ICON Development Solutions, Marlow, Buckinghamshire, UK.
Cancer Chemother Pharmacol. 2013 Jun;71(6):1507-20. doi: 10.1007/s00280-013-2150-9. Epub 2013 Apr 6.
Eltrombopag, a thrombopoietin receptor agonist, is being evaluated for the treatment of chemotherapy-induced thrombocytopenia. Due to the delay in platelet response after the administration of eltrombopag or chemotherapy, a modeling and simulation approach was used to optimize the eltrombopag dosing regimen.
Pharmacokinetic (PK) data from 2 studies in healthy subjects and PK and platelet data from a Phase II study in subjects with cancer receiving carboplatin/paclitaxel (where eltrombopag was given 10 days after chemotherapy) were used to develop a nonlinear mixed-effects PK/PD model. Alternative eltrombopag dosing regimens were then simulated.
The PK model was a linear two-compartment model with first-order absorption. Being Asian, female, and >50 years of age were associated with higher eltrombopag exposure. The time course of platelet counts was described by a four-compartment transit model. Carboplatin inhibited platelet precursor production linearly with dose, with increased effect with each cycle of chemotherapy. Eltrombopag stimulated platelet precursor production, proportional to plasma eltrombopag concentration, and stimulation (slope of the concentration effect) was attenuated with each cycle of chemotherapy.
Simulations indicated that eltrombopag administered 5 days before and 5 days after chemotherapy minimizes the decrease and fluctuations in platelet counts relative to other evaluated dosing regimens.
血小板生成素受体激动剂艾曲泊帕正在被评估用于治疗化疗引起的血小板减少症。由于艾曲泊帕或化疗后血小板反应的延迟，因此采用建模和模拟方法来优化艾曲泊帕的给药方案。
使用来自 2 项健康受试者研究的药代动力学（PK）数据和来自接受卡铂/紫杉醇的癌症受试者的 PK 和血小板数据（其中艾曲泊帕在化疗后 10 天给予）来建立非线性混合效应 PK/PD 模型。然后模拟替代的艾曲泊帕给药方案。
PK 模型为具有一级吸收的线性两室模型。亚洲人、女性和年龄>50 岁与更高的艾曲泊帕暴露相关。血小板计数的时间过程由四室转运模型描述。卡铂呈剂量依赖性线性抑制血小板前体的产生，随着每个化疗周期的增加，其作用增强。艾曲泊帕刺激血小板前体的产生，与血浆艾曲泊帕浓度成正比，并且随着每个化疗周期的进行，刺激（浓度效应的斜率）减弱。
模拟结果表明，与其他评估的给药方案相比，化疗前 5 天和化疗后 5 天给予艾曲泊帕可最大程度地减少血小板计数的减少和波动。
