计算了肾清除率与滤过清除率的比值 (Rnf)。在 GFR >90 mL/min 的受试者中，有 21 种药物的 Rnf >0.74（提示滤过和分泌），其中 13 种药物的 Rnf 与 GFR 之间存在显著变化（线性回归的斜率与零统计学差异），这表明 GFR 无法预测分泌清除率的变化。这种依赖性是阳性的 (n = 3; 组 A) 或阴性的 (n = 10; 组 B)。有 8 种药物没有相关性 (组 C)。研究药物为小分子，大多为亲水性和可电离的，其中一些被认为是肾脏转运体的底物。总之，CKD 中的剂量调整需要进一步细化；除了 GFR 之外，还需要针对分泌药物的肾小管功能的生物标志物。
