APPLICATION OF PHARMACODYNAMIC MODELING FOR DESIGNING TIME-VARIANT DOSING REGIMENS TO OVERCOME NITROGLYCERIN TOLERANCE IN EXPERIMENTAL HEART-FAILURE

Purpose. Prolonged continuous administration of nitroglycerin (NTG) le ads to hemodynamic tolerance. We used a previously developed pharmacok inetic-pharmacodynamic (PK/PD) model of NTG tolerance in experimental heart failure to test whether dosage regimens, designed from this mode l, may allow avoidance of tolerance development upon continuous NTG in fusion. Methods, Simulation experiments (using ADAPT II) were performe d to evolve a time-variant infusion regimen that would theoretically p rovide sustained hemodynamic effect (30% reduction in left ventricular end-diastolic pressure, LVEDP) throughout 10 hours of drug dosing. A computer controlled infusion pump was utilized to deliver this time-va riant input. Infusion experiments were then conducted in CHF rats to c hallenge the predictability of the applied PK/PD model. Results. Simul ations showed that exponentially increasing input functions provided m ore sustained LVEDP effects when compared to linear or hyperbolic inpu t functions delivering the same total NTG dose. A computer-selected in fusion regimen of 6.56e(0.00156xminutes) mu g/min was anticipated to p rovide the desired hemodynamic profile in our animal model. Experiment s conducted in rats with congestive heart failure (n = 4) confirmed th e prediction of sustained hemodynamic effect without tolerance (28 +/- 4% reduction in LVEDP at 10 hrs). Conclusions. These findings support the utility of our PK/PD model of NTG tolerance in predicting NTG act ion, and serve as an example of therapeutic optimization through PK/PD considerations.