Preclinical pharmacokinetics and pharmacodynamics of apixaban, a potent and selective factor Xa inhibitor
Preclinical pharmacokinetics and pharmacodynamics of apixaban, a potent and selective factor Xa inhibitor
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DOI：
10.1007/s13318-011-0037-x
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发表时间：
2011-09-01
影响因子：
1.9
通讯作者：
Grossman, Scott J.
中科院分区：
文献类型：
--
作者：
He, Kan;Luettgen, Joseph M.;Grossman, Scott J.
阿哌沙班是一种有效的、高选择性的、可逆的、口服的、直接的Xa因子（fXa）抑制剂，正在开发用于预防和治疗血栓形成。阿哌沙班的临床前药代动力学（PK）属性具有分布容积（Vd）小、全身清除率（CL）低和口服生物利用度良好的特点。阿哌沙班在大鼠、犬和黑猩猩中吸收良好，绝对口服生物利用度约为50%或更高。在大鼠、犬和黑猩猩中，阿哌沙班的稳态Vd约为0.5、0.2和0.17 l/kg，而CL分别约为0.9、0.04和0.018 l/h/kg。阿哌沙班的体外代谢清除率也较低。在大鼠、犬和黑猩猩中，肾脏清除率约占全身清除率的10-30%。在大鼠、犬和黑猩猩中，抗fXa活性、凝血酶原时间（PT）和HEPTESTA（R）凝血时间（HCT）延长与血浆阿哌沙班浓度密切相关。阿哌沙班血浆浓度与药效学（PD）标志物之间无滞后时间，表明阿哌沙班起效迅速。使用抑制性E（max）模型进行PK/PD分析，用于抗fXa试验，使用线性模型进行PT和HCT试验。大鼠和犬的抗fXa活性的IC 50值分别为0.73 +/-A0.03和1.5 +/-A0.15 μ M。对于大鼠、犬和黑猩猩，PT的表观K（i）值分别约为1.7、6.6和4.8 μ M。对于犬，HCT的表观K（i）约为1.3 μ M。阿哌沙班表现出临床开发所需的PK和PD特性，具有良好的口服生物利用度、较小的Vd、较低的CL和直接、可预测的浓度依赖性PD反应。
Apixaban is a potent, highly selective, reversible, oral, direct factor Xa (fXa) inhibitor in development for thrombosis prevention and treatment. The preclinical pharmacokinetic (PK) attributes of apixaban feature small volume of distribution (Vd), low systemic clearance (CL), and good oral bioavailability. Apixaban is well absorbed in rat, dog, and chimpanzee, with absolute oral bioavailability of approximately 50% or greater. The steady-state Vd of apixaban is approximately 0.5, 0.2, and 0.17 l/kg in rats, dogs, and chimpanzees, while CL is approximately 0.9, 0.04, and 0.018 l/h/kg, respectively. In vitro metabolic clearance of apixaban is also low. Renal clearance comprises approximately 10-30% of systemic clearance in rat, dog, and chimpanzee. Anti-fXa activity, prothrombin time (PT), and HEPTESTA (R) clotting time (HCT) prolongation correlated well with plasma apixaban concentration in rat, dog and chimpanzee. There was no lag time between apixaban plasma concentration and the pharmacodynamic (PD) markers, suggesting a rapid onset of action of apixaban. The PK/PD analyses were performed using an inhibitory E (max) model for anti-fXa assay and a linear model for PT and HCT assays. The IC50 values for anti-fXa activity were 0.73 +/- A 0.03 and 1.5 +/- A 0.15 mu M for rat and dog, respectively. The apparent K (i) values for PT were approximately 1.7, 6.6, and 4.8 mu M for rat, dog and chimpanzee, respectively. The apparent K (i) for HCT was approximately 1.3 mu M for dog. Apixaban exhibits desirable PK and PD properties for clinical development with good oral bioavailability, small Vd, low CL, and direct, predictable, concentration-dependent PD responses.