Mechanism of Action
CADUET
CADUET is a combination of two drugs, a dihydropyridine calcium antagonist (calcium
ion antagonist or slow-channel blocker) amlodipine (antihypertensive/antianginal
agent) and an HMG-CoA reductase inhibitor atorvastatin (cholesterol lowering agent).
The amlodipine component of CADUET inhibits the transmembrane influx of calcium
ions into vascular smooth muscle and cardiac muscle. The atorvastatin component
of CADUET is a selective, competitive inhibitor of HMG-CoA reductase (statin), the rate-limiting
enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor
of sterols, including cholesterol.
The Amlodipine Component of CADUET
Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine
binding sites. The contractile processes of cardiac muscle and vascular smooth muscle
are dependent upon the movement of extracellular calcium ions into these cells through
specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes
selectively, with a greater effect on vascular smooth muscle cells than on cardiac
muscle cells. Negative inotropic effects can be detected in vitro but such
effects have not been seen in intact animals at therapeutic doses. Serum calcium
concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine
is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel
receptor is characterized by a gradual rate of association and dissociation with
the receptor binding site, resulting in a gradual onset of effect.
Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth
muscle to cause a reduction in peripheral vascular resistance and reduction in blood
pressure.
The precise mechanisms by which amlodipine relieves angina have not been fully delineated,
but are thought to include the following:
Exertional Angina: In patients with exertional angina, amlodipine reduces the total
peripheral resistance (afterload) against which the heart works and reduces the
rate pressure product, and thus myocardial oxygen demand, at any given level of
exercise.
Vasospastic Angina: Amlodipine has been demonstrated to block constriction and restore
blood flow in coronary arteries and arterioles in response to calcium, potassium
epinephrine, serotonin, and thromboxane A2 analog in experimental
animal models and in human coronary vessels in vitro. This inhibition of
coronary spasm is responsible for the effectiveness of amlodipine in vasospastic
(Prinzmetal's or variant) angina.
The Atorvastatin Component of CADUET
Cholesterol and triglycerides circulate in the bloodstream as part of lipoprotein
complexes. With ultracentrifugation, these complexes separate into HDL (high-density
lipoprotein), IDL (intermediate-density lipoprotein), LDL (low-density lipoprotein),
and VLDL (very-low-density lipoprotein) fractions. Triglycerides (TG) and cholesterol
in the liver are incorporated into VLDL and released into the plasma for delivery
to peripheral tissues. LDL is formed from VLDL and is catabolized primarily through
the high-affinity LDL receptor.
Clinical and pathologic studies show that elevated plasma levels of total cholesterol
(total-C), LDL-cholesterol (LDL-C), and apolipoprotein B (apo B) promote human atherosclerosis
and are risk factors for developing cardiovascular disease, while increased levels
of HDL-C are associated with a decreased cardiovascular risk.
Epidemiologic investigations have established that cardiovascular morbidity and
mortality vary directly with the level of total-C and LDL-C, and inversely with
the level of HDL-C.
In animal models, atorvastatin lowers plasma cholesterol and lipoprotein levels
by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing
the number of hepatic LDL receptors on the cell-surface to enhance uptake and catabolism
of LDL; atorvastatin also reduces LDL production and the number of LDL particles.
Atorvastatin reduces total-C, LDL-C, and apo B in patients with homozygous and heterozygous
familial hypercholesterolemia (FH), nonfamilial forms of hypercholesterolemia, and
mixed dyslipidemia. Atorvastatin also reduces VLDL-C and TG and produces variable
increases in HDL-C and apolipoprotein A-1. Atorvastatin reduces total-C, LDL-C,
VLDL-C, apo B, TG, and non-HDL-C, and increases HDL-C in patients with isolated
hypertriglyceridemia. Atorvastatin reduces intermediate density lipoprotein
cholesterol (IDL-C) in patients with dysbetalipoproteinemia.
Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, intermediate
density lipoprotein (IDL), and remnants, can also promote atherosclerosis.
Elevated plasma triglycerides are frequently found in a triad with low HDL-C levels
and small LDL particles, as well as in association with non-lipid metabolic risk
factors for coronary heart disease. As such, total plasma TG has not consistently
been shown to be an independent risk factor for CHD. Furthermore, the independent
effect of raising HDL or lowering TG on the risk of coronary and cardiovascular
morbidity and mortality has not been determined.
Pharmacokinetics and Metabolism
Absorption
Studies with amlodipine: After oral administration of therapeutic doses of
amlodipine alone, absorption produces peak plasma concentrations between 6 and 12
hours. Absolute bioavailability has been estimated to be between 64% and 90%. The
bioavailability of amlodipine when administered alone is not altered by the presence
of food.
