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Pharmacodynamic, Pharmacokinetic and ClinicalEffects of Clevidipine, an Ultrashort-Acting Calcium

Antagonist for Rapid Blood Pressure Control

Margareta Nordlander1, Per-Ove Sjöquist1,Hans Ericsson2 and Lars Rydén3

1Department of Integrative Pharmacology, AstraZeneca R&D Mölndal, Sweden2Department of Experimental Medicine, AstraZeneca R&D Mölndal, Sweden

3Department of Cardiology, Karolinska Hospital, Stockholm, Sweden

Keywords: Blood pressure control — Calcium antagonists — Cardiac surgery— Clevidipine.

ABSTRACT

Clevidipine is an ultrashort-acting vasoselective calcium antagonist under developmentfor short-term intravenous control of blood pressure. Studies in animals, healthy volun-teers and patients have demonstrated the vascular selectivity and rapid onset and offset ofantihypertensive action of clevidipine, a synthetic 1,4-dihydropyridine that inhibits L-typecalcium channels. Clevidipine has a high clearance (0.05 L�min�kg). and is rapidly hydro-lyzed to inactive metabolites by esterases in arterial blood. Its half-life in patients under-going cardiac surgery is less than one min.

Unlike sodium nitroprusside, a drug commonly used for the short-term control of bloodpressure, which dilates both arterioles and veins, clevidipine reduces blood pressurethrough a selective effect on arterioles. As documented in animals and in cardiac surgicalpatients, clevidipine reduces peripheral resistance without any undesirable effect oncardiac filling pressure. It increases stroke volume and cardiac output. In anesthetized pa-tients undergoing cardiac surgery clevidipine, unlike sodium nitroprusside, does not in-crease heart rate.

In addition of having a favorable hemodynamic profile, suitable for rapid control ofblood pressure, clevidipine protects against ischemia�reperfusion injuries, which are notuncommon during major surgery. In anesthetized pigs, clevidipine reduced infarct sizeafter 45 min-long myocardial ischemia by 40%. In rats, renal function and splanchnicblood flow were better maintained when blood pressure was reduced with clevidipine thanwith sodium nitroprusside.

227

Cardiovascular Drug ReviewsVol. 22, No. 3, pp. 227–250© 2004 Neva Press, Branford, Connecticut

Address correspondence and reprint requests to: Margareta Nordlander, Integrative Pharmacology,AstraZeneca R&D Mölndal, SE 431 83 Mölndal, Sweden. E-mail: [email protected]

mailto:[email protected]

Clevidipine was well tolerated in Phases I and II of clinical trials that included morethan 300 individuals�patients. Since there are no known compounds with similar pharma-codynamic and pharmacokinetic properties in clinical development, it is anticipated thatclevidipine, a compound tailored to the needs of anesthesiologists, has the potential tobecome a drug of choice for controlling blood pressure during surgical procedures.

INTRODUCTION

Clevidipine is a vasoselective, short-acting dihydropyridine-type calcium antagonist. Itis in development for the treatment of perioperative hypertension. Acute blood pressureelevation is frequently observed in the perioperative setting. Systemic hypertension aftercoronary artery bypass graft (CABG) surgery was first described by Estafanous et al. in1973 as a sustained arterial pressure elevation (19). Perioperative hypertension generallyresults from activation of the sympathetic nervous system in combination with insufficientinhibition of nociceptive stimuli during anesthesia and surgery. This alteration in sympa-thetic nerve activity causes a peripheral vasoconstriction with an increase in systemic vas-cular resistance (SVR) while cardiac output (CO) decreases, increases or remains un-changed (24,51).

A prospective survey investigating therapeutic principles for the management ofperioperative hypertension during cardiac surgery (52) indicated that more than 80% ofpatients required treatment to control blood pressure during surgery. Interestingly, theblood pressure level at which treatment was started ranged from 10 mm Hg above to8 mm Hg below the preoperative blood pressure level, depending on the phase of the op-eration. In addition, blood pressure was maintained at levels that were 15–20% lower thanthe preoperative values. It was concluded that routine cardiothoracic anesthesia practiceshould be to reduce and maintain blood pressure at or below normal preoperative levels inorder to prevent associated morbidities. The most commonly used drugs for controllingperioperative hypertension are nitroglycerin (GTN), sodium nitroprusside (SNP), â-adre-noceptor and calcium antagonists (51,52). Both GTN and SNP have a pharmacokineticprofile that allows rapid titration to the desired blood pressure level (40). However, thesedrugs are non-selective vasodilators, they dilate both arteriolar resistance as well asvenous capacitance vessels (37,40). The latter effect may compromise venous return andthereby reduce cardiac output (CO) (24). In addition, SNP may induce side effects such asrebound hypertension at the cessation of infusion, coronary steal and potentially cyanidetoxicity (24). Moreover, drug tolerance is a common concern with GTN or SNP (24,40).

The ultrashort acting â-adrenoceptor antagonist, esmolol, has commonly been usedduring perioperative hypertension in cardiac surgery (51). This drug has a high plasmaclearance with a terminal half-life of approximately 10 min, allowing for titration to thedesired level (35). However, â-adrenoceptor antagonists decrease blood pressure at leastpartly by reducing CO. They do not affect primarily increased SVR, the most commonreason for elevated blood pressure during cardiac surgery (35,37,40). A potential draw-back of reducing CO is impaired organ perfusion.

Dihydropyridine-type calcium antagonists, like nicardipine, isradipine and nifedipine,have been used successfully to control blood pressure during cardiac surgery (37). Amongcalcium antagonists, dihydropyridines are highly vasoselective; they dilate precapillary re-sistance vessels without depressing cardiac contractility (40,51). Calcium antagonists

Cardiovascular Drug Reviews, Vol. 22, No. 3, 2004

228 M. NORDLANDER ET AL.

protect against organ damage induced by ischemia�reperfusion (40,42), e.g., of the kid-ney, intestines and heart. The functions of these organs are sometimes jeopardized duringmajor cardiac surgery. However, dihydropyridine-type calcium antagonists have been pri-marily developed for oral administration and their long duration of action limits their po-tential for precisely tailored control of rapid blood pressure changes during surgery. Con-sidering this background scientists at Astra research laboratories (now AstraZeneca)developed an ultrashort-acting dihydropyridine-type calcium antagonist, clevidipine, thatcombines pharmacodynamic and pharmacokinetic profiles well suited for blood pressurecontrol in a surgical setting. Clevidipine appears to fulfill the criteria established on thebasis of preclinical and clinical evidence discussed in this review. Further development ofclevidipine is being currently conducted by The Medicines Company, Parsippany, NewJersey, USA.

