Population pharmacodynamics of cilostazol in healthy Korean subjects

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 / (EC ₅₀ ^γ+Cγ)] with E_max being maximum drug effect, EC ₅₀ 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 EC ₅₀ 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.

Keywords: Cilostazol; Closure time; Population pharmacodynamic model; Sigmoid Emax model; Turnover model.

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.

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).

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