Studies with atorvastatin: After oral administration alone, atorvastatin
is rapidly absorbed; maximum plasma concentrations occur within 1 to 2 hours.
Extent of absorption increases in proportion to atorvastatin dose. The absolute
bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic
availability of HMG-CoA reductase inhibitory activity is approximately 30%. The
low systemic availability is attributed to presystemic clearance in gastrointestinal
mucosa and/or hepatic first-pass metabolism. Although food decreases the rate and
extent of drug absorption by approximately 25% and 9%, respectively, as assessed
by Cmax and AUC, LDL-C reduction is similar whether atorvastatin is given with or
without food. Plasma atorvastatin concentrations are lower (approximately 30% for
Cmax and AUC) following evening drug administration compared with morning. However,
LDL-C reduction is the same regardless of the time of day of drug administration
(see DOSAGE AND ADMINISTRATION).
Studies with CADUET: Following oral administration of CADUET peak
plasma concentrations of amlodipine and atorvastatin are seen at 6 to 12 hours and
1 to 2 hours post dosing, respectively. The rate and extent of absorption (bioavailability)
of amlodipine and atorvastatin from CADUET are not significantly different from
the bioavailability of amlodipine and atorvastatin administered separately (see
above).
The bioavailability of amlodipine from CADUET was not affected by food. Although
food decreases the rate and extent of absorption of atorvastatin from CADUET by
approximately 32% and 11%, respectively, as it does with atorvastatin when given
alone. LDL-C reduction is similar whether atorvastatin is given with or without
food.
Distribution
Studies with amlodipine: Ex vivo studies have shown that approximately 93%
of the circulating amlodipine drug is bound to plasma proteins in hypertensive patients.
Steady-state plasma levels of amlodipine are reached after 7 to 8 days of consecutive
daily dosing.
Studies with atorvastatin: Mean volume of distribution of atorvastatin is
approximately 381 liters. Atorvastatin is ≥98% bound to plasma proteins. A
blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red
blood cells. Based on observations in rats, atorvastatin calcium is likely to be
secreted in human milk (see CONTRAINDICATIONS, Pregnancy and Lactation, and
PRECAUTIONS, Nursing Mothers).
Metabolism
Studies with amlodipine: Amlodipine is extensively (about 90%) converted
to inactive metabolites via hepatic metabolism.
Studies with atorvastatin: Atorvastatin is extensively metabolized to ortho-
and parahydroxylated derivatives and various beta-oxidation products. In vitro
inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent
to that of atorvastatin. Approximately 70% of circulating inhibitory activity for
HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest
the importance of atorvastatin metabolism by cytochrome P450 3A4, consistent with
increased plasma concentrations of atorvastatin in humans following coadministration
with erythromycin, a known inhibitor of this isozyme (see PRECAUTIONS, Drug Interactions).
In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.
Excretion
Studies with amlodipine: Elimination from the plasma is biphasic with a terminal
elimination half-life of about 30-50 hours. Ten percent of the parent amlodipine
compound and 60% of the metabolites of amlodipine are excreted in the urine.
Studies with atorvastatin: Atorvastatin and its metabolites are eliminated
primarily in bile following hepatic and/or extra-hepatic metabolism; however, the
drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination
half-life of atorvastatin in humans is approximately 14 hours, but the half-life
of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution
of active metabolites. Less than 2% of a dose of atorvastatin is recovered in urine
following oral administration.
Specific Populations
Geriatric
Studies with amlodipine: Elderly patients have decreased clearance of amlodipine
with a resulting increase in AUC of approximately 40-60%, and a lower initial dose
of amlodipine may be required.
Studies with atorvastatin: Plasma concentrations of atorvastatin are higher
(approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (age
≥65 years) than in young adults. Clinical data suggest a greater degree of
LDL-lowering at any dose of atorvastatin in the elderly population compared to younger
adults (see PRECAUTIONS, Geriatric Use).
Pediatric
Studies with amlodipine: Sixty-two hypertensive patients aged 6 to 17 years
received doses of amlodipine between 1.25 mg and 20 mg. Weight-adjusted clearance
and volume of distribution were similar to values in adults.
Studies with atorvastatin: Pharmacokinetic data in the pediatric population
are not available.
Gender
Studies with atorvastatin: Plasma concentrations of atorvastatin in women
differ from those in men (approximately 20% higher for Cmax and 10% lower for AUC);
however, there is no clinically significant difference in LDL-C reduction with atorvastatin
between men and women.
