Zhang Jianping, Thapar Mita, Farrell Colm, Wire Mary B
Department of Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, North Carolina, 27709, USA,
Pharm Res. 2015 Jun;32(6):2015-28. doi: 10.1007/s11095-014-1594-x. Epub 2014 Dec 23.
The pharmacokinetics of eltrombopag and its stimulation of platelet production were characterized in patients with chronic hepatitis C virus (HCV) infection to optimize an eltrombopag dosing regimen for treatment of HCV-related thrombocytopenia before and throughout peginterferon (pegIFN)-based antiviral therapy.
Population pharmacokinetic analysis for eltrombopag included 663 individuals (healthy subjects, n = 28; patients with HCV, n = 635). Population pharmacokinetic/pharmacodynamic analysis for platelet response involved patients with HCV only. Simulations were conducted using various dosing scenarios in the same patient population.
Eltrombopag pharmacokinetics were described by a two-compartment model with dual sequential first-order absorption and elimination. Age, race, sex, and severity of hepatic impairment were predictors of eltrombopag clearance. The effect of eltrombopag on platelet counts was adequately described by a model with four transit compartments in which eltrombopag concentrations stimulated the production rate of platelet precursors in an Emax manner.
Modeling and simulation results support once-daily eltrombopag 25 mg as an appropriate starting dosing regimen followed by biweekly dose escalation (in 25-mg increments) up to once-daily eltrombopag 100 mg to raise platelet counts sufficiently for initiation of pegIFN-based antiviral therapy in patients with HCV. Biweekly dose adjustment allows patients to stay on the lowest possible eltrombopag dose during antiviral therapy.
对慢性丙型肝炎病毒（HCV）感染患者的艾曲泊帕药代动力学及其对血小板生成的刺激作用进行表征，以优化在基于聚乙二醇干扰素（pegIFN）的抗病毒治疗之前及整个治疗过程中用于治疗HCV相关血小板减少症的艾曲泊帕给药方案。
艾曲泊帕的群体药代动力学分析纳入了663名个体（健康受试者，n = 28；HCV患者，n = 635）。血小板反应的群体药代动力学/药效学分析仅涉及HCV患者。在同一患者群体中使用各种给药方案进行模拟。
艾曲泊帕药代动力学由具有双重顺序一级吸收和消除的二室模型描述。年龄、种族、性别和肝损伤严重程度是艾曲泊帕清除率的预测因素。艾曲泊帕对血小板计数的影响通过一个具有四个转运室的模型得到充分描述，其中艾曲泊帕浓度以Emax方式刺激血小板前体的生成速率。
建模和模拟结果支持将每日一次25 mg艾曲泊帕作为合适的起始给药方案，随后每两周剂量递增（以25 mg增量），直至每日一次100 mg艾曲泊帕，以充分提高血小板计数，使HCV患者能够开始基于pegIFN的抗病毒治疗。每两周进行剂量调整可使患者在抗病毒治疗期间维持在尽可能低的艾曲泊帕剂量。
