Clinical and pharmacokinetic results with a new ultrashort-acting calcium antagonist, clevidipine, following gradually increasing intravenous doses to healthy volunteers

Aims To investigate the tolerability and safety of clevidipine in healthy m ale volunteers during intravenous infusion at gradually increasing dose rat es and to obtain preliminary information on the pharmacokinetics and pharma codynamic effects of the drug. Methods Twenty-five subjects were enrolled in the study and twenty-one of t hem were included twice, resulting in a total of forty-six study entries en compassing 20 min infusions of clevidipine at target dose rates ranging fro m 0.12 to 48 nmol min(-1) kg(-1). Haemodynamic variables and adverse events were recorded throughout the study. Concentrations of clevidipine and its primary metabolite, H 152/81, were followed in whole blood, and the pharmac okinetics were evaluated by non-compartmental and compartmental analysis. A n E-max model was fitted to the effect on mean arterial pressure (MAP) over heart rate (HR) and the corresponding blood concentrations of clevidipine. Results Clevidipine was administered up to a target dose rate of 48 nmol mi n(-1) kg(-1), where a pre-determined escape criterion was reached (HR>120 b eats min(-1)) and the study was stopped. The most common adverse events wer e flush and headache, which can be directly related to the mechanism of act ion of clevidipine. There was a linear relationship between blood concentra tion and dose rate in the range studied. The median clearance value determi ned by non-compartmental analysis was 0.125 l min(-1) kg(-1). Applying the population approach to the sparse data on clevidipine concentrations, an op en two compartment pharmacokinetic model was found to be the best model in describing the disposition of the drug. The population mean clearance value determined by this method was 0.12 l min(-1) kg(-1), and the volume of dis tribution at steady state was 0.56 l kg(-1). The initial half-life, contrib uting by more than 80% to the total area under the blood concentration-time curve following i.v. bolus administration, was 1.8 min, and the terminal h alf-life was 9.5 min. At the highest dose rates, MAP was reduced by approxi mately 10%, and the HR reached the pre-determined escape criterion for this study (>120 beats min(-1)). Conclusions Clevidipine is well tolerated and safe in healthy volunteers at dose rates up to at least 48 nmol min(-1) kg(-1). The pharmacokinetics are linear over a wide dose range. Clevidipine is a high clearance drug with e xtremely short half-lives. The effect of clevidipine on the blood pressure was marginal, probably due to a compensatory baroreflex activation in this population of healthy volunteers. A simple E-max model adequately describes the relationship between the pharmacodynamic response (MAP/HR) and the blo od concentrations of clevidipine.