CLINICAL PHARMACOLOGY
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Mechanism of Action
Azor. Azor is a combination of two
antihypertensive drugs: a dihydropyridine calcium antagonist (calcium ion
antagonist or slow-channel blocker), amlodipine besylate, and an angiotensin II
receptor blocker, olmesartan medoxomil. The amlodipine component of Azor
inhibits the transmembrane influx of calcium ions into vascular smooth muscle
and cardiac muscle, and the olmesartan medoxomil component of Azor blocks the
vasoconstrictor effects of angiotensin II.
Amlodipine. Experimental data
suggests that amlodipine binds to both dihydropyridine and nonhydropyridine
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.
Olmesartan medoxomil. Angiotensin
II is formed from angiotensin I in a reaction catalyzed by angiotensin
converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor
agent of the renin-angiotensin system, with effects that include
vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac
stimulation and renal reabsorption of sodium. Olmesartan blocks the
vasoconstrictor effects of angiotensin II by selectively blocking the binding of
angiotensin II to the AT1 receptor in vascular smooth
muscle. Its action is, therefore, independent of the pathways for angiotensin II
synthesis.
An AT2 receptor is found also in many tissues, but
this receptor is not known to be associated with cardiovascular homeostasis.
Olmesartan has more than a 12,500-fold greater affinity for the AT1 receptor than for the AT2
receptor.
Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit
the biosynthesis of angiotensin II from angiotensin I, is a mechanism of many
drugs used to treat hypertension. ACE inhibitors also inhibit the degradation of
bradykinin, a reaction also catalyzed by ACE. Because olmesartan does not
inhibit ACE (kininase II), it does not affect the response to bradykinin.
Whether this difference has clinical relevance is not yet known.
Blockade of the angiotensin II receptor inhibits the negative regulatory
feedback of angiotensin II on renin secretion, but the resulting increased
plasma renin activity and circulating angiotensin II levels do not overcome the
effect of olmesartan on blood pressure.
Pharmacodynamics
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.
With chronic once daily oral administration, 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.
Amlodipine does not change sinoatrial nodal function or atrioventricular
conduction in intact animals or man. 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.
Olmesartan medoxomil. Olmesartan
medoxomil doses of 2.5 mg to 40 mg inhibit the pressor effects of angiotensin I
infusion. The duration of the inhibitory effect was related to dose, with doses
of olmesartan medoxomil >40 mg giving >90% inhibition at 24 hours.
Plasma concentrations of angiotensin I and angiotensin II and plasma renin
activity (PRA) increase after single and repeated administration of olmesartan
medoxomil to healthy subjects and hypertensive patients. Repeated administration
of up to 80 mg olmesartan medoxomil had minimal influence on aldosterone levels
and no effect on serum potassium.
Pharmacokinetics
The pharmacokinetics of amlodipine and olmesartan medoxomil from
Azor are equivalent to the pharmacokinetics of amlodipine and olmesartan
medoxomil when administered separately. The bioavailability of both components
is well below 100%, but neither component is affected by food. The effective
half-lives of amlodipine (45±11 hours) and olmesartan (7±1 hours) result in a 2-
to 3- fold accumulation for amlodipine and negligible accumulation for
olmesartan with once-daily dosing.
Amlodipine. After oral
administration of therapeutic doses of amlodipine, absorption produces peak
plasma concentrations between 6 and 12 hours. Absolute bioavailability is
estimated as between 64% and 90%.
Olmesartan medoxomil. Olmesartan
medoxomil is rapidly and completely bioactivated by ester hydrolysis to
olmesartan during absorption from the gastrointestinal tract. The absolute
bioavailability of olmesartan medoxomil is approximately 26%. After oral
administration, the peak plasma concentration (Cmax) of
olmesartan is reached after 1 to 2 hours. Food does not affect the
bioavailability of olmesartan medoxomil.
Distribution
Amlodipine.
Ex
vivo studies have shown that approximately 93% of the circulating 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.
Olmesartan medoxomil. The volume
of distribution of olmesartan is approximately 17 L. Olmesartan is highly bound
to plasma proteins (99%) and does not penetrate red blood cells. The protein
binding is constant at plasma olmesartan concentrations well above the range
achieved with recommended doses.
In rats, olmesartan crossed the blood-brain barrier poorly, if at all.
Olmesartan passed across the placental barrier in rats and was distributed to
the fetus. Olmesartan was distributed to milk at low levels in rats.
Metabolism and Excretion
Amlodipine. Amlodipine is
extensively (about 90%) converted to inactive metabolites via hepatic
metabolism. Elimination from the plasma is biphasic with a terminal elimination
half-life of about 30 to 50 hours. Ten percent of the parent compound and 60% of
the metabolites are excreted in the urine.
Olmesartan medoxomil. Following
the rapid and complete conversion of olmesartan medoxomil to olmesartan during
absorption, there is virtually no further metabolism of olmesartan. Total plasma
clearance of olmesartan is 1.3 L/h, with a renal clearance of 0.6 L/h.
Approximately 35% to 50% of the absorbed dose is recovered in urine while the
remainder is eliminated in feces via the bile.
