A phase 1 study to evaluate the effect of dolutegravir on renal function via measurement of iohexol and para-aminohippurate clearance in healthy subjects
A phase 1 study to evaluate the effect of dolutegravir on renal function via measurement of iohexol and para-aminohippurate clearance in healthy subjects
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DOI：
10.1111/j.1365-2125.2012.04440.x
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发表时间：
2013-04-01
影响因子：
3.4
通讯作者：
Piscitelli, Stephen C.
中科院分区：
文献类型：
--
作者：
Koteff, Justin;Borland, Julie;Piscitelli, Stephen C.
目的 Dolutegravir（DTG；S/GSK1349572）正在临床开发中，作为一种每日一次、未增强的整合酶抑制剂，用于治疗 HIV 感染。在 34 名健康志愿者中评估了 DTG 对肾小球滤过率 (GFR)、有效肾血浆流量 (ERPF) 和肌酐清除率 (CLcr) 的影响。方法 受试者接受 DTG 50mg（每天一次或每天两次）或安慰剂，持续 14 天。 GFR通过碘海醇血浆清除率测量，ERPF通过对氨基马尿酸血浆清除率评估，CLcr通过24小时尿液收集测量。结果 所有治疗总体耐受性良好。观察到 CLcr 适度下降（1014%），与临床研究观察结果一致。在健康受试者中，与安慰剂相比，DTG 50mg 每日一次和每日两次对 GFR 或 ERPF 没有显着影响超过 14 天。结论 这些发现支持体外数据，即 DTG 通过良性抑制有机阳离子转运蛋白 2（负责肾小管分泌肌酐）来增加血清肌酐。
Aim Dolutegravir (DTG; S/GSK1349572) is under clinical development as a once daily, unboosted integrase inhibitor for the treatment of HIV infection. The effect of DTG on glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and creatinine clearance (CLcr) was evaluated in 34 healthy volunteers. Methods Subjects received DTG 50mg (once daily or twice daily) or placebo for 14 days. GFR was measured by iohexol plasma clearance, ERPF was assessed by para-aminohippurate plasma clearance and CLcr was measured by 24h urine collection. Results All treatments were generally well tolerated. A modest decrease (1014%) in CLcr was observed, consistent with clinical study observations. DTG 50mg once daily and twice daily had no significant effect on GFR or ERPF compared with placebo over 14 days in healthy subjects. Conclusions These findings support in vitro data that DTG increases serum creatinine by the benign inhibition of the organic cation transporter 2, which is responsible for tubular secretion of creatinine.