Pharmacokinetic modeling analysis of cilostazol and its active metabolites (OPC-13015 and OPC-13213) after multiple oral doses of cilostazol in healthy Korean volunteers.

Cilostazol is a selective inhibitor of phosphodiesterase III (PDE III), which is prescribed for patients with peripheral arterial disease, especially intermittent claudication. The purpose of the study was to investigate the pharmacokinetic (PK) of cilostazol and its metabolites on the immediate (IR) formulation of cilostazol in healthy Korean male volunteers by population PK modeling analysis implemented using NONMEM software.A 2 × 2 crossover study comparing multiple oral doses of IR and SR formulations of cilostazol were conducted. Serial plasma concentrations of cilostazol and its active metabolites were used in this analysis.The PK was best depicted by one-compartment model, with absorption kinetics of cilostazol having mixed first- and zero-order kinetics with a time delay at the beginning of absorption. The introduction of interoccasion variabilities into zero-order (D1), first-order (Ka), and relative bioavailability (F1) significantly improved the model fit, and total body water (TBW) was identified as a significant covariate positively affecting the clearance of cilostazol. The model validation suggested that the model constructed in this study predicted the plasma concentration of cilostazol and its two active metabolites reasonably well.The PK model we developed explored the PK characteristics of cilostazol in Korean male subjects, and may be useful for identifying optimal individual dosing regimens of cilostazol.

Evaluation of pharmacokinetic and pharmacodynamic profiles and tolerability after single (2.5, 5, or 10 mg) and repeated (2.5, 5, or 10 mg bid for 4.5 days) oral administration of ivabradine in healthy male Korean volunteers.

BACKGROUND: Ivabradine, a selective inhibitor of the pacemaker current in the sinoatrial node, has shown pure heart rate (HR)-reducing effects with anti-ischemic efficacy as well as improvement in heart failure outcomes. OBJECTIVE: The purpose of this study was to explore pharmacokinetic (PK) and pharmacodynamic (PD) characteristics and tolerability in healthy male Korean volunteers, as well as to compare them with PK/PD profiles of white subjects. METHODS: This was a randomized, double-blind, placebo-controlled Phase I study conducted in healthy male subjects. For each of the 3 dosing groups, 9 subjects were randomized to receive ivabradine and 3 to receive placebo. Subjects received a single oral dose of ivabradine 2.5, 5, or 10 mg and after a 3-day washout period, repeat doses of 2.5, 5, or 10 mg BID for 4.5 days. Blood and urine samples were collected over 72 hours during each period, and levels of ivabradine and its metabolite S18982 were determined by using validated LC-MS/MS, followed by noncompartmental PK analysis. For PD properties and tolerability, 24-hour Holter recordings were obtained: at baseline, after a single dose, after repeated doses, and after the last dose. Serial resting 12-lead ECG assessments were also performed throughout the study. RESULTS: Forty-eight subjects were enrolled, and 45 completed the study. After single doses of 2.5, 5, and 10 mg, respective mean Cmax levels of ivabradine were 9, 15, and 39 ng/mL, and mean AUC0-last values were 30, 52, and 121 ng h/mL. At steady state, mean Cmax,ss levels were 11, 19, and 42 ng/mL, reached at a median Tmax of 0.67 hour for all 3 doses. The mean AUC0-τ levels were 43, 58, and 139 ng h/mL, respectively. The PK findings were linear with dose and time. Decreases in mean HR on both the Holter recordings and ECGs were observed in all of the ivabradine groups compared with placebo. After the repeated doses, mean decreases in HR were greater than those for the single doses for the same period. Statistically significant differences were observed between the 5- and 10-mg ivabradine groups and placebo. A total of 3 adverse events were reported in 2 subjects receiving ivabradine; both fully recovered without sequelae. CONCLUSIONS: Single and repeated administration of ivabradine were generally well tolerated in these healthy male Korean volunteers. Ivabradine induced significant reductions in HR, especially at doses of 5 and 10 mg. PK/PD characteristics were similar to those found in white subjects, suggesting that the dose concentration-response relationship of ivabradine is similar between Korean and white subjects.