Pharmacokinetics and arteriovenous differences in clevidipine concentration following a short- and a long-term intravenous infusion in healthy volunteers

Background: Clevidipine is an ultra-short-acting calcium antagonist develop ed for reduction and control of blood pressure during cardiac surgery. The objectives of the current study were to determine the pharmacokinetics of c levidipine after 20-min and 24-h intravenous infusions, and to determine th e relation between the arterial and venous concentrations and the hemodynam ic responses to clevidipine in healthy volunteers. Methods: Four volunteers received clevidipine for 20 min, and eight subject s were administered clevidipine intravenously for 24 h at two different dos e rates. Arterial and venous blood samples were drawn for pharmacokinetic e valuation, and blood pressure and heart rate were recorded. Results: A triexponential disposition model described the pharmacokinetics of clevidipine. The mean arterial blood clearance of clevidipine was 0.069 1 . kg(-1) . min(-1) and the mean volume of distribution at steady state wa s 0.19 1/kg. The duration of the infusion had negligible effect on the phar macokinetic parameters, and the context-sensitive half-time for clevidipine , simulated from the mean pharmacokinetic parameters derived after 24 h inf usion at the highest dose, was less than 1 min The arterial blood levels re ached steady state within 2 min of the start of infusion and were about twi ce as high as those in the venous blood at steady state. The peak response preceded the peak venous concentration and was slightly delayed from the pe ak arterial blood concentration. Conclusion: Clevidipine is a high clearance drug with a small volume of dis tribution, resulting in extremely short half-lives in healthy subjects. The initial rapid Increase in the arterial blood concentrations and the short equilibrium time between the blood and the biophase suggest that clevidipin e can be rapidly titrated to the desired effect.