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Son, Cho, Choi, Kim, Kwon, Jin, Kim, and Hong: Pharmacokinetic characteristics of cilostazol 200 mg controlled-release tablet compared with two cilostazol 100 mg immediate-release tablets (Pletal) after single oral dose in healthy Korean male volunteers
Original Article

Translational and Clinical Pharmacology 2016;24(4):183-188.

Published online: 19 January 2016

DOI: https://doi.org/10.12793/tcp.2016.24.4.183

Pharmacokinetic characteristics of cilostazol 200 mg controlled-release tablet compared with two cilostazol 100 mg immediate-release tablets (Pletal) after single oral dose in healthy Korean male volunteers

Jin Dong Son1, 4, Sang Min Cho2, Youn Woong Choi2, Soo-Hwan Kim3, In Sun Kwon4, Eun-Heui Jin4, Jae Woo Kim4, Jang Hee Hong∗, 1, 4, 5

1Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea

2Korea United Pharm. Inc., Seoul 06116, Republic of Korea

3Caleb Multilab Inc., Seoul 06745, Republic of Korea

4Clinical Trials Center, Chungnam National University Hospital, Daejeon 35015, South Korea

5Department of Pharmacology, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea

∗Correspondence: J.H. Hong; Tel: +82-42-280-6940, Fax: +82-42-280-6940, E-mail: boniii@cnu.ac.kr

Received 8 September 2016       Revised 28 November 2016       Accepted 29 November 2016

Copyright © 2016 Korean Society for Clinical Pharmacology and Therapeutics

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Cilostazol controlled-release (CR) tablets have recently been developed by Korea United Pharm (Seoul, Korea). The tablets use a patented double CR system, which improves drug compliance by allowing “once daily” administration and reduces adverse events by sustaining a more even plasma concentration for 24 h. We conducted an open, randomized, two-period, two-treatment, crossover study to compare the pharmacokinetic (PK) characteristics and tolerability of cilostazol when administered to healthy Korean male volunteers as CR or immediate release (IR) tablets (Pletal, Korea Otsuka Pharmaceutical Co., Gyeonggi-do, Korea). Each volunteer was randomly allocated to receive a single tablet of cilostazol CR (200 mg) or two tablets of cilostazol IR (100 mg) with a 7-day washout period between treatments. Plasma cilostazol, OPC-13015 (3,4-dehydrocilostazol), and OPC-13213 (4'-trans-hydroxycilostazol) were assayed using liquid chromatography-tandem mass spectrometry for PK analysis. Thirty participants completed the study with no clinically relevant safety issues. The peak concentrations (Cmax, mean ± SD) of cilostazol CR and cilostazol IR were 1414.6 ± 49.3 and 1413.1 ± 35.2 ng/mL, respectively, and the areas under the plasma concentration–time curve from 0 to the last concentration (AUClast) were 23928.7 ± 65.9 and 25312.0 ± 62.6 ng∙h/ mL, respectively. The geometric mean ratios (cilostazol CR/ cilostazol IR, GMR) of the Cmax and AUClast values were 1.001 (90% CI: 0.822, 1.220) and 0.945 (90% CI: 0.814, 1.098), respectively. The frequencies of adverse events were similar. The present study showed that cilostazol PK and tolerability were comparable when administered to healthy Korean men, regardless of whether administered as cilostazol CR or IR.

Keywords: Cilostazol, OPC-13015, OPC-13213, bioequivalence, pharmacokinetics

REFERENCES

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Figure 1.
Disposition of the study participants.
tcp-24-183f1.tif
Figure 2.
Mean plasma concentration–time profiles of cilostazol (A), OPC13015(3,4-dehydrocilostazol) (B) and OPC13213 (4´-trans-hydroxycilostazol) (C) after oral administration of a single tablet of cilostazol CR 200 mg or two tablets of cilostazol IR 100 mg in healthy Korean male study participants (n = 30). The error bars represent standard deviation. ∗Reference drug: cilostazol 100 mg IR two tablets, test drug: cilostazol 200 mg CR one tablet.
tcp-24-183f2.tif
Table 1.
Demographic characteristics of the study participants
    Group A (n=15) Group B (n=15) Total (n = 30) P
Age (years)   22.9 ± 2.0 23.9 ±2.1 23.4 ± 2 0.188∗
Weight (kg)   68.7 ± 7.1 66.9 ± 6.9 67.7 ± 6.8 0.471∗
Height (cm)   176.5 ± 5.3 174.0 ± 4.5 175.2 ± 4.9 0.183∗
Drinking‡ Yes 8 8 16 > 0.999§
No 7 7 14
Smoking‡ Yes 7 8 15 > 0.999§
No 8 7 15
Caffeine‡ Yes 4 9 13 0.139§
No 11 6 17

Values are presented as mean ± SD;

∗ Mann–Whitney U test.

