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Population pharmacokinetic analysis of diurnal and seasonal variations of plasma concentrations of cilostazol in healthy volunteers.

 Donghwan Lee  ;  Hankil Son  ;  Lay A. Lim  ;  Kyungsoo Park 
 THERAPEUTIC DRUG MONITORING, Vol.36(6) : 771-780, 2014 
Journal Title
Issue Date
Administration, Oral ; Circadian Rhythm/drug effects ; Circadian Rhythm/physiology* ; Female ; Healthy Volunteers* ; Humans ; Male ; Metabolic Clearance Rate/drug effects ; Metabolic Clearance Rate/physiology ; Models, Biological* ; Seasons* ; Tetrazoles/administration & dosage* ; Tetrazoles/blood*
population model ; diurnal variation ; seasonal variation ; cilostazol pharmacokinetics ; optimal dosing time ; therapeutic drug monitoring
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Park, Kyungsoo(박경수) ORCID logo https://orcid.org/0000-0002-6972-1143
Son, Han kil(손한길)
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