Pharmacokinetics and pharmacodynamics of clevidipine in healthy volunteersafter intravenous infusion

Objective: To determine the pharmacokinetics and pharmacodynamics of clevid ipine, a new ultrashort-acting calcium antagonist, in healthy male voluntee rs following a constant rate infusion. Methods: Eight healthy male volunteers received 1030 nmol.min(-1) of clevid ipine together with a tracer dose of (3)[H]-clevidipine for 1 h as an i.v. infusion. Frequent venous blood samples and effect recordings were obtained during ongoing infusion and up to 32 h following termination of the infusi on. The excretion of radioactivity in urine and faeces was followed for 7 d ays. Results: A two-compartment model gave the best fit to the individual clevid ipine blood levels, resulting in a mean blood clearance of 0.14 (0.03) 1.mi n(-1).kg(-1) and a mean volume of distribution at steady state of 0.6 (0.1) 1.kg(-1). The initial half-life was 1.6 (0.3) min, and the terminal half-l ife was 15 (5) min. The maximum concentration of the metabolite H 152/81 wa s reached 2.2 (1.3) min following termination of the infusion. The mean ter minal half-life of the inactive primary metabolite was 9.5 (0.8) h and the mean recovery of the radioactive dose reached 83 (3)%. Following terminatio n of the 1 h infusion, the effect on blood pressure (BP) and heart rate was back to pre-dose values within 15 min. Conclusion: Clevidipine is a high clearance drug, which is rapidly metaboli zed to the corresponding inactive acid. The t(max) value of the primary met abolite, and a virtually identical value of the initial half-life and the h alf-life for elimination from the central compartment, indicate that the in itial rapid decline of the post-infusion blood levels is mainly due to elim ination rather than distribution. The duration of action of clevidipine is short.