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

Abstract

Aims: To investigate the tolerability and safety of clevidipine in healthy male volunteers during intravenous infusion at gradually increasing dose rates and to obtain preliminary information on the pharmacokinetics and pharmacodynamic effects of the drug.

Methods: Twenty-five subjects were enrolled in the study and twenty-one of them were included twice, resulting in a total of forty-six study entries encompassing 20 min infusions of clevidipine at target dose rates ranging from 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 pharmacokinetics were evaluated by non-compartmental and compartmental analysis. An Emax 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 min-1 kg-1, where a pre-determined escape criterion was reached (HR>120 beats min-1 ) and the study was stopped. The most common adverse events were flush and headache, which can be directly related to the mechanism of action of clevidipine. There was a linear relationship between blood concentration and dose rate in the range studied. The median clearance value determined by non-compartmental analysis was 0.125 l min-1 kg-1. Applying the population approach to the sparse data on clevidipine concentrations, an open 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 0.121 l min-1 kg-1, and the volume of distribution at steady state was 0.56 l kg-1. The initial half-life, contributing 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 half-life was 9.5 min. At the highest dose rates, MAP was reduced by approximately 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 extremely 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 Emax model adequately describes the relationship between the pharmacodynamic response (MAP/HR) and the blood concentrations of clevidipine.

Figures

Figure 1

The initial metabolic pathway of clevidipine. Clevidipine is metabolised by esterases in the blood and extravascular tissue to the primary metabolite H 152/81. The star indicates the chiral centre of clevidipine.

Figure 2

The venous blood concentrations of clevidipine (a) and the primary metabolite (b) vs time in four different individuals after a target dose rate of 36 nmol min−1 kg−1during 20 min infusion of clevidipine.

Figure 3

The population fit (thick line) and the posterior individual fit (thin lines) of a two-compartment model to the data, normalized to a dose rate of 12 nmol min−1 kg−1 (a) and the observed blood concentrations of clevidipine vs the predicted mean population concentrations (b).

Figure 4

The mean±s.d. effect on MAP (, mean basal value=83 mmHg) and HR (□, mean basal value=55 beats min−1) at steady state during clevidipine infusion at different dose rates. n=4, *n=3.

Figure 5

The mean±s.d. effect on SBP (, mean basal value=109 mmHg) and DBP (□, mean basal value=71 mmHg) at steady state during clevidipine infusion at different dose rates. n=4, *n=3.

Figure 6

The individual values of MAP/HR vs the blood concentrations of clevidipine. The solid line represents the model-derived relationship between the blood concentration and effect.