Population Pharmacokinetics of Eltrombopag in Healthy Subjects and Patients With Chronic Idiopathic Thrombocytopenic Purpura
Population Pharmacokinetics of Eltrombopag in Healthy Subjects and Patients With Chronic Idiopathic Thrombocytopenic Purpura
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DOI：
10.1177/0091270010375427
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发表时间：
2011-06-01
影响因子：
2.9
通讯作者：
Ouellet, Daniele
中科院分区：
文献类型：
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作者：
Gibiansky, Ekaterina;Zhang, Jianping;Ouellet, Daniele
使用非线性混合效应模型，在健康受试者（n = 111）和特发性血小板减少性紫癜（ITP）患者（n = 88）中描述了艾曲泊帕的群体药代动力学。通过图形诊断和预测检查和非参数自举程序对最终模型进行评价。具有双序贯一级吸收、吸收滞后时间和吸收的病例间变异性的二室模型充分描述了数据。对于未使用皮质类固醇的典型70 kg白人男性ITP患者，估计参数为表观清除率（CL/F）= 0.668 L/h，中央室表观容积（Vc/F）= 8.76 L，外周室表观容积（Vp/F）= 11.3 L，分布清除率（Q/F）= 0.399 L/h。艾曲波帕CL/F、Vc/F、Q/F和Vp/F随体重增加而增加。对于纳入的体重范围（43-122 kg），参数范围为比70 kg个体低26%至高41%。东亚受试者的典型艾曲泊帕CL/F比其他人种低33%，合并使用皮质类固醇的患者低26%，女性比男性低19%，健康受试者比ITP患者高17%。也存在剂量效应，20 mg或更低剂量的CL/F和Vc/F估计分别高出68%和55%。总之，东亚人种对艾曲泊帕暴露量的影响最大，建议使用较低的初始剂量。
The population pharmacokinetics of eltrombopag were characterized in healthy subjects (n = 111) and patients with idiopathic thrombocytopenic purpura (ITP) (n = 88) using nonlinear mixed-effects modeling. The final model was evaluated via graphical diagnostics and through predictive check and nonparametric bootstrap procedures. A 2-compartment model with dual sequential first-order absorption, absorption lag time, and interoccasion variability in absorption adequately described the data. For a typical 70-kg Caucasian male ITP patient not taking corticosteroids, estimated parameters were apparent clearance (CL/F) = 0.668 L/h, apparent volume of the central compartment (Vc/F) = 8.76 L, apparent volume of the peripheral compartment (Vp/F) = 11.3 L, and distributional clearance (Q/F) = 0.399 L/h. Eltrombopag CL/F, Vc/F, Q/F, and Vp/F increased with body weight. For the range of weights included (43-122 kg), the parameters ranged from 26% lower to 41% higher than for a 70-kg individual. The typical eltrombopag CL/F was 33% lower in East Asians compared with other races, 26% lower in patients taking corticosteroids concomitantly, 19% lower in females compared with males, and 17% higher in healthy subjects compared with ITP patients. There was also a dose effect, with CL/F and Vc/F estimated to be respectively 68% and 55% higher for doses 20 mg or less. In conclusion, East Asian race had the largest impact on eltrombopag exposure with a lower initial dose being recommended.