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

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 (AUC(T)), the measured peak plasma concentration at steady state (C(max,ss)), and the time to reach C(max,ss) (t(max,ss)) were analyzed using a noncompartmental method. RESULTS: A total of 24 healthy male subjects completed the study. The mean (standard deviation [SD]) AUC(T) (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) C(max,ss) values were 2,741.4 (836.0) ng/mL and 2,051.0 (433.2) ng/mL, respectively. The median t(max,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 AUC(T) and 0.644 (0.590–0.703), 0.586 (0.536–0.642), and 0.636 (0.577–0.702) for dose-normalized C(max,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 AUC(T) 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.