Background : We tried to develop a PK/PD analysis method using the spline function and mixed effect modeling, applicable to drug formulations showing atypical pharmacokinetic behavior such as CR formulations with double peak concentrations. Methods : For this purpose, investigational diltiazem CR formulations with different characteristics were administered to 12 healthy volunteers by a crossover design. Plasma concentrations and EKG changes were measured up to 48 hours after administration Diltiazem plasma concentrations were measured by HPLC. PQ and QT intervals on EKG lead II were analyzed by EKG analysis software. Pharmacokinetic parameters were calculated using the spline function and compared with those obtained by the trapezoidal rule ; pharmacodynamic parameters were estimated nonparametrically by mixed-effect modeling using a direct link model. Results : After administration of 90 mg formulations, the plasma concentration-time curve demonstrated a single peak at 3 hours after administration and a monophasic decay pattern thereafter; after 180 mg formulations two peaks, one immediately after administration and another at 8 hours after administration, were noted. Pharmacokinetic parameters obtained using the spline function were similar to those calculated using the trapezoidal rule. A linear pharmacodynamic model was used for mixed-effect modeling between plasma concentrations and PQ intervals in the 180 mg group ; the results were keo=$4.47;hr^{-1}$, slope=$0.0792;msec{cdot}ml/ng$, and intercept=0.358 msec. Conclusion : The spline function and nonparametric modeling can be applied to PK/PD analyses for formulations such as controlled-release formulations, patch formulations, drugs with a great Pharmacokinetic variability, and population PK/PD modeling.