Amgen SA, Barcelona, Spain.
J Clin Pharmacol. 2012 Oct;52(10):1540-51. doi: 10.1177/0091270011420843. Epub 2011 Dec 13.
A pharmacodynamic model was developed for platelet counts in 52 patients with immune thrombocytopenia (ITP) receiving subcutaneous romiplostim in 3 phase I/II studies (dose range, 0.2-10 µg/kg). The model consisted of a drug-sensitive progenitor cell compartment linked to a peripheral blood compartment through 4 transition compartments. The baseline platelet count, mean transit time, and kinetics of drug effect constant were 11.1 × 10(9)/L, 170 hours, and 0.6 day(-1), respectively. The ITP patients had a shorter platelet life span and lower progenitor cell production rates than healthy volunteers. Romiplostim response was described for 2 subpopulations. The romiplostim stimulatory effect in ITP patients was 351%/100 µg/wk and 12%/100 µg/wk in 68% and 32% of patients, respectively. Visual and numerical predictive checks suggested accurate prediction of platelet time course and durable response rate in ITP patients. Model-based simulations confirmed the effectiveness of dose reduction to prevent platelet counts >400 × 10(9)/L.
在 3 项 I/II 期研究中（剂量范围为 0.2-10μg/kg），对 52 例接受皮下罗米司亭治疗的免疫性血小板减少症（ITP）患者的血小板计数进行了药效动力学模型开发。该模型由一个药物敏感祖细胞隔室通过 4 个过渡隔室与外周血隔室相连。基线血小板计数、平均转运时间和药物效应常数的动力学分别为 11.1×10(9)/L、170 小时和 0.6 天(-1)。与健康志愿者相比，ITP 患者的血小板寿命更短，祖细胞生成率更低。罗米司亭反应可用于描述 2 个亚群。ITP 患者的罗米司亭刺激作用分别为 351%/100μg/周和 12%/100μg/周，分别占 68%和 32%的患者。视觉和数值预测性检查表明，该模型可准确预测 ITP 患者的血小板时间过程和持久应答率。基于模型的模拟证实了减少剂量以预防血小板计数>400×10(9)/L 的有效性。
