Pharmacokinetic comparison of sustained- and?immediate-release formulations of cilostazol after multiple oral doses in fed healthy male Korean volunteers

摘要

Background: A new extended-release form of cilostazol has recently been developed. This study was conducted to compare the pharmacokinetic characteristics of sustained-release (SR) and immediate-release (IR) formulations of cilostazol after multiple oral doses in healthy male Korean volunteers.Methods: This was an open-label, randomized, multiple-dose, crossover study conducted in 30 healthy Korean subjects. In each treatment period, subjects received oral doses of 200?mg SR formulation every 24?hours or 100?mg IR formulation every 12?hours for 5 consecutive days in a fed state, with a washout period of 9?days. The plasma concentrations of cilostazol and its metabolites were determined using a validated liquid chromatography-tandem mass spectrometry method. The area under the plasma concentration–time curve within a dosing interval (AUCT), the measured peak plasma concentration at steady state (Cmax,ss), and the time to reach Cmax,ss (tmax,ss) were analyzed using a noncompartmental method. Results: A total of 24 healthy male subjects completed the study. The mean (standard deviation [SD]) AUCT (96–120?hours) values for SR and IR were 27,378.0 (10,301.6) ng·h/mL and 27,860.3 (7,152.3) ng·h/mL, respectively. The mean (SD) Cmax,ss values were 2,741.4 (836.0)?ng/mL and 2,051.0 (433.2) ng/mL, respectively. The median tmax,ss values were 8.0?hours and 4.0?hours, respectively. The geometric mean ratios (90% confidence intervals) of the SR to IR formulations were 0.937 (0.863–1.017), 0.960 (0.883–1.043), and 0.935 (0.859–1.017) for AUCT and 0.644 (0.590–0.703), 0.586 (0.536–0.642), and 0.636 (0.577–0.702) for dose-normalized Cmax,ss of cilostazol, OPC-13015 (3,4-dehydro-cilostazol), and OPC-13213 (4'-trans-hydroxyl-cilostazol), respectively. All formulations were well tolerated. Conclusion: At steady state, the AUCT of cilostazol SR 200?mg is comparable to that of cilostazol IR 100?mg twice a day in healthy male Korean subjects. Both formulations are well tolerated.