Kupcová Viera, Sperl Jan, Pannier Anne, Jordan Paul, Dougherty Frank C, Reigner Bruno
IIIrd Department of Internal Medicine, Dérer's Hospital, Bratislava, Slovakia.
Curr Med Res Opin. 2008 Jul;24(7):1943-50. doi: 10.1185/03007990802176467. Epub 2008 May 29.
To examine the effect of severe hepatic impairment (HI) on the pharmacokinetics (PK) and pharmacodynamics (PD) of the continuous erythropoietin receptor activator, C.E.R.A.
A non-randomised, multicentre, single-dose, open-label study in patients with HI (n=12) and healthy subjects (n=12). After 2 weeks of screening, participants received a single intravenous dose of C.E.R.A. (200 mug), and were then followed for approximately 8 weeks. The area under the concentration-time curve (AUC) from drug administration to last measurable concentration (AUC(last)), and maximum C.E.R.A. concentration (C(max)) were calculated to assess PK. The baseline-corrected area under the effect curve over 22 days (AUE(corr)) for reticulocyte count was the primary PD parameter.
The PK profile was similar in patients and healthy subjects (AUC(last): 6678 vs 6985 ng*h/mL; C(max): 63 vs 75 ng/mL) C.E.R.A. produced a sustained erythropoietic response in bothgroups, with increases in reticulocyte counts peaking 7-9 days post-dose and returning to baseline by Day 22. Although mean AUE(corr) was 64% lower in patients, this may have been an artefact of higher baseline reticulocyte counts. Lower reticulocyte responses in patients did not translate into lower responses for haemoglobin, haematocrit or erythrocytes, suggesting that HI had no clinically relevant effect on the PD of C.E.R.A. C.E.R.A. was well tolerated. Four AEs (none considered drug related) were reported in three patients (mild myocardial ischaemia; mild pyrexia and liver transplant; severe bacterial peritonitis [serious AE]); no AEs were reported in healthy subjects.
Severe HI has no clinically relevant effect on PK parameters or haematological response after single-dose C.E.R.A.
研究严重肝功能损害（HI）对连续促红细胞生成素受体激活剂C.E.R.A.的药代动力学（PK）和药效学（PD）的影响。
一项针对HI患者（n = 12）和健康受试者（n = 12）的非随机、多中心、单剂量、开放标签研究。经过2周的筛查，参与者接受单次静脉注射C.E.R.A.（200微克），然后随访约8周。计算从给药到最后可测量浓度的浓度-时间曲线下面积（AUC）（AUC(last)）以及最大C.E.R.A.浓度（C(max)）以评估PK。网织红细胞计数在22天内的基线校正效应曲线下面积（AUE(corr)）是主要的PD参数。
患者和健康受试者的PK曲线相似（AUC(last)：6678对6985纳克·小时/毫升；C(max)：63对75纳克/毫升）。C.E.R.A.在两组中均产生持续的促红细胞生成反应，网织红细胞计数增加在给药后7 - 9天达到峰值，并在第22天恢复到基线。虽然患者的平均AUE(corr)低64%，但这可能是基线网织红细胞计数较高导致的假象。患者中网织红细胞反应较低并未转化为血红蛋白、血细胞比容或红细胞反应较低，这表明HI对C.E.R.A.的PD没有临床相关影响。C.E.R.A.耐受性良好。三名患者报告了4例不良事件（均不认为与药物相关）（轻度心肌缺血；轻度发热和肝移植；严重细菌性腹膜炎[严重不良事件]）；健康受试者未报告不良事件。
严重HI对单次剂量C.E.R.A.后的PK参数或血液学反应没有临床相关影响。
