Assessment of the Effects of the Nitroimidazo-Oxazine PA-824 on Renal Function in Healthy Subjects
Assessment of the Effects of the Nitroimidazo-Oxazine PA-824 on Renal Function in Healthy Subjects
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DOI：
10.1128/aac.00112-09
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发表时间：
2009-09-01
影响因子：
4.9
通讯作者：
Spigelman, Mel K.
中科院分区：
文献类型：
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作者：
Ginsberg, Ann M.;Laurenzi, Martino W.;Spigelman, Mel K.
在47名健康男性和女性志愿者中评价了PA-824（一种新型硝基咪唑并恶嗪）给药引起的剂量依赖性、可逆性血清肌酐（SC）升高的机制。受试者接受800或1，000 mg PA-824或匹配安慰剂每日一次给药，持续8天。在给药前和给药期间以及7天洗脱期后测定以下肾功能参数：SC，肾小球滤过率（GFR;测量为碘海醇清除率），有效肾血浆流量（ERPF;测量为对氨基马尿酸清除率）、滤过分数（FF）、肌酐清除率（CrCl）、肾小球外肌酐排泄（EGCE;定义为CrCl减去GFR）、血尿素氮（BUN）和尿酸（UA）水平。800或1，000 mg PA-824给药8天与SC增加以及CrCl和EGCE降低趋势相关。SC、CrCl和EGCE值在1周洗脱期内恢复至正常/基线。在治疗和洗脱期间，各组的GFR、ERPF、FF、BUN和UA值相似。因此，在本试验和早期PA-824试验中观察到的SC可逆性增加似乎不是对肾功能的病理学影响的结果（通过GFR、ERPF、FF、BUN或UA测量）。药代动力学分析证实，PA-824暴露量与既往健康志愿者临床研究中的暴露量相似。药物水平最高时EGCE下降最大，表明PA-824通过抑制肾小管肌酐分泌导致肌酐水平升高。这种作用被认为是临床良性的，已经在几种上市药物中描述过。
The mechanism underlying a dose-dependent, reversible increase in serum creatinine (SC) caused by the administration of PA-824, a novel nitroimidazo-oxazine, was evaluated in 47 healthy male and female volunteers. Subjects were administered either 800 or 1,000 mg PA-824 or matching placebo once daily for 8 days. The following renal function parameters were determined before and during dosing and after a 7-day washout: SC, glomerular filtration rate (GFR; measured as the iohexol clearance), effective renal plasma flow (ERPF; measured as the para-amino hippurate clearance), filtration fraction (FF), creatinine clearance (CrCl), extraglomerular creatinine excretion (EGCE; defined as CrCl minus GFR), blood urea nitrogen (BUN), and uric acid (UA) levels. Eight days' administration of 800 or 1,000 mg PA-824 was associated with increased SC and a trend toward decreased CrCl and EGCE. SC, CrCl, and EGCE values returned to normal/baseline within 1 week's washout. GFR, ERPF, FF, BUN, and UA values were similar across groups during treatment and washout. The reversible increase in SC observed in this and earlier trials of PA-824, thus, did not appear to be the result of a pathological effect on renal function (as measured by GFR, ERPF, FF, BUN, or UA). Pharmacokinetic analyses confirmed that PA-824 exposures were similar to those in previous healthy-volunteer clinical studies. That EGCE declined maximally when drug levels were highest suggests that PA-824 causes creatinine levels to rise by inhibiting renal tubular creatinine secretion. Such an effect, considered clinically benign, has been described for several marketed drugs.