Renal Impairment
Studies with amlodipine: The pharmacokinetics of amlodipine are not significantly
influenced by renal impairment. Patients with renal failure may therefore receive
the usual initial amlodipine dose.
Studies with atorvastatin: Renal disease has no influence on the plasma concentrations
or LDL-C reduction of atorvastatin; thus, dose adjustment of atorvastatin in patients
with renal dysfunction is not necessary (see DOSAGE AND ADMINISTRATION and WARNINGS, Skeletal Muscle).
Hemodialysis
While studies have not been conducted in patients with end-stage renal disease,
hemodialysis is not expected to significantly enhance clearance of atorvastatin
and/or amlodipine since both drugs are extensively bound to plasma proteins.
Hepatic Impairment
Studies with amlodipine: Elderly patients and patients with hepatic insufficiency
have decreased clearance of amlodipine with a resulting increase in AUC of approximately
40-60%, and a lower initial dose may be required.
Studies with atorvastatin: In patients with chronic alcoholic liver disease,
plasma concentrations of atorvastatin are markedly increased. Cmax and AUC are each
4-fold greater in patients with Childs-Pugh A disease. Cmax and AUC of atorvastatin
are approximately 16-fold and 11-fold increased, respectively, in patients with
Childs-Pugh B disease (see CONTRAINDICATIONS).
Heart Failure
Studies with amlodipine: In patients with moderate to severe heart
failure, the increase in AUC for amlodipine was similar to that seen in the elderly
and in patients with hepatic insufficiency.
Pharmacokinetic Studies of Atorvastatin and Co-Administered Drugs
TABLE 2. Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin
TABLE 3. Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs
Pharmacodynamics
Hemodynamic Effects of Amlodipine: Following administration of therapeutic
doses to patients with hypertension, amlodipine produces vasodilation resulting
in a reduction of supine and standing blood pressures. These decreases in blood
pressure are not accompanied by a significant change in heart rate or plasma catecholamine
levels with chronic dosing. Although the acute intravenous administration of amlodipine
decreases arterial blood pressure and increases heart rate in hemodynamic studies
of patients with chronic stable angina, chronic administration of oral amlodipine
in clinical trials did not lead to clinically significant changes in heart rate
or blood pressures in normotensive patients with angina.
With chronic once daily oral administration of amlodipine, antihypertensive effectiveness
is maintained for at least 24 hours. Plasma concentrations correlate with effect
in both young and elderly patients. The magnitude of reduction in blood pressure
with amlodipine is also correlated with the height of pretreatment elevation; thus,
individuals with moderate hypertension (diastolic pressure 105-114 mmHg) had about
a 50% greater response than patients with mild hypertension (diastolic pressure
90-104 mmHg). Normotensive subjects experienced no clinically significant change
in blood pressures (+1/-2 mmHg).
In hypertensive patients with normal renal function, therapeutic doses of amlodipine
resulted in a decrease in renal vascular resistance and an increase in glomerular
filtration rate and effective renal plasma flow without change in filtration fraction
or proteinuria.
As with other calcium channel blockers, hemodynamic measurements of cardiac function
at rest and during exercise (or pacing) in patients with normal ventricular function
treated with amlodipine have generally demonstrated a small increase in cardiac
index without significant influence on dP/dt or on left ventricular end diastolic
pressure or volume. In hemodynamic studies, amlodipine has not been associated with
a negative inotropic effect when administered in the therapeutic dose range to intact
animals and man, even when co-administered with beta-blockers to man. Similar findings,
however, have been observed in normals or well-compensated patients with heart failure
with agents possessing significant negative inotropic effects.
Electrophysiologic Effects of Amlodipine: Amlodipine does not
change sinoatrial nodal function or atrioventricular conduction in intact animals
or man. In patients with chronic stable angina, intravenous administration of 10
mg did not significantly alter A-H and H-V conduction and sinus node recovery time
after pacing. Similar results were obtained in patients receiving amlodipine and
concomitant beta blockers. In clinical studies in which amlodipine was administered
in combination with beta-blockers to patients with either hypertension or angina,
no adverse effects on electrocardiographic parameters were observed. In clinical
trials with angina patients alone, amlodipine therapy did not alter electrocardiographic
intervals or produce higher degrees of AV blocks.
LDL-C Reduction with Atorvastatin: Atorvastatin as well as some of
its metabolites are pharmacologically active in humans. The liver is the primary
site of action and the principal site of cholesterol synthesis and LDL clearance.
Drug dosage, rather than systemic drug concentration, correlates better with LDL-C
reduction. Individualization of drug dosage should be based on therapeutic response
(see DOSAGE AND ADMINISTRATION).