Olmesartan appears to be eliminated in a biphasic manner with a terminal
elimination half-life of approximately 13 hours. Olmesartan shows linear
pharmacokinetics following single oral doses of up to 320 mg and multiple oral
doses of up to 80 mg. Steady-state levels of olmesartan are achieved within 3 to
5 days and no accumulation in plasma occurs with once-daily dosing.
Geriatric
The pharmacokinetic properties of Azor in the elderly are similar to those of
the individual components.
Amlodipine. Elderly patients have
decreased clearance of amlodipine with a resulting increase in AUC of
approximately 40% to 60%, and a lower initial dose may be required.
Olmesartan medoxomil. The
pharmacokinetics of olmesartan medoxomil were studied in the elderly (> 65
years). Overall, maximum plasma concentrations of olmesartan were similar in
young adults and the elderly. Modest accumulation of olmesartan was observed in
the elderly with repeated dosing; AUCѕѕ, τ was 33% higher in elderly patients, corresponding to an
approximate 30% reduction in CLR.
Pediatric
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.
Olmesartan medoxomil. The
pharmacokinetics of olmesartan medoxomil have not been investigated in patients
<18 years of age.
Gender
Population pharmacokinetic analysis indicated that female patients had
approximately 15% smaller clearances of olmesartan than male patients. Gender
had no effect on the clearance of amlodipine.
Olmesartan medoxomil. Minor
differences were observed in the pharmacokinetics of olmesartan medoxomil in
women compared to men. AUC and Cmax were 10% to 15%
higher in women than in men.
Renal Insufficiency
Amlodipine. The pharmacokinetics
of amlodipine are not significantly influenced by renal impairment. Patients
with renal failure may therefore receive the usual initial dose.
Olmesartan medoxomil. In patients
with renal insufficiency, serum concentrations of olmesartan were elevated
compared to subjects with normal renal function. After repeated dosing, the AUC
was approximately tripled in patients with severe renal impairment (creatinine
clearance <20 mL/min). The pharmacokinetics of olmesartan medoxomil in
patients undergoing hemodialysis has not been studied. No initial dosage
adjustment is recommended for patients with moderate to marked renal impairment
(creatinine clearance <40 mL/min).
Hepatic Insufficiency
Amlodipine. Patients with hepatic
insufficiency have decreased clearance of amlodipine with a resulting increase
in AUC of approximately 40% to 60%.
Olmesartan medoxomil. Increases in
AUC0-∞ and Cmax were observed in
patients with moderate hepatic impairment compared to those in matched controls,
with an increase in AUC of about 60%.
Heart Failure
Amlodipine. Patients with heart
failure have decreased clearance of amlodipine with a resulting increase in AUC
of approximately 40% to 60%.
NONCLINICAL TOXICOLOGY
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Carcinogenesis, Mutagenesis, Impairment of Fertility
Amlodipine. Rats and mice treated
with amlodipine maleate in the diet for up to two years, at concentrations
calculated to provide daily dosage levels of amlodipine 0.5, 1.25, and 2.5
mg/kg/day showed no evidence of a carcinogenic effect of the drug. For the
mouse, the highest dose was, on a mg/m2 basis, similar to
the maximum recommended human dose (MRHD) of amlodipine 10 mg/day. For the rat,
the highest dose was, on a mg/m2 basis, about two and a
half times the MRHD. (Calculations based on a 60 kg patient.)
Mutagenicity studies conducted with amlodipine maleate revealed no drug
related effects at either the gene or chromosome level.
There was no effect on the fertility of rats treated orally with amlodipine
maleate (males for 64 days and females for 14 days prior to mating) at doses of
amlodipine up to 10 mg/kg/day (about 10 times the MRHD of 10 mg/day on a
mg/m2 basis).
Olmesartan medoxomil. Olmesartan
was not carcinogenic when administered by dietary administration to rats for up
to 2 years. The highest dose tested (2000 mg/kg/day) was, on a mg/m2 basis, about 480 times the maximum recommended human dose
(MRHD) of 40 mg/day. Two carcinogenicity studies conducted in mice, a 6-month
gavage study in the p53 knockout mouse and a 6-month dietary administration
study in the Hras2 transgenic mouse, at doses of up to 1000 mg/kg/day (about 120
times the MRHD), revealed no evidence of a carcinogenic effect of olmesartan.
Both olmesartan medoxomil and olmesartan tested negative in the in vitro Syrian hamster embryo cell transformation assay
and showed no evidence of genetic toxicity in the Ames (bacterial mutagenicity)
test. However, both were shown to induce chromosomal aberrations in cultured
cells in vitro (Chinese hamster lung) and tested
positive for thymidine kinase mutations in the in
vitro mouse lymphoma assay. Olmesartan medoxomil tested negative in vivo for mutations in the MutaMouse intestine and kidney
and for clastogenicity in mouse bone marrow (micronucleus test) at oral doses of
up to 2000 mg/kg (olmesartan not tested).
Fertility of rats was unaffected by administration of olmesartan at dose
levels as high as 1000 mg/kg/day (240 times the MRHD) in a study in which dosing
was begun 2 (female) or 9 (male) weeks prior to mating.
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