Development of a population model to describe diurnal and chronokinetic variation in cilostazol pharmacokinetics
D. Lee (1,2), L.A. Lim(1,2), H. Son(1,2), J Chung (1,2), K. Park (1,2)
(1) Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea (2) Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
Objectives: Diurnal variation, characterized by higher Cmax and shorter Tmax after the morning dose in oral twice-a-day treatment, has been reported in many lipophilic drugs, which is known to occur due to higher gastrointestinal perfusion rates and faster gastric emptying times in the morning. [1-3] The primary purpose of this study was to investigate such variation in cilostazol pharmacokinetics (PK) , and assess seasonal or chronokinetic variation of the drug also. The secondary purpose was to explain the pharmacokinetic relationship between the parent drug (cilostazol, OPC-13013) and its potent active metabolite, OPC-13015.
Methods: A total of 1,856 plasma concentrations ware obtained from 2 PK studies recently conducted in healthy Korean subjects, Study 1 conducted in 26 subjects in February (winter), and Study 2 conducted in 37 subjects in August (summer). A population model was developed using NONMEM 7. To model diurnal variation, the circadian rhythm consisting of cosign functions with various periods were incorporated into the absorption rate constant (KA). Study effect was described as a covariate influencing the typical value of PK parameters. On the assumption that the PK of OPC13015 doesn't affect the PK cilostazol, the model building for the metabolite was conducted after completing the modeling for the parent drug. The central volume of metabolite was fixed to 1. The developed model was then validated using visual predictive check (VPC) using 1000 simulated datasets.
Results: A two compartment model with first order absorption was selected for fixed effect, and proportional models for inter and intra-individual errors, allowing for a lag time. The final estimated values (RSE%) of KA, oral clearance (CL/F), central volume (Vc/F), inter-compartment clearance(Q/F), peripheral volume (Vp/F) and lag time (LAG) were 0.249 hr-1 (25.2%), 13.8 L·hr-1 (6.61%), 30.7 L (31.4%), 15.0 L·hr-1 (13.2%), 88.0 L (10.2%), and 0.443 hr (12.8%) , respectively. The circadian rhythm was best described by the combination of periods of 24 and 12 hrs, yielding estimated values (RSE%) of amplitude and acrophase for 24 hour rhythm being 0.185 (16.1%) and 1.50 (48.4%), and those for 12 hour rhythm being 0.337 (17.3%) and 7.24 (5.62%), which decreased OFV by 356.658 Study differences were found significant in CL/F and KA2M (p<0.001), yielding 9.43 L·hr-1 and 8.80 hr in Study 1 versus 13.8 L·hr-1 and 7.24 hr in Study 2, respectively. A two compartment model was selected for fixed effect in the metabolite model, and proportional models for individual errors. The final estimated values (CV%) of Q4, CLM, V5, and Q5 were 1.12 L·hr-1, 3.30 L·hr-1 (18.4%), 8.84 L (30.9%), and 15.0 L·hr-1 (21.5%), respectively.
Conclusions: These results show that cilostazol PK in Korean population are influenced not only by diurnal variation but also by seasonable variation, indicating the importance of considering such variations in optimal drug therapy of this drug. To validate our results, further study with more patients will be necessary.
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