Translational Medicine, Quantitative Pharmacology, The Healthcare Business of Merck KGaA, Darmstadt, Germany.
Global Clinical Development Oncology, The Healthcare Business of Merck KGaA, Darmstadt, Germany.
CPT Pharmacometrics Syst Pharmacol. 2022 May;11(5):594-603. doi: 10.1002/psp4.12743. Epub 2021 Nov 29.
Pan-proteasome inhibitors (pPIs) significantly improve outcomes in patients with multiple myeloma; however, their indiscriminate inhibition of multiple proteasome and immunoproteasome subunits causes diverse toxicities, including thrombocytopenia. We investigated the mechanisms underlying the platelet depletion induced by the pPIs bortezomib, carfilzomib, and ixazomib. An established thrombocytopenia model was adapted for each compound (bortezomib, ixazomib, and carfilzomib) to compare the following two pharmacodynamic mechanisms: a reversible inhibition of new progenitor cell formation (the myelosuppression model) and a reversible effect on the function of megakaryocytes to bud new platelets (platelet formation model). Bortezomib, ixazomib, and carfilzomib plasma concentration profiles and platelet counts were extracted from the literature. Pharmacokinetic (PK) and thrombocytopenia models were developed to predict the PK of these drugs and to describe their effects on proliferating cells and platelet budding. The PK models reproduced the exposure of the three compounds at steady state well compared with those reported in the literature. Both the platelet formation and myelosuppression models seemed able to describe the platelet depletion caused by bortezomib, ixazomib, and carfilzomib. Estimated structural parameters in the myelosuppression model were in the range of the values reported in the literature, whereas the mean transit time estimated with the platelet formation model was 3-fold to 10-fold higher than the highest reported value. The model of drug-induced myelosuppression yielded estimates of structural parameters in the range of those previously reported. The platelet formation model captured the temporal variation reported in clinical studies.
泛蛋白酶体抑制剂 (pPIs) 显著改善多发性骨髓瘤患者的预后；然而，它们对多种蛋白酶体和免疫蛋白酶体亚基的非选择性抑制会导致多种毒性，包括血小板减少症。我们研究了 pPIs 硼替佐米、卡非佐米和伊沙佐米引起血小板减少的机制。为了比较以下两种药效学机制，我们为每种化合物（硼替佐米、伊沙佐米和卡非佐米）改编了已建立的血小板减少症模型：新祖细胞形成的可逆抑制（骨髓抑制模型）和对巨核细胞功能的可逆影响以产生新的血小板（血小板生成模型）。从文献中提取了硼替佐米、伊沙佐米和卡非佐米的血浆浓度曲线和血小板计数。开发了药代动力学 (PK) 和血小板减少症模型来预测这些药物的 PK，并描述它们对增殖细胞和血小板芽生的影响。与文献报道的相比，PK 模型很好地再现了三种化合物在稳态下的暴露。血小板生成和骨髓抑制模型似乎都能够描述硼替佐米、伊沙佐米和卡非佐米引起的血小板减少。骨髓抑制模型中的估计结构参数在文献报道的范围内，而血小板生成模型中估计的平均传输时间比文献报道的最高值高 3 到 10 倍。药物诱导的骨髓抑制模型的结构参数估计值在以前报道的范围内。血小板生成模型捕获了临床研究中报告的时间变化。