CHEMISTRY AND FORMULATION

Clevidipine is a synthetic dihydropyridine selected for development on the basis of itsvasoselective properties and short duration of action. It was selected after synthesis andscreening of many dihydropyridines with easily hydrolyzable ester substituents. Clevidi-pine, butyroxymethyl methyl 4-(2�,3�-dichlorophenyl)-1,4-dihydro-2,6-dimethyl, 3-5-pyridinedicarboxylate (Fig. 1), has a molecular weight of 456.3 g �mol. It is a racemicmixture, with a log KD estimated to be �5. Both enantiomers have been synthesized andare equally potent with half-lives similar to that of clevidipine. Clevidipine is practicallyinsoluble in water (0.1 mg�mL); therefore, a clevidipine emulsion in soybean oil was de-veloped. The dosage form used in most clinical trials contains 0.5 mg clevidipine�mL.

PHARMACOLOGY

In Vitro Mechanism of Action Studies

Cellular action

Calcium antagonists exert their effects by inhibiting the transmembrane calcium influxthrough voltage-dependent L-type calcium channels. Dihydropyridines have a distinctbinding site at the á1 subunit, which contains voltage–gated channel pore (55). Like otherdihydropyridines, clevidipine decreases L-type calcium channel current in guinea pigmyocytes (55). The magnitude of this inhibition is voltage-dependent. Clevidipine has


CLEVIDIPINE 229

NH

H

H C3 CH3

O

O

O

O O

O

Cl

Cl

FIG. 1. Chemical structure of clevidipine.

been shown to be three to six times more potent when the holding potential is raised to –40from –80 mV. Because the resting potential of vascular smooth muscle cells is less neg-ative than that of cardiac myocytes, this voltage dependence may in part explain why cle-vidipine selectively depresses contractility of vascular smooth muscle and thereby causesvasodilatation with a very limited impact on myocardial contractility (36).

Vascular and cardiac effects

The portal vein is a suitable in vitro model of the type of smooth muscle present in thearterial resistance vessels, since both exhibit spontaneous myogenic activity (38). Clevidi-pine is an equipotent inhibitor of spontaneous myogenic, neurogenic and agonist-inducedcontractions of the rat portal vein, suggesting a common inhibitory pathway (4). Clevidi-pine also causes dose-dependent relaxation of thromboxane A2-induced contraction of ar-terial smooth muscle in in vitro preparations of intact and endothelial-denuded human in-ternal mammary artery (28).

The inhibitory effects of clevidipine on myocardial contractility and on spontaneousheart rate were studied in isolated Langendorff-perfused rat hearts and compared to thoseof isradipine and nifedipine (47). In this setting nifedipine and isradipine, at high concen-trations reduced heart rate and caused atrioventricular block, while clevidipine was devoidof such effects at any concentration studied, although the maximal rate of pressure gener-ation in the left ventricle (dP�dtmax) decreased at the highest concentration used. Thus, incontrast to nifedipine and isradipine, clevidipine did not interfere with spontaneous heartrate or AV conduction even at concentrations that reduced cardiac contractility by morethan 50% (47).

In contrast to calcium antagonists of the phenylalkylamine (e.g., verapamil) and benzo-thiazepine (e.g., diltiazem) drug classes, dihydropyridines are more potent in relaxing vas-cular smooth muscle than in inhibiting myocardial contractility (38). The vascular versusmyocardial selectivity of clevidipine was determined in vitro and compared to that of felo-dipine, a highly vasoselective antihypertensive dihydropyridine-type calcium antagonist(38). Selectivity was determined as the ratio between IC50s for the contractility of a pacedrat papillary muscle and for spontaneous activity of the portal vein mounted in the sameorgan bath. In accordance with previous reports (38), the vascular versus myocardial se-lectivity of clevidipine was 48 and that of felodipine was 126 (4). It was concluded thatclevidipine is a highly vasoselective calcium antagonist (Table 1).

Hemodynamic Effects in Vivo

Effects on arterial blood pressure in rats

The antihypertensive potency and the duration of action of clevidipine and its main me-

tabolite H 152�81 [4-(2�3�-dichlorophenyl)-2,â-dimethyl-1,4-dihedropyridine-3,5-dicar-boxylic acid monomethylester] were determined in anesthetized spontaneously hyper-tensive (SHR) and in normotensive rats. The following compounds were also tested inSHR: GTN, SNP, felodipine, nicardipine and isradipine. The drugs were infused intrave-nously at increasing rates for 15 min until blood pressure was reduced by 30%. Antihyper-tensive potency was defined as the accumulated molar dose of the drug required to lowermean arterial pressure (MAP) by 30% (ED30). At the end of drug infusion, the duration ofaction was estimated as the time required for MAP to recover to 10% of the control bloodpressure. As shown in Table 2, the recovery time following clevidipine is similar to that of



GTN, longer than that of SNP and considerably shorter than that of the calcium antago-nists felodipine, isradipine and nicardipine.

The potency of clevidipine in lipid emulsion (the clinically used dosage form) and in1% Solutol (polyethylene glycol-15-hydroxystearate, BASF) in saline was the same. Itsblood pressure lowering potency was higher in spontaneously hypertensive than in normo-

tensive rats. The main metabolite, H 152�81 (butyroxymethyl methyl 4-(2�,3�-dichloro-phenyl)-1,4-dihydro-2,6-dimethyl, 3-5-pyridinedicarboxylic acid), did not influence bloodpressure at a molar dose 70 times higher than that required for clevidipine to lower arterialblood pressure by 30%. In separate experiments on anesthetized SHR, clevidipine and itstwo enantiomers were tested. The recovery rate and potency values did not differ betweenthese three compounds. These results demonstrate that clevidipine is an effective andultrashort-acting antihypertensive agent.

