APPLICATION OF A SYSTEM-ANALYSIS APPROACH TO POPULATION PHARMACOKINETICS AND PHARMACODYNAMICS OF NICARDIPINE HYDROCHLORIDE IN HEALTHY-MALES

Nicardipine hydrochloride, a dihydropyridine calcium channel blocker, possesses antihypertensive and arterial vasodilator properties. A system analysis approach, which makes fewer structural assumptions than compartmental methods, is presented for determining the pharmacokinetics and pharmacodynamics of nicardipine hydrochloride in healthy males following a discontinuous infusion at four dose levels. The results indicate that the average total body clearance of nicardipine is 0.920 L/h/kg and the volume of distribution is 0.275 L/kg. Nicardipine hydrochloride has a mean residence time in the body of 1.27 h, of which 0.324 h were spent in the systemic circulation and the remainder in the periphery. The determined pharmacokinetic model was linked to a pharmacodynamic model that allowed the change in the mean arterial blood pressure and heart rate to be described and predicted. A population pharmacokinetic-pharmacodynamic model was derived and the predictive power of the proposed model was assessed with a cross-validation technique that employs a relative predictive quotient for comparing the predictions to the fitted model. The results indicate that the proposed model describes the pharmacodynamics of nicardipine in healthy males and has good predictive ability when tested with a cross-validation procedure.