Characterizing the Impact of Renal Impairment on the Clinical Pharmacology of Biologics
Characterizing the Impact of Renal Impairment on the Clinical Pharmacology of Biologics
复制标题
DOI：
10.1177/0091270011413894
复制
发表时间：
2012-01-01
影响因子：
2.9
通讯作者：
Zhou, Honghui
中科院分区：
文献类型：
--
作者：
Meibohm, Bernd;Zhou, Honghui
与小分子药物类似，基于蛋白质的治疗药物在肾功能损害（包括肾功能不全和终末期肾病）患者中的临床应用也令人担忧，这可能会调节这些化合物的疗效和/或安全性。理论考虑和临床证据表明，肾脏在分解代谢中起着相关作用，因此只有那些小于肾小球滤过阈值约60 kDa的蛋白质治疗药物才会被消除。因此，肾损害对蛋白质治疗的影响似乎是可预测的，并且仅与低于该分子量临界值的化合物相关。这一点得到临床证据的支持，临床证据表明，肾损害对单克隆抗体等大蛋白质缺乏影响，而低于临界值的小蛋白质，如白细胞介素-10、生长激素、促红细胞生成素、阿那白的清除率逐渐降低全身暴露量随着肾功能损害的加重而增加。因此，在进行肾小球滤过的蛋白质疗法的临床开发项目中，有必要进行专门的肾功能损害研究，以建立其在肾功能不全患者中安全有效使用的科学依据。
Similar to small-molecule drugs, there is also concern for protein-based therapeutics about their clinical use in patients with renal impairment including renal insufficiency and end-stage renal disease, which may modulate the efficacy and/or safety profile of these compounds. Theoretical considerations and clinical evidence suggest that the kidneys play a relevant role in the catabolism and thus elimination of only those protein therapeutics that have a size below the cutoff for glomerular filtration of approximately 60 kDa. Thus, the effect of renal impairment on protein therapeutics seems to be predictable and only relevant for compounds below this molecular weight cutoff This is supported by clinical evidence that shows a lack of effect of renal impairment on large proteins such as monoclonal antibodies, whereas smaller proteins below the cutoff such as interleukin-10, growth hormone, erythropoietin, and anakinra experience a gradual decrease of their clearance and increase of their systemic exposure with increasing severity of renal impairment. Thus, dedicated renal impairment studies are warranted in the clinical development program of protein therapeutics that undergo glomerular filtration to establish the scientific rationale for their safe and efficacious use in patients with renal insufficiency.