Effects in anesthetized dogs

The effects of clevidipine, at increasing i. v. doses, on central hemodynamics of anes-thetized beagles were compared with those of SNP (39). Clevidipine reduced mean aortic


CLEVIDIPINE 231

TABLE 1. Vascular and myocardial inhibitory potency of various calcium antagonists

Compounds

pIC50 IC50 ratio

NVascular Myocardial Selectivity

Verapamil* 6.60 6.46 1.4 7Diltiazem* 6.36 5.50 7 6Nifedipine* 7.62 6.47 14 12Felodipine* 7.47 5.40 118 6Felodipine† 7.61 5.51 126 5Clevidipine† 6.37 4.69 48 5

Note. pIC50 is the negative logarithm of the molar concentration (IC50), which would reduce by 50%the integrated spontaneous force of the isolated rat portal vein (vascular) and of the peak contractileforce of the rat left ventricular papillary muscle (myocardial) residing in the same organ bath. Testcompounds were added cumulatively at 10-min intervals; N, number of experiments in each group.*Data from ref. 38; †data from ref. 4.

TABLE 2. Recovery time and potency of clevidipine and other antihypertensive drugs in rats

Recovery time(min)

ED30(nmol�kg)

Clevidipine in 20% lipid emulsion — hypertensive rats (SHR) 2.4 ± 0.6 58 ± 9Clevidipine in 20% lipid emulsion — normotensive rats 3.0 ± 0.6 316 ± 57*Clevidipine in Solutol® saline — SHR 2.4 ± 0.8 59 ± 8Sodium nitroprusside 0.6 ± 0.2* 184 ± 32*Nitroglycerin 3.9 ± 3.0 2315 ± 2106*Felodipine 58.7 ± 26* 26 ± 11*Isradipine 43.4 ± 26* 17 ± 2*Nicardipine 18.7 ± 8.3* 55 ± 18

Note. Mean values ± S.D., for 6 rats per treatment.*p < 0.05 compared to clevidipine in 20% lipid emulsion given to SHR.

blood pressure in a dose-dependent manner by decreasing total peripheral resistance. Car-diac output (CO) increased as a result of an increase in stroke volume, very likely causedby reduced afterload, while heart rate remained unaffected. Thus, despite relaxation ofvascular smooth muscle causing a 40% reduction of total peripheral resistance, clevidipinehad no direct negative chronotropic or dromotropic effects. This confirms in vitro findingsthat clevidipine has a high vascular versus myocardial selectivity. The hemodynamic ef-fects of clevidipine and SNP at dosages causing a comparable reduction of MAP areshown in Fig. 2.

The blood pressure reduction caused by clevidipine is due to a profound lowering oftotal peripheral resistance (TPR) associated with increased cardiac output (CO), while theeffect of SNP results mainly from a reduction in CO, which is caused by its venodilatoryeffect and leads to reduced ventricular filling.

Miscellaneous effects

Like other dihydropyridines, clevidipine has a mild natriuretic�diuretic effect whengiven to rats at a dose, which barely lowers blood pressure (3). At doses well above thetherapeutic range, clevidipine inhibits gastrointestinal transport, a property also character-istic of other calcium antagonists. Clevidipine is devoid of effects on the autonomic andcentral nervous systems and does not interfere with neuromuscular transmission or skele-tal muscle function (4,6). Clevidipine has no adverse pharmacological effects on respi-ratory, liver or endocrine function or on bleeding time.

Effects on ischemia�reperfusion-induced injury

Interruption of organ blood flow causes ischemia, organ malfunction and induces celldeath after a critical period of time. Accordingly, early restitution of the arterial bloodflow is mandatory to the preservation of organ function. There is, however, ample evi-



Cha

nge

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drug

(%)

MAP

CO

ns

TPR dP dt� LVEDP

Cha

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(mm

Hg)

140

130

120

110

100

90

80

70

60

2

1

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–2

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FIG. 2. Effects, percentage change from control value, of clevidipine 6 nmol�kg�min (hatched bars, n = 7), andof sodium nitroprusside 7 nmol�kg�min (black bars, n = 7) on central hemodynamics in anesthetized dogs. CO,cardiac output; TPR, total peripheral resistance; dP�dt, rate of maximal pressure generation during ventricularcontraction; LVEDP, left ventricular end diastolic pressure. Effects on LVEDP are expressed as change in ab-solute values (mm Hg) from control. * p < 0.05 between groups. Reproduced from ref. 39 with permission fromOxford University Press.

dence that restoration of arterial blood flow per se will increase functional and structuralinjury in the jeopardized tissue. The exact mechanisms underlying this injury are still un-clear and have been much debated during the last two decades (1,8,10,42). The initial hy-peremic reflow may cause hemorrhage, edema or harmful changes in the inter- and intra-cellular environments (43). Formation of free radicals, neutrophil and platelet aggregationand calcium overload are among the factors that have been suggested (9,26,50). Calciumantagonists have protective capacity against ischemia�reperfusion injury, but their site ofaction and protective mechanisms are incompletely understood. The effect of clevidipineon ischemia�reperfusion-related organ injuries has been investigated in a series ofexperiments.

Free radical-mediated injury

Rats subjected to i.v. infusion of xanthine in combination with xanthine oxidase have amortality of 90% within 120 min; this effect appears to be related to the generation ofoxygen free radicals (29). Clevidipine, at a dose, which reduces MAP by 20%, was studiedin this model. Infusion of vehicle or clevidipine was initiated before the administration ofxanthine and xanthine oxidase. The 120-min survival rate was 10% in the vehicle groupand 50% in rats receiving clevidipine (p < 0.05 vs. vehicle) (23). It was concluded thatclevidipine, at a therapeutically relevant dose that reduces MAP by 20%, reduces lethalitycaused by oxygen free radicals.

Effects on splanchnic and renal ischemia

Ischemia and subsequent reperfusion of the splanchnic vascular bed can cause severecirculatory shock characterized by hemodynamic deterioration with persistently reducedsplanchnic blood flow finally leading to death. The possible protective effects of thera-peutic and non-therapeutic doses of clevidipine were compared to that of a therapeuticdose of SNP and a vehicle in the rat model of splanchnic ischemia. Blood flow in the su-perior mesenteric artery was measured before, during and after 60-min occlusion of theceliac and superior mesenteric arteries in anesthetized normotensive rats. Drug adminis-tration was started 10 min before the release of the arterial occlusion and lasted 60 min.Blood pressure, heart rate and blood flow were measured for 120 min after the arterial oc-clusion was released (23). By then, the mesenteric vascular resistance had increased two-to three-fold and mesenteric blood flow recovered to only 20–25% of pre-occlusion value.These variables were similar in rats receiving vehicle, a low dose of clevidipine and SNP.In contrast, the mesenteric blood flow was significantly better maintained following thehigh dose of clevidipine (23). These results suggest that clevidipine prevents deteriorationof the mesenteric circulation during re-oxygenation after mesenteric ischemia.

