Transl Clin Pharmacol.  2018 Jun;26(2):93-98. 10.12793/tcp.2018.26.2.93.

Population pharmacodynamics of cilostazol in healthy Korean subjects

• Jung YS
• Chae D
• Park K

• KMID: 2413833
• DOI: http://doi.org/10.12793/tcp.2018.26.2.93

Abstract

Cilostazol is used for the treatment of intermittent claudication, ulceration and pain. This study was conducted to develop a population pharmacodynamic (PD) model for cilostazol's closure time (CT) prolongation effect in healthy Korean subjects based on a pharmacokinetic (PK) model previously developed. PD data were obtained from 29 healthy subjects who participated in a study conducted in 2009 at Severance Hospital. The PK model used was a two-compartment model with first order absorption. CT data were best described by a turnover model with a fractional turnover rate constant (K(out)) inhibited by drug effects (Eff), which were represented by a sigmoid E(max) model [Eff = E(max) · C(γ) / (ECâ‚…â‚€(γ)+C(γ))] with E(max) being maximum drug effect, ECâ‚…â‚€ drug plasma concentration at 50% of E(max), C drug plasma concentrations, and γ the Hill coefficient. For the selected PD model, parameter estimates were 0.613 hr⁻¹ for K(out), 0.192 for E(max), 730 ng/ml for ECâ‚…â‚€ and 5.137 for γ. Sex and caffeine drinking status significantly influenced the baseline CT, which was 85.36 seconds in male non-caffeine drinkers and increased by 15.5% and 16.4% in females and caffeine drinkers, respectively. The model adequately described the time course of CT. This was the first population PD study for cilostazol's CT prolongation effect in a Korean population.

Keyword

Cilostazol; Closure time; Population pharmacodynamic model; Turnover model; Sigmoid E(max) model

MeSH Terms

Absorption
Caffeine
Colon, Sigmoid
Drinking
Female
Healthy Volunteers
Humans
Intermittent Claudication
Male
Plasma
Ulcer
Caffeine

Figure

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  Figure 1 Observed cilostazol concentrations and closure times; the solid line represents a smoothed line of concentrations and the dashed line a smoothed line of closure times.

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  Figure 2 Goodness-of-fit plots for the final PD model; open circles are observations, red lines smoothed lines, and black lines the line of identity (upper panels) and the zero residual line (lower panels).

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  Figure 3 Visual predictive check for the final PD model; circles represent observed closure times, dashed lines represent 5th, median, and 95th percentiles of predictions, solid lines represent 5th, median, and 95th percentiles of observations, and shaded areas represent 95% confidence intervals of 5th, median, and 95th percentiles of predictions. Time ranges are 0~192 hr in upper panel and 168~192 hr in lower panel, respectively.

Reference

1. Horie N, Kaminogo M, lzumo T, Hayashi K, Tsujino A, Nagata I. Cilostazol may prevent cardioembolic stroke in patients undergoing antiplatelet therapy. Neurol Res. 2015; 37:619–623. DOI: 10.1179/1743132815Y.0000000021. PMID: 25798683.

2. Falconer TM, Eikelboom JW, Hankey GJ, Norman PE. Management of peripheral arterial disease in the elderly: focus on cilostazol. Clin Interv Aging. 2008; 3:17–23. PMID: 18488875.

3. Chi YW, lavie CJ, Milani RV, White CJ. Safety and efficacy of cilostazol in the management of intermittent claudication. Vasc health Risk Manag. 2008; 4:1197–1203. PMID: 19337533.

4. O'Donnell ME, Badger SA, Sharif MA, Young IS, Lee B, Soong CV. The vascular and biochemical effects of cilostazol in patients with peripheral arterial disease. J Vasc Surg. 2009; 49:1226–1234. DOI: 10.1016/j.jvs.2008.11.098. PMID: 19217745.

5. Ikeda U, Ikeda M, Kano S, Kanbe T, Shimada K. Effect of cilostazol, a cAMP phosphodiesterase inhibitor, on nitric oxide production by vascular smooth muscle cells. Eur J Pharmacol. 1996; 314:197–202. PMID: 8957237.

6. Yoo HD, Cho HY, Lee YB. Population pharmacokinetic analysis of cilostazol in healthy subjects with genetic polymorphisms of CYP3A5, CYP2C19 and ABCB1. Br J Clin Pharmacol. 2010; 69:27–37. DOI: 10.1111/j.1365-2125.2009.03558.x. PMID: 20078610.

7. Shao JS, Zhong FL, Hua TC, Fan DZ. Cardiovascular effects and simultaneous pharmacokinetic and pharmacodynamic modeling of cilostazol in healthy subjects. Asian J Drug Metab Pharmacokinet. 2005; 5:301–308.

