A MATHEMATICAL-MODEL FOR DYNAMICS OF CARDIOVASCULAR DRUG-ACTION - APPLICATION TO INTRAVENOUS DIHYDROPYRIDINES IN HEALTHY-VOLUNTEERS

A physiologically, based mathematical model was built to describe the pharmacodynamic effects in response to the administration of intraveno us (iv) dihydropyridine drugs in healthy volunteers. This model incorp orates a limited number of hemodynamic variables, namely, mean arteria l blood pressure (MAP), cardiac output (CO) or heart rate (HR), stroke volume (SV), and total peripheral resistance (TPR), into a closed-loo p system supposed to represent essential features of the cardiovascula r regulation. We also defined an additional auxiliary, control variabl e (U) which is thought to represent primarily the role of the barorece ptor reflex. It was assumed that the variable U was related to MAP cha nges through both deviation- and rate-sensitive mechanisms. Other mode l parameters are the baseline levels for MAP, CO (or HR), and TPR, as well as time constants to account for further temporal aspects of the regulation. Finally, TPR was assumed to be linked to the plasma concen trations of dihydropyridine drugs via a conventional pharmacokinetic/p harmacodynamic (PK/PD) model, relying upon an effect compartment and a linear, hyperbolic, or sigmoidal relationship between the reduction i n TPR and the drug concentrations at the effect site. The model charac teristics were explored by studying the influence of various parameter s, including baseline levels and deviation- and rate-sensitive control parameters, on the hemodynamic responses to a fictive constant rate i v infusion of a vasodilator drug. Attempts were also made to mimic lit erature data with nifedipine, following iv administration under both c onstant and exponentially decreasing infusion rates. The applicability of the model was demonstrated by fitting hemodynamic data following i v infusion of nicardipine to healthy volunteers, under experimental co nditions similar to those described above for nifedipine. The effect m odel for the action of nicardipine on TPR, combined with the physiolog ical model including a feedback control loop, allowed an adequate quan titative description of time profiles for both cardiac output and mean arterial pressure. The suggested model is a useful tool for integrate d data analysis of hemodynamic responses to vasodilator drugs in healt hy volunteers. Computer simulations suggest that a graded variation of a few model parameters-including baseline levels of TPR and MAP and t he deviation-sensitive parameter of the arterial pressure control-woul d also be able to account for the pattern of hemodynamic response obse rved in hypertensive patients, which is qualitatively different to tha t seen in normotensive subjects. Extrapolation of drug response from t he healthy volunteer to the hypertensive patient is allowed by our mod el. Its usefulness for an early evaluation of drug efficacy during dru g development is under current investigation.