The pharmacokinetics and pharmacodynamics of clevidipine, a new ultrashort-acting calcium antagonist, in different animal species and man

Sammanfattning: Clevidipine is a new ultrashort-acting calcium antagonist of the dihydropyridine type developed for reduction and control of blood pressure in connection with cardiac surgery. The aim of this thesis was to characterise the in vitro hydrolysis rate of clevidipine in different biological matrices and the pharmacokinetics and pharmacodynamics in animal species and various human populations. The data analyses were performed in WinNonlin and PPHARM.Clevidipine is rapidly metabolised in blood and extravascular tissues to an inactive carboxylic acid. The hydrolysis in human blood seems to be mediated primarily by esterase(s) associated with the red blood cells and is temperature dependent. Both clevidipine and the individual enantiomers are more than 99.5% bound to plasma proteins. In all species studied, clevidipine is a high clearance drug with a small volume of distributionand an extremely short half-life. The initial rapid decline following cessation of clevidipine infusion is mainly due to elimination and the resulting context-sensitive half-time in man is approximately 1 minute regardless of the duration of the infusion. The twofold difference between the clevidipine concentration in arterial and venous blood in man during ongoing infusion demonstrates the importance of taking this arteriovenous difference into account in the PK/PD analysis. The reductions in the ratio of mean arterial blood pressure and heart rate in healthy subjects and essential hypertensive patients are similar, although a more pronounced decrease in blood pressure is observed in the latter population. The reduced clearance during cardiopulmonary bypass is probably related to the lower body temperature during this condition. The initial rapid increase in the arterial blood concentrations and the short equilibrium time between the blood and the biophase suggest that clevidipine can berapidly titrated to the desired effect in cardiac surgical patients in whom acute changes in blood pressure frequently occur.