Macias William L, Dhainaut Jean-Francois, Yan Sau Chi Betty, Helterbrand Jeffrey D, Seger Mary, Johnson Gerald, Small David S
Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Ind 46285, USA.
Clin Pharmacol Ther. 2002 Oct;72(4):391-402. doi: 10.1067/mcp.2002.128148.
We aimed to characterize the pharmacokinetics and pharmacodynamics of drotrecogin alfa (activated) (recombinant human activated protein C) in patients with severe sepsis.
Patients (N = 1690) in a randomized, double-blind, placebo-controlled phase 3 trial received a 96-hour infusion of placebo (n = 840) or drotrecogin alfa (activated) (n = 850), 24 microg x kg(-1) x h(-1). Plasma samples from 680 patients were collected for pharmacokinetic assessment. Pharmacodynamic effects on activated partial thromboplastin time, D-dimer, protein C, and interleukin 6 were analyzed by drotrecogin alfa (activated) steady-state plasma concentration (C(ss)) quartile.
Transient endogenous activated protein C concentrations above 10 ng/mL were observed in 11 placebo-treated patients (3.3%). In drotrecogin alfa (activated)-treated patients, the median C(ss) was 44.9 ng/mL and the median plasma clearance (CL(p)) was 40.1 L/h. C(ss) was reached within 2 hours after the infusion was started. Plasma concentrations were below the assay quantitation limit of 10 ng/mL within 2 hours after the infusion was stopped in 92% of patients. CL(p) increased with increasing body weight, so infusion rates should be based on predose body weight. Mean CL(p) associated with age, sex, or baseline hepatic or renal function differed by less than 30% from the mean CL(p) in all patients and resided within the interquartile range of CL(p) in all patients. Dose adjustment is not required on the basis of these factors alone or in combination. No correlation was detected between C(ss) quartile and bleeding risk or the magnitudes of effect on biomarkers of coagulopathy (D-dimers and protein C) and inflammation (interleukin 6).
Plasma concentrations of drotrecogin alfa (activated) attain steady state rapidly after the infusion is started and decline rapidly after the infusion is stopped. The infusion rate should be based on predose body weight and not on any other demographic or baseline clinical covariate.
我们旨在描述重组人活化蛋白C（drotrecogin alfa，活化型）在严重脓毒症患者中的药代动力学和药效学特征。
在一项随机、双盲、安慰剂对照的3期试验中，1690例患者接受96小时的安慰剂（n = 840）或重组人活化蛋白C（drotrecogin alfa，活化型）（n = 850）输注，剂量为24μg·kg⁻¹·h⁻¹。收集680例患者的血浆样本进行药代动力学评估。根据重组人活化蛋白C（drotrecogin alfa，活化型）稳态血浆浓度（C(ss)）四分位数分析其对活化部分凝血活酶时间、D - 二聚体、蛋白C和白细胞介素6的药效学作用。
11例接受安慰剂治疗的患者（3.3%）观察到内源性活化蛋白C浓度短暂高于10 ng/mL。在接受重组人活化蛋白C（drotrecogin alfa，活化型）治疗的患者中，C(ss)中位数为44.9 ng/mL，血浆清除率（CL(p)）中位数为40.1 L/h。输注开始后2小时内达到C(ss)。92%的患者在输注停止后2小时内血浆浓度低于检测定量下限10 ng/mL。CL(p)随体重增加而升高，因此输注速率应基于给药前体重。与年龄、性别或基线肝肾功能相关的平均CL(p)与所有患者的平均CL(p)相差不到30%，且处于所有患者CL(p)的四分位间距内。仅基于这些因素单独或联合使用时无需调整剂量。未检测到C(ss)四分位数与出血风险或对凝血障碍生物标志物（D - 二聚体和蛋白C）及炎症（白细胞介素6）的影响程度之间存在相关性。
重组人活化蛋白C（drotrecogin alfa，活化型）输注开始后血浆浓度迅速达到稳态，输注停止后迅速下降。输注速率应基于给药前体重，而非任何其他人口统计学或基线临床协变量。
