Application of pharmacodynamic modeling for designing time-variant dosing regimens to overcome nitroglycerin tolerance in experimental heart failure

John Anthony Bauer, Joseph P. Balthasar, Ho Leung Fung

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1140-1145
Number of pages6
JournalPharmaceutical Research
Volume14
Issue number9
DOIs
StatePublished - 1997

Funding

FundersFunder number
National Heart, Lung, and Blood Institute (NHLBI)R37HL022273

    Keywords

    • Hemodynamics
    • Nitrate
    • Nitroglycerin
    • Pharmacodynamics
    • Tolerance

    ASJC Scopus subject areas

    • Biotechnology
    • Molecular Medicine
    • Pharmacology
    • Pharmaceutical Science
    • Organic Chemistry
    • Pharmacology (medical)

    Fingerprint

    Dive into the research topics of 'Application of pharmacodynamic modeling for designing time-variant dosing regimens to overcome nitroglycerin tolerance in experimental heart failure'. Together they form a unique fingerprint.

    Cite this