Mechanism Of Action
Clevidipine is a dihydropyridine L-type calcium channel
blocker. L-type calcium channels mediate the influx of calcium during
depolarization in arterial smooth muscle. Experiments in anesthetized rats and
dogs show that clevidipine reduces mean arterial blood pressure by decreasing
systemic vascular resistance. Clevidipine does not reduce cardiac filling
pressure (pre-load), confirming lack of effects on the venous capacitance vessels.
Cleviprex is titrated to the desired reduction in blood
pressure. The effect of Cleviprex appears to plateau at approximately 25% of
baseline systolic pressure. The infusion rate for which half the maximal effect
is observed is approximately 10 mg/hour.
Onset of Effect
In the perioperative patient population, Cleviprex
produces a 4-5% reduction in systolic blood pressure within 2-4 minutes after
starting a 0.4 mcg/kg/min infusion (approximately 1-2 mg/hr).
Maintenance of Effect
In studies up to 72 hours of continuous infusion, there
was no evidence of tolerance or hysteresis.
Offset of Effect
In most patients, full recovery of blood pressure is
achieved in 5-15 minutes after the infusion is stopped.
In studies up to 72 hours of continuous infusion, in
patients that were not transitioned to other antihypertensive therapies, there
was some evidence of rebound hypertension following Cleviprex discontinuation.
Cleviprex causes a dose-dependent decrease in systemic
An increase in heart rate is a normal response to
vasodilation and decrease in blood pressure; in some patients these increases
in heart rate may be pronounced [see WARNINGS AND PRECAUTIONS].
In healthy volunteers, clevidipine or its major
carboxylic acid metabolite, at therapeutic and supratherapeutic concentrations
(approximately 2.8 times steady-state), did not prolong cardiac repolarization.
Clevidipine is rapidly distributed and metabolized
resulting in a very short half-life. The arterial blood concentration of
clevidipine declines in a multi-phasic pattern following termination of the
infusion. The initial phase half-life is approximately 1 minute, and accounts
for 85-90% of clevidipine elimination. The terminal half-life is approximately 15
Clevidipine is > 99.5% bound to proteins in plasma at
37°C. The steadystate volume of distribution was determined to be 0.17 L/kg in
Metabolism and Elimination
Clevidipine is rapidly metabolized by hydrolysis of the ester
linkage, primarily by esterases in the blood and extravascular tissues, making
its elimination unlikely to be affected by hepatic or renal dysfunction. The
primary metabolites are the carboxylic acid metabolite and formaldehyde formed
by hydrolysis of the ester group. The carboxylic acid metabolite is inactive as
an antihypertensive. This metabolite is further metabolized by glucuronidation
or oxidation to the corresponding pyridine derivative. The clearance of the
primary dihydropyridine metabolite is 0.03 L/h/kg and the terminal half-life is
approximately 9 hours.
In vitro studies show that clevidipine and its metabolite
at the concentrations achieved in clinical practice will not inhibit or induce
any CYP enzyme.
In a clinical study with radiolabeled clevidipine, 83% of
the drug was excreted in urine and feces. The major fraction, 63-74% is
excreted in the urine, 7-22% in the feces. More than 90% of the recovered
radioactivity is excreted within the first 72 hours of collection.
When pregnant rats were dosed with clevidipine during
late gestation and lactation, there were dose-related increases in mortality,
length of gestation and prolonged parturition at dose levels as low as 13
mg/kg/day (about 1/4th the maximum recommended human dose of 504 mg/day (21
mg/hour x 24 hours) on a body surface area basis). When offspring of these dams
were mated, they had a conception rate lower than that of controls. Clevidipine
crosses the placental membrane in this species and doses of 35 or more mg/kg/day
(about 0.7 times the MRHD) administered during organogenesis adversely affected
fetal survival. Fetal survival was also adversely affected when pregnant
rabbits were treated during organogenesis with 55 mg/kg/day (about twice the
MRHD on a body surface area basis).
Cleviprex was evaluated in two double-blind, randomized,
parallel, placebo-controlled, multicenter trials of cardiac surgery
patients—pre-operative use in ESCAPE-1 (n=105) and post-operative use in
ESCAPE-2 (n=110). Patients were undergoing coronary artery bypass grafting,
with or without valve replacement. Inclusion in ESCAPE-1 required a systolic
pressure ≥ 160 mmHg. In ESCAPE-2, the entry criterion was systolic
pressure of ≥ 140 mmHg within 4 hours of the completed surgery. The mean
baseline blood pressure was 178/77 mmHg in ESCAPE -1 and 150/71 mmHg in ESCAPE
-2. The population of both studies included 27% females and 47% patients older
than age 65.