Ischemic renal failure can occur due to trauma, circulatory shock or certain clinical sit-uations, such as cardiac surgery or renal transplantation. The effects of clevidipine havebeen studied in a model of renal ischemic failure in anesthetized normotensive rats ex-posed to unilateral renal artery occlusion for 40 min. Renal function (creatinine clearance)and hemodynamics were evaluated at 30-min intervals prior to, during and 60 min afterrenal artery occlusion (49). Vehicle or clevidipine were infused for 60 min, starting at10 min prior to the release of renal artery occlusion. In both groups, creatinine clearancewas markedly reduced, indicating loss of functional nephrons after ischemia�reperfusion.However, despite a similar reduction in creatinine clearance in both groups, urinaryvolume and sodium excretion were significantly better maintained in rats given clevidi-


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pine than in the vehicle group. This suggests that renal tubular reabsorption of sodium andwater is partially maintained after reperfusion in the clevidipine group, and that clevidi-pine, at a therapeutically relevant dose, has salutary effects on renal function after renalartery occlusion and reperfusion.

Cardioprotective effects

Interruption of the coronary blood flow causes myocardial ischemia and, after a criticaltime period, induces myocardial cell death. Accordingly, immediate revascularization isnecessary to salvage viable myocardium at risk. Clinically, coronary occlusion is usuallytriggered by an intracoronary thrombus. Restoration of blood flow can be accomplishedby means of thrombolytic agents or coronary interventions like percutaneous coronary an-gioplasty or coronary artery bypass grafting. However, reperfusion of the ischemic tissuemay itself activate pathophysiological processes contributing to the final myocardialinjury (10,25).

Calcium antagonists have been shown to decrease myocardial ischemia�reperfusioninjury (42). The exact site of action and myocardial protective mechanisms of these drugsare not understood. Before the development of clevidipine, only long-acting calcium an-tagonists were available for studies on the mechanism of this phenomenon. This made itdifficult to distinguish direct effects on the ischemic myocardium from effects on pe-ripheral circulation and on non-jeopardized myocardial tissue. The development of clevi-dipine created new opportunities to investigate the site of action, mechanisms and timewindows of the cardioprotective effects of calcium antagonists. A summary of experi-ments conducted to elucidate the role of clevidipine in this setting follows.

Pigs were subjected to 45 min of myocardial ischemia through ligation of the left cor-onary artery followed by 4 h of reperfusion. During the ischemic period before reper-fusion, clevidipine or other test compounds or combinations of compounds were adminis-tered to the ischemic myocardium by retrograde coronary venous or coronary arterialinfusions. The area at risk was determined by infusion of Evans Blue dye into the leftatrium, and the infarct size was estimated by triphenyl tetrazolium chloride staining of themyocardial tissue following animal sacrifice (48). In the first set of experiments, clevidi-pine reduced infarct size by 36% (p < 0.01) when given 10 min before the onset of reper-fusion. Central hemodynamics or coronary blood flow were not affected. This experimentverified that clevidipine exerts cardioprotective effects against ischemia�reperfusioninjury and indicates that this effect relates to local mechanisms within the ischemic myo-cardium (48).

The effect of clevidipine on the development of myocardial ischemia�reperfusioninjury during the early and late phases of ischemia and during early reperfusion wasstudied in the same experimental model, applying another study protocol. Clevidipine wasinfused over 5 min into the ischemic myocardium in three groups of pigs starting at 5, 35,or 44 min after the onset of ischemia (13). The infarct size, expressed as a percentage ofthe myocardial tissue at risk, was significantly smaller in pigs given clevidipine at 5 min(58%; p < 0.01) and at 44 min (42%; p < 0.01) of ischemia than in pigs receivingclevidipine after 35 min of ischemia (85%). This shows that blockade of calcium influx byclevidipine at the early phase of ischemia and at the time of reperfusion limits infarct sizeinduced by ischemia and reperfusion.

This interpretation is based on the assumption that clevidipine given locally to ische-mic myocardium in anesthetized pigs has a very short half-life. When this assumption was



tested using the same protocol (54), the mean blood clearance of clevidipine was calcu-lated to be 0.17 L�min�kg, and the estimated half-life was ~0.5 min. Very low levels ofclevidipine were detected in the coronary venous blood in animals subjected to differentperiods of ischemia, and then during the first two min of reperfusion only. There were nodetectable levels in the arterial blood at any time. Blood concentration profiles of clevidi-pine did not differ with the length of myocardial ischemia. Accordingly, it could be con-cluded that the systemic concentration of clevidipine does not reach pharmacologicallyactive levels when a dose known to exert cardioprotection is administered into the cor-onary artery.

Possible mechanisms of myocardial protection by clevidipine

Nitric oxide (NO) is an important regulator of vascular tone; it prevents platelet andleukocyte adherence, and acts as a scavenger of oxygen radicals. An experimental pigmodel (21) was used to study the effects of clevidipine on preservation of endothelialfunction and protection against myocardial injury by local NO-mediated mechanismsduring late ischemia and early reperfusion. Five groups of pigs were given vehicle, clevi-dipine, the NO-synthesis inhibitor N-monomethyl-L-arginine (L-NMMA), clevidipine incombination with L-NMMA, or clevidipine in combination with L-NMMA and the NOprecursor L-arginine. Figure 3 shows the infarct size expressed as a percentage of themyocardial area at risk in these experimental groups. Clevidipine reduced infarct size sig-nificantly, but this protective effect was abolished when the drug was given together withL-NMMA, whereas addition of L-arginine restored the cardioprotective effect. Further-more, endothelium-dependent coronary vasodilatation induced by substance P was signif-


CLEVIDIPINE 235

0

20

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Infa

rct

siz

e(%

ofa

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Ve

hic

le

Cle

v

Cle

v+

L-N

MM

A

L-N

MM

A

Cle

v+

L-N

MM

A+

L-A

rg

FIG. 3. Infarct size expressed as percent of area at risk after 45 min of ischemia followed by 4 h of reperfusion.The animals were given either vehicle (n = 9), clevidipine (Clev, n = 8), the NO synthase inhibitor L-NMMA(n = 6), Clev plus L-NMMA (n = 6) or Clev in the combination with L-NMMA and the NO precursor L-arginine(n = 6) into the left coronary artery during the last 10 min of ischemia and the first 5 min of reperfusion. Data arepresented as mean ± S.E.M. Significant differences between the groups and vehicle are shown, ***P < 0.001.Reproduced from ref. 21 with permission from the European Society of Cardiology.

icantly larger in the clevidipine group than in other groups. Therefore, by local adminis-tration, clevidipine reduces infarct size during late ischemia and early reperfusion andpreserves coronary endothelial function, possibly by maintaining the local bioavailabilityof NO.

The possible involvement of bradykinin was tested in further investigations of the car-dioprotective effects of clevidipine. Bradykinin, a potent endogenous vasodilator, inducesendothelial-dependent relaxation via multiple mechanisms, including those involving cy-clooxygenase-derived prostanoids and endothelium-derived hyperpolarizing factor (41).Bradykinin contributes to the limitation of infarct size during myocardial ischemia and re-perfusion via B2 receptors (30). Four groups of pigs were given vehicle, clevidipine, clevi-dipine in combination with the bradykinin B2 receptor antagonist HOE 140; icatibant (D-Arg[Hyp3-Thi5-D-Tic7-Oic8]-bradykinin) or clevidipine in combination with HOE 140and the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP) during the last 10 min ofischemia (22). As in the previously described studies, clevidipine reduced ischemia �reper-fusion-induced infarct size. This effect was abolished by the concomitant administrationof HOE 140, while further addition of SNAP restored cardioprotection (Fig. 4). This sug-gests that the cardioprotective effects of clevidipine during late ischemia and early reper-fusion are mediated via bradykinin- and NO-related mechanisms.

Summary of the effects of clevidipine on ischemia�reperfusion injury

It can be concluded from this set of experiments that clevidipine protects against ische-mia�reperfusion-induced injury of various organs including kidney, splanchnic region and



0

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Vehicle Clev Clev+ HOE

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+ SNAP

FIG. 4. Infarct size as percent of the area at risk after 45 min of ischemia followed by 4 h of reperfusion. The an-imals were treated with vehicle (n = 10), clevidipine (Clev, n = 10), a combination of clevidipine and bradykininB2 receptor antagonist HOE 140 (Clev + HOE, n = 6), or a combination of clevidipine and HOE, with the nitricoxide donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP) administered into the coronary sinus during the last10 min of ischemia and the first 5 min of reperfusion (Clev + HOE + SNAP, n = 6). Data are presented asmeans ± S.E.M. Significant differences from the vehicle group are shown, ***P < 0.001. Reproduced fromref. 22 with permission from Lipincott Williams and Wilkins.

heart. Experiments performed in the myocardial ischemia�reperfusion model clearly indi-cates that the mechanisms of the protective action of clevidipine are located within theischemic tissues, and that they are multifactorial, involving inhibition of free radicals,calcium overload and possibly also comprising bradykinin- and NO-related mechanisms.The evidence suggests that clevidipine has the potential for being clinically beneficial inthe treatment of reperfusion-induced injuries, for example in association with cardiacsurgery, cardiopulmonary bypass (CPB), percutaneous coronary intervention (PCI), organtransplantation and multi-organ failure.

TOXICOLOGY

Clevidipine has been evaluated in a toxicological program in animals and in in vitro

studies with bacteria, mammalian cells and human blood. In single-dose toxicity studies,the maximal tolerated i.v. dose (MTD) of clevidipine in rodents was determined to be140 mg�kg in the mouse and 110 mg�kg in rats.

Repeated-dose toxicity studies were performed by exposing rats and dogs to con-tinuous i.v. administration of clevidipine for up to four weeks. In these studies, clevidipinewas administered at doses resulting in blood concentrations 4 to 8 times those reachedwith clevidipine in hypertensive patients Clevidipine was used as a lipid emulsion, thesame formulation as in the clinical trials. The few adverse effects observed in these studiesthat are possibly related to clevidipine included small biochemical and organ weight devi-ations. These effects were observed only at the highest doses tested. It was, therefore, con-cluded that satisfactory safety margins exist in clinical settings for patients receiving ther-apeutic doses of clevidipine.

A battery of genotoxicity studies of clevidipine included the Ames mutagenicity text,the mouse lymphoma thymidine kinase locus assay, test for chromosome aberrations inhuman lymphocytes, the lymphocyte transformation test in vitro and the mouse micro-nucleus test in vivo. Additionally, fertility and embryofetal studies of clevidipine in the ratand�or rabbits have been performed. Results from in vitro and in vivo genotoxic studiesindicate absence of any clinically relevant mutagenic risk with clevidipine.

Two studies were conducted in dogs and one in rabbits to assess the potential for intra-vascular, perivascular or skin irritation at administration sites. It was determined that atconcentrations and infusion rates far above those intended for clinical use, the infusion ofclevidipine caused a slight local vascular irritant effect. These and repeated-dose studiessuggest that the clinical administration of clevidipine is likely to be associated with onlyminimal, if any, irritant effects at the site of injection.

Overall, the results of the toxicology studies indicated that the majority of the clinical,hematological, biochemical as well as morphological effects observed were due to lipidoverload, induced by the vehicle. Most of these findings are well-known from previousanimal studies performed with agents, like Intralipid®. However, Intralipid® and similaremulsions have been administered to humans for decades. Thus, the vast majority of toxi-cological findings in animals receiving repeated administration of clevidipine at doses farabove those that would be used in clinical practice, have little or no relevance to the use oftherapeutic doses of clevidipine in a clinical setting.


CLEVIDIPINE 237

CLINICAL STUDIES

Clevidipine has been studied in healthy volunteers, patients with essential hyperten-sion, and in anesthetized or sedated patients during and after cardiac surgery.

Metabolism and Pharmacokinetics

Metabolism

Clevidipine is rapidly hydrolyzed in the blood by cleavage of the ester group resultingin an equivalent formation of the primary metabolite as illustrated in Fig. 5 (18). The rateof hydrolysis of clevidipine is much higher in whole blood than in plasma alone. This sug-gests that esterases located in the membrane or the cytosol of the red blood cells is mostefficient in hydrolyzing clevidipine in blood. The half-life of clevidipine increases withlower blood temperatures. Clevidipine is highly protein-bound in human plasma (~99.7%)(18). No concentration-dependent protein binding of clevidipine has been observed in thedose range studied (18).

The metabolism of clevidipine to the primary inactive metabolite occurs in two steps.Clevidipine is initially metabolized by esterases in the blood to a hemiacetal ester and bu-tyric acid. The unstable hemiacetal ester is chemically converted to the primary and majorpharmacologically inactive metabolite of clevidipine found in plasma (Fig. 5). This me-tabolite is subsequently metabolized to a large extent by glucuronidation, oxidation ordecarboxylation before excretion. The pharmacokinetics of the main metabolite, with aterminal half-life of approximately 9 h, differs markedly from clevidipine (15,16). Re-covery of approximately 15% of administered radioactivity in feces following intravenous



Oxidation

DecarboxylationGlucuronidation

esterases

rapid

Clevidipine

OO

O

O

NH

Cl

O

O

Cl

OO

OH

NH

Cl

O

O

Cl

unstable intermediate

OH

O

HH

O

OH

O

NH

Cl

O

O

Cl

FIG. 5. Metabolic pathways of clevidipine following administration to humans (L. Fryklund, personalcommunication).

administration of tritium-labeled clevidipine suggests biliary elimination and �or intestinalsecretion of clevidipine and�or its metabolites (15).

Pharmacokinetics

In venous blood collected from healthy volunteers and patients with essential hyper-tension, there is a lag time of 0.5–1.0 min between the termination of a clevidipine in-fusion and the start of a rapid decay of clevidipine blood concentrations (15). In contrast,there was no lag time in arterial blood collected from the left radial artery in patients un-dergoing CABG surgery (53). The presence of an arteriovenous concentration differencewas verified when arterial and venous blood samples were collected in healthy volunteerswho received clevidipine infusions for up to 24 h (14) (Fig. 6 and Table 3).

Volume of distribution and clearance

The steady state volume of distribution (Vss) for clevidipine derived from arterial andvenous blood concentrations is listed in Table 3 (14). The mean Vss of clevidipine derivedfrom venous blood is larger than that derived from arterial blood. Irrespective of the bloodpool, the volume of distribution for clevidipine is smaller than that reported for other di-hydropyridine calcium antagonists, such as felodipine (45). The blood clearance of clevi-dipine has been determined by non-compartmental and compartmental analysis of indi-vidual data, as well as by population approach (Table 3). These distinct methods providedsimilar results in comparative study groups. It is noteworthy that blood clearance of clevi-dipine during hypothermic CPB is only half of the value found during normothermia.

As already described, arterial blood concentrations are approximately twice as high asthose in venous blood at steady state (Fig. 6). Accordingly, mean blood clearance valuesderived from venous blood are approximately twice those obtained from arterial bloodconcentrations (Table 3).


CLEVIDIPINE 239

infusion

0 20 40 60 800.1

1

10

100

Blo

od

co

nce

ntr

atio

n(n

mo

l/L

)

Time (min)

FIG. 6. Arterial (�) and venous (�) blood concentrations (log scale) of clevidipine in a representative subjectfollowing intravenous infusion over a 20-min period (14).

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M.N

OR

DL

AN

DE

RE

TA

L.

TABLE 3. Summary of derived pharmacokinetic parameters of clevidipine determined in different populations

Ref. Population ModelDose

(nmol�min�kg)Duration

(h)Sample

siteCL

(L�min�kg)Vc

(L�kg)Vss

(L�kg)k10

(min–1)Half life (t1�2)

(min)Fract constant (C)

(%)AUCë1

(%)

15 Healthy subjects N.C. 0.1–48 0.33 Ven 0.146 —– — — — — —2-Cpop

0.121 0.36 0.56 0.34 ë1 = 1.8ëz = 9.5

1 = 95.92 = 4.1

81.6

14 Healthy subjects 2-C 12 1 Ven 0.142 0.36 0.58 0.40 ë1 = 1.6ëz = 15.5

1 = 98.92 = 1.1

92.0

13 Healthy subjects ë1 ë2 ëz 1 2 33-C 7 0.33 Art 0.070 0.07 0.22 1.02 0.6 2.3 16 94.2 5.6 0.2 96.7

2 24.0 Art 0.072 0.08 0.20 0.79 0.7 2.2 18 86.7 13.0 0.3 94.67 24.0 Art 0.066 0.10 0.14 0.82 0.8 2.3 22 89.3 10.4 0.2 94.3

45 Essent. hypert. 2-C 0.4–12 4 Ven 0.105 0.36 0.51 0.32 ë1 = 2.2ëz = 16.8

1 = 98.92 = 1.1

92.4

6 Post operative 3-Cpop

0.1–21 2 Art 0.053 0.08 0.39 — ë1 = 0.6ë2 = 5.2ëz = 21

1 = 0.9472 = 0.0453 = 0.008

—

52 CABG-patients 2-Cpop

pre-CPB2.4–7.2

0.17 Art 0.054 0.06 0.11 0.86 ë1 = 0.7ëz = 3.8

1 = 95.02 = 5.0

76.9

2-Cpop

CPB2.0–5.5

0.17 Art 0.030 0.07 0.11 0.49 ë1 = 1.3ëz = 7.6

1 = 96.72 = 3.1

83.5

Note. Pop, population approach; N.C., non compartmental analysis; 2-C, two-compartment model; 3-C, three-compartment model; CPB, cardiopulmonarybypass.

Half-life and decrement times

As shown in Table 3, the half-lives associated with the exponential phases of the bloodconcentration vs. time curve vary slightly in different studies (12,14). However, character-izing pharmacokinetics of a drug with disposition models containing two or three expo-nential phases with different half-lives is sometimes done by arbitrary judgments. Theimportant phases in describing the pharmacokinetic properties of clevidipine are those im-mediately after cessation of the infusion, since the initial rapid post-infusion decline inclevidipine levels is primarily related to elimination (15). Thus, use of decremental timesrather than different half-lives is more appropriate for describing the pharmacokinetics ofclevidipine. In order to illustrate the initial rapid decline, the time to reach 50% and 90%post-infusion decline in concentrations of clevidipine and nicardipine following variousinfusion times are shown in Fig. 7 (12,14,27). The simulations showed that the 50% post-infusion decline (context-sensitive half-time) of clevidipine is less than 1 min regardlessof the duration of the infusion. The time to reach a 90% decline is approximately 5 minfollowing clinically relevant infusion times. The corresponding times for nicardipinechanged with the duration of the infusion. The reason for this difference is that the initialrapid post-infusion decline in clevidipine blood levels is primarily related to elimination,whereas the corresponding decline for nicardipine is due to distribution.

Influence of dose and duration of infusion

There is a linear relationship between the dose and the steady state blood concentra-tions of clevidipine in healthy volunteers receiving clevidipine at rates between 1.5 and 48nmol�min�kg and in patients with essential hypertension receiving between 0.4–12nmol�min�kg (14,16,46). Furthermore, the pharmacokinetic parameters of clevidipine areessentially unaffected by the duration of the infusion. Results obtained during infusiontimes from 10 min to 24 h, are comparable (14) (Table 3).


CLEVIDIPINE 241

0 200 400 6000

25

50

75

800

1000

Nic 50%

Cle 90%

Nic 90%

Cle 50%

Infusion time (min)

FIG. 7. Simulations of decrement time for a 50 and 90% decline in clevidipine (Cle) and nicardipine (Nic)blood�plasma concentrations following increasing infusion times. Data from refs. 12, 14. Note break on they-axis.

Pharmacodynamic Effects in Clinical Trials

Studies in healthy volunteers

In three studies with healthy volunteers (14–16), clevidipine was administered intrave-nously as a continuous infusion at different rates for different time periods. A dose-de-pendent effect on blood pressure was fully established within an average of 2 min afterinitiation of clevidipine infusion (14). The dose and duration of infusion did not signifi-cantly impact the time of recovery of blood pressure to pre-drug values after the end of in-fusion (24). In these conscious individuals, there was a concomitant, dose-dependent andmodest increase in heart rate. Clevidipine was considered well tolerated up to a dose of16 ìg�kg�min. At the highest dose of 22 ìg�kg�min, MAP was reduced by 10%. At thisdose, the heart rate had reached the predetermined safety endpoint of 120 bpm, the reasonto stop further dose escalation in accordance with the protocol (16).

Studies in patients with essential hypertension

Two studies with clevidipine were performed in conscious patients with essential hy-pertension (4,7). In the first study (5), clevidipine was titrated to obtain a predeterminedeffect on MAP, with the infusion being stopped when the MAP was reduced by 15% frombaseline. As illustrated in Fig. 8, there was a rapid decline of the clevidipine effect afterdiscontinuation of the infusion, with blood pressure returning to baseline within minutes.These patients were on chronic oral treatment with â-adrenoceptor antagonists and dem-onstrated no change in HR.

In the second study (46), a placebo-controlled trial, clevidipine was slowly titrated topredetermined dose rates in 20 patients from whom antihypertensive treatment had beenwithdrawn for two weeks. Clevidipine caused dose-dependent reductions in arterial bloodpressure with a maximum reduction of approximately 30% at the highest infusion rate.These patients, who were off concomitant beta blockade, had a modest increase in HR.The effects of clevidipine rapidly vanished after the end of drug infusion.



95

90

85

1000.1 g/kg/minì

0.4

0.7

20 40 60 80 100 120 min0

MA

P%

ofb

asal(1

25

mm

Hg)

Clevidipine infusion

FIG. 8. Effect of increasing doses of clevidipine given to reduce mean arterial blood pressure (MAP) 5, 10, and15% from basal MAP (125 mm Hg) in one patient with essential hypertension. Data from ref. 5. Note the rapidreturn of MAP to control after end of infusion.

Studies in patients undergoing cardiac surgery

The clinical efficacy and safety of clevidipine in anesthetized patients undergoingcardiac surgery have been investigated in five studies. Three of these studies were con-ducted postoperatively (7,31,44) and two were performed perioperatively (2,53).

Postoperative studies in cardiac surgery patients

A placebo-controlled parallel-group dose-finding study was performed in 91 anesthe-tized patients with a MAP exceeding 90 mm Hg (n = 9–12�group) post-CABG (7). Clevi-dipine was given for a minimum of 10 min at six different dose rates. As shown in Fig. 9,the administration of clevidipine resulted in a dose-dependent reduction in MAP with amaximum reduction of 38%. There was no increase in heart rate in these anesthetized pa-tients, probably due to attenuation of the baroreflex sensitivity during anesthesia (33).

In another study (31) evaluating central and coronary hemodynamics, clevidipine wastitrated in 8 anesthetized, normotensive patients post-CABG in the intensive care unit.Dose-dependent reductions in MAP were achieved, mainly due to a decrease in SVR.Cardiac filling pressures were not influenced, reflecting the fact that clevidipine does notcause venous dilation. Afterload reduction was associated with a dose-dependent increasein stroke volume (Fig. 10). Heart rate was not influenced in these patients.

Each patient had a four-thermistor catheter inserted via the jugular vein and positionedfor coronary blood flow determinations and blood sampling. High doses of clevidipinecaused coronary vasodilatation as indicated by a reduction in myocardial oxygen ex-traction. There were no adverse effects on myocardial lactate metabolism, indicating thatthe coronary vasodilatation did not result in shunting of blood from ischemic areas, i.e.,coronary steal (31).

The hemodynamic effects of clevidipine were compared with those of SNP, using acrossover study design (31). Patients in need of blood pressure control after CABG(n = 13) were recruited. Therapy was initiated with SNP and a hemodynamic evaluationwas performed when blood pressure control was satisfactory. Subsequently, the SNP in-fusion was discontinued and replaced by clevidipine infusion. The dose was adjusted to


CLEVIDIPINE 243

Placebo 0.1 0.3 1 3 10

MAP

HR

Dose rate ( g/kg/min)ì

–40

–30

–20

–10

0

–50

10

FIG. 9. Percent change from pre-drug valuein mean arterial blood pressure (MAP �)and in heart rate (HR �) during increasingdose rates of clevidipine in anesthetized pa-tients after CABG surgery (n = 9–12�doserate). Values were obtained at the end of10 min infusion, or just before MAP reacheda critical level requiring reduction or increaseof dose rate. *p < 0.05 from placebo. Datafrom ref. 7.

control MAP at the same level (70–80 mm Hg) as reached with SNP. Repeated hemodyna-mic evaluation revealed that clevidipine had a more pronounced effect on SVR than SNP.With clevidipine, there was no reduction in central venous pressure or pulmonary cap-illary wedge pressure and stroke volume was higher than with SNP. HR was statisticallysignificantly lower during clevidipine than with SNP, although the difference in actualnumber of beats per minute was small (Fig. 11).

In the third study in post-cardiac surgical patients, Powroznyc et al. (44) evaluatedblood pressure control with clevidipine and SNP in hypertensive patients (MAP = 90mm Hg) in a parallel group (n = 15 in each group), double-blind comparison after electiveCABG. Blood pressure was equally well controlled with both drugs, but heart rate re-mained significantly higher in the SNP group.

In summary, these studies in post-cardiac surgical patients reveal that clevidipinerapidly reduces blood pressure in a dose-dependent manner without affecting cardiacfilling pressures or heart rate. This effect contrasts with that of SNP , which besides ex-erting its effects on blood pressure, also reduces cardiac filling pressure and increasesheart rate in anesthetized patients after cardiac surgery.



0

70

80

90

(mm Hg)

1.5 3.00.750.375 C2C1 1.5 3.00.750.375 C2C1

1.5 3.00.750.375 C2C1 1.5 3.00.750.375 C2C1

Mean arterial pressure

0

70

80

(bpm) Heart rate

0

8

10

12

14

(units )–2

Systemic vascular resistance

0

65

70

75

80

(ml/beat) Stroke volume

FIG. 10. Effects of increasing dose rates of clevidipine (ìg�kg�min) given for 10 min to 8 anesthetized cardiacpatients. C1 and C2 indicate values obtained during control situations 10 min before or after infusion ofclevidipine, respectively. **p > 0.01, ***p < 0.001 from C1 mean ± S.E.M. Data from ref. 31.

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EV

IDIP

INE

245

SNP 2SNP 1 Clevidipine


0

10

15

(mm Hg) PCWP

0

10

15(mm Hg) CVP

70

80

(mm Hg) Mean arterial pressure



60

70

80

(ml) Stroke volume

0



75

80

85

90

(bpm) Heart rate

0

9

10

11

(units )–2 SVR

FIG. 11. Hemodynamic effects of shifting antihypertensive therapy from sodium nitroprusside (SNP 1) to clevidipine for 10 min and then back to sodium nitroprusside (SNP 2)in 8 anesthetized cardiac surgical patients requiring pharmacological treatment for blood pressure control during and after cardiac surgery. Mean ± S.E.M., *p < 0.05 from SNP.PCWP, pulmonary capillary wedge pressure; SVR, systemic vascular resistance; CVP, central venous pressure. Data from ref. 31.

Perioperative studies in cardiac surgery patients

The dose of clevidipine required to control blood pressure before and during cardiopul-monary bypass (CPB) was compared in 8 patients during CABG surgery (53). Theinfusion rate of clevidipine needed to reduce MAP to the required level during the pre-by-pass stage (normothermic) was two times the infusion rate required during bypass (hypo-thermic) conditions. The lower infusion rate during CPB is likely to be secondary to thedecreased blood clearance of clevidipine during hypothermia and blood dilution (see thePharmacokinetics and Metabolism section of this review).

Clevidipine was shown to be significantly more effective than placebo in the peri-operative reduction of blood pressure in a double-blind study of 60 patients undergoingCABG (2). The MAP reduction within 10 min after start of drug infusion with clevidipinewas 28.2 mm Hg, compared to 10.5 mm Hg with placebo (p < 0.001). Control of MAPwas estimated by the AUC relating MAP outside a predetermined blood pressure level vs.time. During the first 4 h, blood pressure was significantly better controlled with cle-vidipine than with placebo, AUC during clevidipine being only 63% of that duringplacebo administration. Bailout with GTN to protect against too high blood pressurelevels while on drug was performed for only 4�29 (14%) of patients in the clevidipinetreatment group, compared with 27�31 (87%) of patients in the placebo group. In addition,the number of pharmacological or mechanical interventions needed to control bloodpressure either upwards or downwards were higher for patients in the placebo group thanin patients receiving clevidipine.

Adverse events

Many of the patients evaluated in the cardiac surgery studies described here, includingthose on placebo, were reported as having adverse events. The most frequently reportedadverse events were atrial tachyarrhythmia, and overall the most frequently affected bodysystems included the cardiovascular, gastrointestinal and respiratory functions. Thesefindings probably reflect the complex situation in patients undergoing heart surgery, sinceno clear differences in the incidence of adverse events were observed for patients onplacebo vs. patients on clevidipine. In the placebo controlled study including 60 patients(2), treatment with clevidipine or placebo was discontinued due to adverse events in 13cases (hypotension n = 8; hypertension n = 4; bleeding n = 1; bradycardia n = 1). All pa-tients recovered completely. Twenty-seven patients of the 212 patients in the program un-dergoing cardiac surgery experienced a total of 53 serious adverse events (2,7,31,35,53)but only one of these events (7) was considered as possibly related to clevidipine.

Time to effect, offset of effect and PK�PD relation

When time to onset of hemodynamic effect(s) was determined in healthy volunteers, itwas found that the arterial blood concentrations of clevidipine had reached steady statewithin 2 min after start of drug infusion. There was a close relation between blood concen-tration and observed changes in mean arterial blood pressure and in heart rate. However,there was a very brief delay between the change in the arterial blood concentrations and



the hemodynamic response (14). As illustrated in Fig. 12, the effects of clevidipine can berapidly titrated to a desired blood pressure level.

CONCLUSIONS

Clevidipine is a new vasoselective, short-acting dihydropyridine calcium antagonistwith pharmacological and pharmacokinetic properties well suited for acute blood pressurecontrol requiring rapid onset and offset of action. The therapeutic effects of clevidipinehave been demonstrated in clinical situations such as cardiac surgery and post-operativeintensive care after coronary bypass procedures. Clevidipine is likely to be similarly ef-fective in other clinical situations requiring rapidly tailored blood pressure control. Inanimal models, clevidipine exerts organ protective properties in association withischemia�reperfusion. These properties may provide added benefit to patients treated withclevidipine, particularly since ischemia�reperfusion frequently occurs in the same clinicalsettings as those in which acute blood pressure control may be useful. Further clinicalstudies in this area are warranted. Based on results from the ongoing clinical programclevidipine has a rapid onset dose-dependent blood pressure lowering effect, along with arapid offset of effect and favorable hemodynamic properties. These results suggest thatclevidipine has suitable attributes to become a useful novel therapeutic agent for use inacute care situations requiring rapid blood pressure control.

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CLEVIDIPINE 247

0 10 200

50

100

–25

0

25

50

Clevidipine infusion %cha

ng

efr

om

ba

se

line

va

lue

Cle

vid

ipin

eco

nc

(nm

ol/L)

FIG. 12. Arterial (�) and venous (�) blood concentrations of clevidipine and the hemodynamic responses in

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