Nagata Masashi, Ishiwata Yasuyoshi, Takahashi Yutaka, Takahashi Hiromitsu, Saito Kazutaka, Fujii Yasuhisa, Kihara Kazunori, Yasuhara Masato
Department of Pharmacy, Medical Hospital, Tokyo Medical and Dental University.
Biol Pharm Bull. 2015;38(3):402-10. doi: 10.1248/bpb.b14-00636.
The aim of the present study was to clarify the therapeutic range and adequate dose of sunitinib in Japanese renal cell carcinoma patients by means of a pharmacokinetic-pharmacodynamic analysis of sunitinib-induced thrombocytopenia. Six patients with renal cell carcinoma were enrolled in this study. After starting the sunitinib treatment, between three and seven blood samples were obtained from each patient just before the administration of sunitinib. Serum concentrations of sunitinib and its active metabolite N-desethyl-sunitinib were fit to the 1-compartment model with first-order absorption. Changes in platelet counts were fit to the pharmacokinetic-pharmacodynamic model, in which the proliferation of platelet progenitor cells was assumed to be linearly inhibited by sunitinib and its metabolite. All patients using 50 mg as an initial dose of sunitinib developed grade 2 or 3 thrombocytopenia. The pharmacokinetic-pharmacodynamic model created successfully described the time course of sunitinib-induced thrombocytopenia and could predict changes in platelet counts after alterations to the dosage of sunitinib administered. The simulation results indicated that the total trough level of sunitinib to avoid severe thrombocytopenia should be <100 ng/mL, and also that the initial daily dose of sunitinib could be reduced to 37.5 mg or 25 mg in most Japanese patients. In addition to the pharmacokinetic-guided dosage adjustment, the careful monitoring of platelet counts is required for the safe use of sunitinib.
本研究的目的是通过对舒尼替尼诱导的血小板减少症进行药代动力学-药效学分析，阐明舒尼替尼在日本肾细胞癌患者中的治疗范围和合适剂量。本研究纳入了6例肾细胞癌患者。舒尼替尼治疗开始后，在每次给药前从每位患者采集3至7份血样。舒尼替尼及其活性代谢物N-去乙基舒尼替尼的血清浓度符合具有一级吸收的单室模型。血小板计数的变化符合药代动力学-药效学模型，其中假设血小板祖细胞的增殖受到舒尼替尼及其代谢物的线性抑制。所有以50mg作为舒尼替尼初始剂量的患者均出现2级或3级血小板减少症。成功建立的药代动力学-药效学模型描述了舒尼替尼诱导的血小板减少症的时间进程，并能预测舒尼替尼给药剂量改变后血小板计数的变化。模拟结果表明，为避免严重血小板减少症，舒尼替尼的总谷浓度应<100ng/mL，并且在大多数日本患者中，舒尼替尼的初始日剂量可降至37.5mg或25mg。除了药代动力学指导的剂量调整外，为安全使用舒尼替尼，还需要仔细监测血小板计数。
