CLINICAL PHARMACOLOGY
Mechanism of Action
Irbesartan
Angiotensin
II is a potent vasoconstrictor formed from angiotensin I in a reaction catalyzed
by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the
principal pressor agent of the RAS and also stimulates aldosterone synthesis
and secretion by adrenal cortex, cardiac contraction, renal resorption of
sodium, activity of the sympathetic nervous system, and smooth muscle cell
growth. Irbesartan blocks the vasoconstrictor and aldosterone-secreting effects
of angiotensin II by selectively binding to the AT1 angiotensin
II receptor. There is also an AT2 receptor in many
tissues, but it is not involved in cardiovascular homeostasis.
Irbesartan
is a specific competitive antagonist of AT1 receptors
with a much greater affinity (more than 8500-fold) for the AT1 receptor
than for the AT2 receptor, and no agonist activity.
Blockade
of the AT1 receptor removes the negative feedback of
angiotensin II on renin secretion, but the resulting increased plasma renin
activity and circulating angiotensin II do not overcome the effects of irbesartan
on blood pressure.
Irbesartan does not inhibit ACE
or renin or affect other hormone receptors or ion channels known to be involved
in the cardiovascular regulation of blood pressure and sodium homeostasis.
Because irbesartan does not inhibit ACE, it does not affect the response to
bradykinin; whether this has clinical relevance is not known.
Hydrochlorothiazide
Hydrochlorothiazide
is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte
reabsorption, directly increasing excretion of sodium and chloride in approximately
equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide
reduces plasma volume, with consequent increases in plasma renin activity,
increases in aldosterone secretion, increases in urinary potassium loss, and
decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin
II, so coadministration of an angiotensin II receptor antagonist tends to
reverse the potassium loss associated with these diuretics.
The
mechanism of the antihypertensive effect of thiazides is not fully understood.
Pharmacodynamics
Irbesartan
In
healthy subjects, single oral irbesartan doses of up to 300 mg produced dose-dependent
inhibition of the pressor effect of angiotensin II infusions. Inhibition was
complete (100%) 4 hours following oral doses of 150 mg or 300 mg and partial
inhibition was sustained for 24 hours (60% and 40% at 300 mg and 150 mg, respectively).
In
hypertensive patients, angiotensin II receptor inhibition following chronic
administration of irbesartan causes a 1.5- to 2-fold rise in angiotensin II
plasma concentration and a 2- to 3-fold increase in plasma renin levels. Aldosterone
plasma concentrations generally decline following irbesartan administration,
but serum potassium levels are not significantly affected at recommended doses.
In
hypertensive patients, chronic oral doses of irbesartan (up to 300 mg) had
no effect on glomerular filtration rate, renal plasma flow or filtration fraction.
In multiple dose studies in hypertensive patients, there were no clinically
important effects on fasting triglycerides, total cholesterol, HDL-cholesterol,
or fasting glucose concentrations. There was no effect on serum uric acid
during chronic oral administration and no uricosuric effect.
Hydrochlorothiazide
After
oral administration of hydrochlorothiazide, diuresis begins within 2 hours,
peaks in about 4 hours and lasts about 6 to 12 hours.
Pharmacokinetics
Irbesartan
Irbesartan
is an orally active agent that does not require biotransformation into an
active form. The oral absorption of irbesartan is rapid and complete with
an average absolute bioavailability of 60% to 80%. Following oral administration
of irbesartan, peak plasma concentrations of irbesartan are attained at 1.5
to 2 hours after dosing. Food does not affect the bioavailability of irbesartan.
Irbesartan
exhibits linear pharmacokinetics over the therapeutic dose range.
The
terminal elimination half-life of irbesartan averaged 11 to 15 hours. Steady-state
concentrations are achieved within 3 days. Limited accumulation of irbesartan
(<20%) is observed in plasma upon repeated once-daily dosing.
Hydrochlorothiazide
When
plasma levels have been followed for at least 24 hours, the plasma half-life
has been observed to vary between 5.6 and 14.8 hours.
Metabolism and Elimination
Irbesartan
Irbesartan
is metabolized via glucuronide conjugation and oxidation. Following oral or
intravenous administration of 14C-labeled irbesartan,
more than 80% of the circulating plasma radioactivity is attributable to unchanged
irbesartan. The primary circulating metabolite is the inactive irbesartan
glucuronide conjugate (approximately 6%). The remaining oxidative metabolites
do not add appreciably to irbesartan’s pharmacologic activity.
Irbesartan
and its metabolites are excreted by both biliary and renal routes. