Lee Donghwan, Son Hankil, Lim Lay A, Park Kyungsoo
*Department of Pharmacology, Yonsei University College of Medicine; and †Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
Ther Drug Monit. 2014 Dec;36(6):771-80. doi: 10.1097/FTD.0000000000000077.
The background of this study was (1) to examine factors influencing cilostazol pharmacokinetics by developing a population model incorporating diurnal variation and other covariate effects and (2) to assess the feasibility of applying the developed model to determine the optimal dosing times.
Data obtained from a cilostazol pharmacokinetic study consisting of 2 clinical trials (a single twice-a-day (BID) dosing trial in winter and a multiple BID dosing trial in summer) conducted in healthy Korean subjects were used for model building. A basic model was built, followed by a diurnal variation model, and then a final model was built incorporating covariates, including a seasonal difference. The optimal morning and evening dosing times were determined from simulations.
Diurnal variation in cilostazol pharmacokinetics was explained by the morning absorption rate constant being faster than in the evening, yielding values of 0.278 versus 0.234/h in summer, when 24- and 12-hour circadian rhythms were included in the model. The seasonal variation was explained by a 26.9% and a 31.8% decrease in the absorption rate constant and clearance, respectively, in winter compared with summer. Based on twice-a-day (BID) dosing, dosing times of 9 AM and 5 PM in summer and 10 AM and 7 PM in winter were expected to produce the smallest peak-to-peak fluctuations in cilostazol concentration, possibly minimizing unwanted effects of the drug.
This study demonstrated the intraday and interseasonal time-varying nature of cilostazol pharmacokinetics using a population modeling approach and developed a strategy for optimizing dosing times. It is suggested that these methods can be similarly applied to analyses and controls of other drugs that exhibit characteristics of time-varying pharmacokinetics.
本研究的背景是：（1）通过建立一个纳入昼夜变化和其他协变量效应的群体模型来研究影响西洛他唑药代动力学的因素；（2）评估应用所建立的模型确定最佳给药时间的可行性。
从一项西洛他唑药代动力学研究中获得的数据用于模型构建，该研究由在健康韩国受试者中进行的2项临床试验组成（一项在冬季进行的每日两次给药试验和一项在夏季进行的多次每日两次给药试验）。先建立一个基本模型，接着建立昼夜变化模型，然后建立一个纳入包括季节差异在内的协变量的最终模型。通过模拟确定最佳的上午和晚上给药时间。
西洛他唑药代动力学的昼夜变化可解释为上午的吸收速率常数比晚上快，在纳入24小时和12小时昼夜节律的模型中，夏季时上午和晚上的吸收速率常数分别为0.278/h和0.234/h。与夏季相比，冬季的吸收速率常数和清除率分别下降26.9%和31.8%，这解释了季节变化。基于每日两次给药，预计夏季上午9点和下午5点以及冬季上午10点和晚上7点的给药时间会使西洛他唑浓度的峰峰波动最小，可能会将药物的不良影响降至最低。
本研究使用群体建模方法证明了西洛他唑药代动力学的日内和季节间时变特性，并制定了优化给药时间的策略。建议这些方法可类似地应用于对其他表现出时变药代动力学特征的药物的分析和控制。