† t test.

§ Chi-square test

Table 2.
Summary of pharmacokinetic parameters after a single oral administration of the two formulations
Parameters Cilostazol CR (n = 30) Cilostazol IR (n = 30) P
Cilostazol      
Cmax (ng/ml) 1414.6 (49.3) 1413.1 (35.2) 0.993
  [335.9 to 3097.7] [420.4 to 2557.4]  
AUClast (ng∙h/ml) 23928.7 (65.9) 25312.0 (62.6) 0.528
  [9898.6 to 75046.5] [6473.8 to 70296.3]  
AUCinf (ng∙h/ml) 28232.8 (69.2) 28606.6 (60.6) 0.886
  [13789.1 to 91534.3] [10160.4 to 79973.5]  
Tmax∗ (h) 4.0 [2.0 to 8.0] 15 [2.0 to 24.0] -
t1/2 (h) 15.7 (58.4) 10.6 (68.5) 0.017
  [6.1 to 47.6] [3.2 to 38.1]  
OPC-13015      
Cmax (ng/ml) 261.1 (52.5) 290.2 (33.2) 0.370
  [94.9 to 736.6] [86.9 to 497.1]  
AUClast (ng∙h/mL) 6968.8 (82.3) 7630.3 (60.9) 0.317
  [2991.7 to 27186.7] [2695.0 to 22252.9]  
AUCinf (ng∙h/mL) 7348.6 (97.3) 7890.6 (72.0) 0.435
  [3130.4 to 31866.9] [2846.0 to 28462.5]  
Tmax∗ (h) 6.0 [3.0 to 36.0] 16 [15.0 to 36.0]  
t1/2 (h) 10.3 (90.1) 8.3 (64.6) 0.052
  [5.2 to 45.0] [4.7 to 23.9]  
OPC-13213      
Cmax (ng/mL) 121.3 (57.6) 147.6 (43.2) 0.046
  [30.6 to 326.4] [76.8 to 349.6]  
AUClast (ng∙h/mL) 2412.6 (53.0) 2964.0 (48.1) 0.007
  [996.1 to 5552.8] [1636.1 to 7767.6]  
AUCinf (ng∙h/mL) 2909.3 (52.8) 3183.4 (46.9) 0.260
  [1418.3 to 6648.8] [1759.6 to 7832.2]  
Tmax∗ (h) 5.0 [3.0 to 8.0] 16.0 [3.0 to 24.0] -
t1/2 (h) 15.6 (112.0) 10.5 (4.6) 0.012
  [6.2 to 92.7] [4.7 to 22.7]  

Values are presented as the geometric mean (CV%) [min to max].

∗ Median [min to max]. Cmax: Maximum plasma concentration. AUClast: Area under the plasma concentration–time curve to the last sampling time. AUCinf: Area under the plasma concentration–time curve to infinity. Tmax: Time to Cmax. t1/2: Terminal half-life.

Table 3.
Bioequivalence assessment of pharmacokinetic parameters
PK parameter Geometric mean ratio (Cilostazol CR/cilostazol IR)
Point estimate 90% Confidence interval
Cilostazol    
Cmax (ng/ml) 1.001 0.822 to 1.220
AUClast (ng∙h/ml) 0.945 0.814 to 1.098
AUCinf (ng∙h/ml) 0.987 0.845 to 1.152
OPC-13015    
Cmax (ng/ml) 0.873 0.717 to 1.063
AUClast (ng∙h/ml) 0.907 0.786 to 1.047
AUCinf (ng∙h/ml) 0.923 0.795 to 1.071
OPC-13213    
Cmax (ng/mL) 0.831 0.713 to 0.969
AUClast (ng∙h/ml) 0.818 0.728 to 0.919
AUCinf (ng∙h/ml) 0.902 0.788 to 1.032

Cmax: Maximum plasma concentration. AUClast: Area under the plasma concentration–time curve to the last sampling time. AUCinf: Area unde the plasma concentration–time curve to infinity.

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