Cui Ailing, Kim Yo Han, Ghim Jong-Lyul, Ah Jung Jin, Cho Sang-Heon, Choe Sangmin, Choi Hee Youn, Bae Kyun-Seop, Lim Hyeong-Seok
Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Department of Clinical Pharmacology, Inje University, Busan Paik Hospital, Busan, Republic of Korea.
Xenobiotica. 2020 Mar;50(3):288-296. doi: 10.1080/00498254.2019.1629042. Epub 2019 Jul 3.
Cilostazol is a selective inhibitor of phosphodiesterase III (PDE III), which is prescribed for patients with peripheral arterial disease, especially intermittent claudication. The purpose of the study was to investigate the pharmacokinetic (PK) of cilostazol and its metabolites on the immediate (IR) formulation of cilostazol in healthy Korean male volunteers by population PK modeling analysis implemented using NONMEM software.A 2 × 2 crossover study comparing multiple oral doses of IR and SR formulations of cilostazol were conducted. Serial plasma concentrations of cilostazol and its active metabolites were used in this analysis.The PK was best depicted by one-compartment model, with absorption kinetics of cilostazol having mixed first- and zero-order kinetics with a time delay at the beginning of absorption. The introduction of interoccasion variabilities into zero-order (D1), first-order (Ka), and relative bioavailability (F1) significantly improved the model fit, and total body water (TBW) was identified as a significant covariate positively affecting the clearance of cilostazol. The model validation suggested that the model constructed in this study predicted the plasma concentration of cilostazol and its two active metabolites reasonably well.The PK model we developed explored the PK characteristics of cilostazol in Korean male subjects, and may be useful for identifying optimal individual dosing regimens of cilostazol.
西洛他唑是磷酸二酯酶III（PDE III）的选择性抑制剂，用于治疗外周动脉疾病患者，尤其是间歇性跛行患者。本研究的目的是通过使用NONMEM软件进行群体药代动力学建模分析，研究西洛他唑及其代谢产物在健康韩国男性志愿者中对西洛他唑速释（IR）制剂的药代动力学（PK）。进行了一项2×2交叉研究，比较了西洛他唑IR和SR制剂的多次口服剂量。本分析使用了西洛他唑及其活性代谢产物的系列血浆浓度。PK最好用单室模型描述，西洛他唑的吸收动力学具有混合的一级和零级动力学，在吸收开始时有时间延迟。将给药间隔变异性引入零级（D1）、一级（Ka）和相对生物利用度（F1）显著改善了模型拟合，并且全身水（TBW）被确定为对西洛他唑清除率有显著正向影响的协变量。模型验证表明，本研究构建的模型能够较好地预测西洛他唑及其两种活性代谢产物的血浆浓度。我们开发的PK模型探索了西洛他唑在韩国男性受试者中的PK特征，可能有助于确定西洛他唑的最佳个体化给药方案。
