Pharmacodynamic model of the haemodynamic effects of pinacidil in normotensive volunteers

Abstract

The concentration-effect relationships of pinacidil, a peripheral vasodilator, have been measured in 12 healthy adults who received placebo or pinacidil 25 mg daily for 1 week in a cross-over experiment. Diastolic blood pressure (DBP) and heart rate (HR) were recorded and blood samples were taken on days 1 and 7. Plasma drug concentration-time data were fitted by a biexponential function with zero-order input. The pharmacokinetic model was incorporated into a combined pharmacokinetic-dynamic model (PK-PD) using the Hill equation, which has three parameters: n, the sigmoidicity parameter, Emax the maximum effect and EC50 the concentration which gives 50% of Emax. For delta DBP, the parameter medians were estimated as n = 5, EC50 = 44.6 ng.ml-1 and Emax = 13.5 mmHg. A hysteresis loop was found when delta HR was plotted against concentration, which could be fitted by a linear effect compartment model. Simulations showed that experimental delta DBP points on Day 7 could be predicted from a simulated curve computed by the model using parameters estimated on Day 1. Using the simulation, it was possible to suggest an optimal dosage regimen for pinacidil tablets.