Cleviprex was infused in ESCAPE-1 preoperatively for 30
minutes, until treatment failure, or until induction of anesthesia, whichever
came first. Cleviprex was infused in ESCAPE-2 postoperatively for a minimum of
30 minutes unless alternative therapy was required. The maximum infusion time
allowed in the ESCAPE studies was 60 minutes.
In both studies infusion of Cleviprex was started at a
dose of 1- 2 mg/hour and was titrated upwards, as tolerated, in doubling
increments every 90 seconds up to an infusion rate of 16 mg/hour in order to
achieve the desired blood pressure-lowering effect. At doses above 16 mg/hour,
increments were 7 mg/hour. The average Cleviprex infusion rate in ESCAPE-1 was
15.3 mg/hour and in ESCAPE-2 it was 5.1 mg/hour. The mean duration of exposure
in the same ESCAPE studies was 30 minutes for the Cleviprextreated patients.
Approximately 4% of Cleviprex-treated subjects in
ESCAPE-1 and 41% in ESCAPE-2 were on concomitant vasodilators during the first
30 minutes of Cleviprex administration.
Cleviprex lowered blood pressure within 2-4 minutes. The
change in systolic blood pressure over 30 minutes for ESCAPE-1 (preoperative)
and ESCAPE-2 (postoperative) are shown in Figure 1 and 2.
Figure 1: Mean change in systolic blood pressure
(mmHg) during 30-minute infusion, ESCAPE-1 (preoperative)
Figure 2: Mean change in systolic blood pressure
(mmHg) during 30-minute infusion, ESCAPE-2 (postoperative)
The change in heart rate over 30 minutes for ESCAPE-1
(preoperative) and ESCAPE-2 (postoperative) are shown in Figure 3 and 4.
Figure 3: Mean change in heart rate (bpm) during
30-minute infusion, ESCAPE-1 (preoperative)
Figure 4: Mean change in heart rate (bpm) during
30-minute infusion, ESCAPE-2 (postoperative)
In three Phase 3 open-label clinical trials (ECLIPSE),
1512 patients were randomized to receive Cleviprex, nitroglycerin
(perioperative hypertension), sodium nitroprusside (perioperative
hypertension), or nicardipine (postoperative hypertension), for the treatment
of hypertension in cardiac surgery. The mean exposure in the ECLIPSE studies was
8 hours at 4.5 mg/hour for the 752 patients who were treated with Cleviprex. Blood
pressure control was assessed by measuring the magnitude and duration of SBP excursions
outside the predefined pre- and post-operative SBP target range of 75-145 mmHg
and the predefined intra-operative SBP range of 65-135 mmHg. In general, blood
pressure control was similar with the four treatments.
Cleviprex was evaluated in an open-label, uncontrolled
clinical trial (VELOCITY) in 126 patients with severe hypertension (SBP > 180
mmHg or diastolic blood pressure [DBP] > 115 mmHg). Cleviprex infusion was
initiated at 2 mg/hour and up-titrated every 3 minutes, doubling up to a
maximum dose of 32 mg/hour as required to achieve a prespecified target blood
pressure range within 30 minutes (primary endpoint). The transition to oral
antihypertensive therapy was assessed for up to 6 hours following cessation of
The blood pressure effect in this study is shown in
Figure 5. The average infusion rate was 9.5 mg/hour. The mean duration of
Cleviprex exposure was 21 hours.
Figure 5: Mean percent change in SBP (%) during the
first 30 minutes of infusion, VELOCITY (severe hypertension)
Oral antihypertensive therapy was instituted 1 hour prior
to the anticipated cessation of Cleviprex infusion. Transition to oral
antihypertensive therapy within 6 hours after discontinuing Cleviprex infusion
was successful in 91% (115/126) of patients. No patient had IV antihypertensive
therapy reinstituted following transition to oral therapy.
Cleviprex was evaluated in a randomized,
placebo-controlled, single-blind, parallel 72-hour continuous infusion study in
61 mild to moderate essential hypertensives. The mean baseline blood pressure
was 151/86 mmHg.
Subjects were randomized to placebo or to 2, 4, 8, or 16
mg/hour. Doses above 2 mg/hour were started at 2 mg/hour and force-titrated in
2-fold increments at 3-minute intervals. Blood pressure, heart rate, and blood
levels of clevidipine were measured during the infusion period. Blood levels
were monitored 1 hour after the infusion was discontinued. Blood pressure and
heart rate were monitored for 8 hours and also at 96 hours after the termination
of infusion. Systolic blood pressure effect was related to the concentration of
clevidipine and plateaued at higher measured concentrations, with the maximal
effect estimated at 25% of baseline systolic blood pressure. The estimated
infusion rate necessary to achieve half of this maximal effect was
approximately 10 mg/hour.