8. Lee D, Son H, Lim LA, Park K. Population pharmacokinetic analysis of diurnal and seasonal variations of plasma concentrations of cilostazol in healthy volunteers. Ther Drug Monit. 2014; 36:771–780. DOI: 10.1097/FTD.0000000000000077. PMID: 24739664.

9. Suri A, Forbes WP, Bramer SL. Pharmacokinetics of multiple-dose oral cilostazol in middle-age and elderly men and women. J Clin Pharmacol. 1998; 38:144–150. PMID: 9549645.

10. Lee D, Lim LA, Jang SB, Lee YJ, Chung JY, Choi JR, et al. Pharmacokinetic comparison of sustained- and immediate-release oral formulations of cilostazol in healthy Korean subjects: a randomized, open-label, 3-part, sequential, 2-period, crossover, single-dose, food-effect, and multiple-dose study. Clin Ther. 2011; 33:2038–2053. DOI: 10.1016/j.clinthera.2011.10.024. PMID: 22129569.

11. Woo SK, Kang WK, Kwon KI. Pharmacokinetic and pharmacodynamic modeling of the antiplatelet and cardiovascular effects of cilostazol in healthy humans. Clin Pharmacol Ther. 2002; 71:246–252. PMID: 11956507.

12. Yun HY, Kang W, Lee BY, Park S, Yoon YR, Yeul Ma J, et al. Semi-mechanistic modeling and simulation of inhibition of platelet aggregation by antiplatelet agents. Basic Clin Pharmacol Toxicol. 2014; 115:352–359. DOI: 10.1111/bcpt.12222. PMID: 24612881.

13. Paniccia R, Priora R, Liotta AA, Abbate R. Platelet function tests: a comparative review. Vasc Health Risk Manag. 2015; 11:133–148. DOI: 10.2147/VHRM.S44469. PMID: 25733843.

14. Karger R, Donner-Banzhoff N, Müller HH, Kretschmer V, Hunink M. Diagnostic performance of the platelet function analyzer (PFA-100) for the detection of disorders of primary haemostasis in patients with a bleeding history–a systematic review and meta-analysis. Platelets. 2007; 18:249–260. PMID: 17538845.

15. Felmlee MA, Morris ME, Mager DE. Mechanism-based pharmacodynamic modeling. Methods Mol Biol. 2012; 929:583–600. PMID: 23007443.

16. Mould DR, Upton RN. Basic Concepts in Population Modeling, Simulation, and Model-Based Drug Development: part 3-Introduction to Pharmacodynamic Modeling Methods. CPT Pharmacometrics Syst Pharmacol. 2014; 3:e88. DOI: 10.1038/psp.2013.71. PMID: 24384783.

17. Cho YU, Chi HS, Jang S, Park CJ. Reconfirmation of preanalytical variables and establishment of reference intervals of platelet function analyzer-100 closure times in Korean adults. Korean J Lab Med. 2007; 27:318–323. PMID: 18094595.

18. Kim YS, Lee IO, Park HY, Park JH, Lim BG, Kim H. Platelet function assay to determine the optimal preoperative cessation period of aspirin. Anesth Pain Med. 2014; 9:31–35.

19. Varani K, Portaluppi F, Gessi S, Merighi S, Ongini E, Belardinelli L, et al. Dose and Time Effects of Caffeine Intake on Human Platelet Adenosine A_2A Receptors. Circulation. 2000; 102:285–289. PMID: 10899090.

20. Natella F, Nardini M, Belelli F, Pignatelli P, Di Santo S, Ghiselli A, et al. Effect of coffee drinking on platelets: inhibition of aggregation and phenols incorporation. Br J Nutr. 2008; 100:1276–1282. DOI: 10.1017/S0007114508981459. PMID: 18439332.

21. Becker DM, Segal J, Vaidya D, Yanek LR, Herrera-Galeano JE, Bray PF, et al. Sex differences in platelet reactivity and response to low-dose aspirin therapy. JAMA. 2006; 295:1420–1427. PMID: 16551714.

22. Miller CH, Rice AS, Garrett K, Stein SF. Gender, race and diet affect platelet function tests in normal subjects, contributing to a high rate of abnormal results. Br J Haematol. 2014; 165:842–853. DOI: 10.1111/bjh.12827. PMID: 24617520.

23. Hobson AR, Qureshi Z, Banks P, Curzen N. Gender and responses to aspirin and clopidogrel: insights using short thrombelastography. Cardiovasc Ther. 2009; 27:246–252. DOI: 10.1111/j.1755-5922.2009.00106.x. PMID: 19903188.

24. Chae D, Son M, Kim Y, Son H, Park K. Mechanistic model for blood pressure and heart rate changes produced by telmisartan in human beings. Basic Clin Pharmacol Toxicol. 2018; 122:139–148. DOI: 10.1111/bcpt.12856. PMID: 28805311.