TY - JOUR
T1 - Application of pharmacodynamic modeling for designing time-variant dosing regimens to overcome nitroglycerin tolerance in experimental heart failure
AU - Bauer, John Anthony
AU - Balthasar, Joseph P.
AU - Fung, Ho Leung
PY - 1997
Y1 - 1997
N2 - Purpose. Prolonged continuous administration of nitroglycerin (NTG) leads to hemodynamic tolerance. We used a previously developed pharmacokinetic-pharmacodynamic (PK/PD) model of NTG tolerance in experimental heart failure to test whether dosage regimens, designed from this model, may allow avoidance of tolerance development upon continuous NTG infusion. Methods. Simulation experiments (using ADAPT II) were performed to evolve a time-variant infusion regimen that would theoretically provide 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-variant input. Infusion experiments were then conducted in CHF rats to challenge the predictability of the applied PK/PD model. Results. Simulations showed that exponentially increasing input functions provided more sustained LVEDP effects when compared to linear or hyperbolic input functions delivering the same total NTG dose. A computer-selected infusion regimen of 6.56e(0.00156xminutes) μg/min was anticipated to provide the desired hemodynamic profile in our animal model. Experiments conducted in rats with congestive heart failure (n = 4) confirmed the 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 action, and serve as an example of therapeutic optimization through PK/PD considerations.
AB - Purpose. Prolonged continuous administration of nitroglycerin (NTG) leads to hemodynamic tolerance. We used a previously developed pharmacokinetic-pharmacodynamic (PK/PD) model of NTG tolerance in experimental heart failure to test whether dosage regimens, designed from this model, may allow avoidance of tolerance development upon continuous NTG infusion. Methods. Simulation experiments (using ADAPT II) were performed to evolve a time-variant infusion regimen that would theoretically provide 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-variant input. Infusion experiments were then conducted in CHF rats to challenge the predictability of the applied PK/PD model. Results. Simulations showed that exponentially increasing input functions provided more sustained LVEDP effects when compared to linear or hyperbolic input functions delivering the same total NTG dose. A computer-selected infusion regimen of 6.56e(0.00156xminutes) μg/min was anticipated to provide the desired hemodynamic profile in our animal model. Experiments conducted in rats with congestive heart failure (n = 4) confirmed the 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 action, and serve as an example of therapeutic optimization through PK/PD considerations.
KW - Hemodynamics
KW - Nitrate
KW - Nitroglycerin
KW - Pharmacodynamics
KW - Tolerance
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U2 - 10.1023/A:1012138320003
DO - 10.1023/A:1012138320003
M3 - Article
C2 - 9327439
AN - SCOPUS:0030771208
SN - 0724-8741
VL - 14
SP - 1140
EP - 1145
JO - Pharmaceutical Research
JF - Pharmaceutical Research
IS - 9
ER -