Enantioselective pharmacokinetics of the enantiomers of clevidipine following intravenous infusion of the racemate in essential hypertensive patients

Abstract

The aim of the study was to characterize the individual pharmacokinetics of (-)-R- and (+)-S-clevidipine following intravenous constant rate infusion of rac-clevidipine to essential hypertensive patients. Twenty patients received three out of five randomized treatments with clevidipine. The pharmacokinetics of the separate enantiomers were evaluated by compartmental analysis of blood concentrations vs. time curves using the population approach. The derived pharmacokinetic parameters were used to simulate the time for 50 and 90% postinfusion decline following various infusion times of rac-clevidipine. A two-compartment model was used to describe the dispositions of the enantiomers; there were only minor differences between the estimated pharmacokinetic parameters of the separate enantiomers. The mean blood clearance values of (-)-R- and (+)-S-clevidipine were 0.103 and 0.096 l/min/kg, and the corresponding volumes of distribution at steady state were 0.39 and 0.54 l/kg, respectively. The context-sensitive half-time was approximately 2 min regardless of stereochemical configuration, and a 90% decline in concentration was achieved approximately 8 min postinfusion for (-)-R-clevidipine and 11 min for (+)-S-clevidipine, following clinically relevant infusion times with clevidipine. In conclusion, both enantiomers are high-clearance compounds with similar blood clearance values. The volume of distribution for the enantiomers is slightly different, presumably due to differences in the protein binding. From a pharmacokinetic point of view, the use of a single enantiomer as an alternative to the racemic clevidipine will not offer any clinical advantages.

Intravenous clevidipine for management of hypertension

“…17 It is considered unique because of its very short duration of action (ie, rapid onset and offset), achieved by the incorporation of an additional ester group in the molecule. 17,18 This results in rapid hydrolysis of the molecule by blood and tissue esterases, producing the carboxylic acid metabolite H 152/81. Clevidipine is a racemic mixture of enantiomers, ie, R(-)-clevidipine and S(+)-clevidipine, both of which impact BP, but the latter contributes to a larger extent at equivalent plasma levels.…”

“…16 Clevidipine is similar to felodipine in its structure but is functionally closer to nicardipine. 17 It is considered unique because of its very short duration of action (ie, rapid onset and offset), achieved by the incorporation of an additional ester group in the molecule. 17,18 This results in rapid hydrolysis of the molecule by blood and tissue esterases, producing the carboxylic acid metabolite H 152/81.…”

“…Clevidipine is a racemic mixture of enantiomers, ie, R(-)-clevidipine and S(+)-clevidipine, both of which impact BP, but the latter contributes to a larger extent at equivalent plasma levels. 17 Clevidipine has no effects on venous vascular tone and its ability to modify afterload prevents it from affecting other hemodynamic parameters, including left ventricular filling pressure and pulmonary capillary wedge pressure. …”

New therapeutic perspectives with clevidipine: an ultra-short-acting intravenous Ca2+channel blocker

“…The half-life of clevidipine is ∼ 2 min regardless of the stereochemical configuration. A 90% decline in concentration is achieved ∼ 8 min postinfusion for (R) -clevidipine and 11 min for (S) -clevidipine [8] . In both normal volunteers and patients with hypertension, a linear relationship exists between the clevidipine dose and steady-state blood concentrations over a wide range of doses and infusion rates.…”

Perioperative acute hypertension—role of Clevidipine butyrate

“…The drug did not cause any cardiovascular instability or metabolic changes (Kieler-Jensen et al, 2000; Ericsson et al, 2001; Bailey et al, 2002). …”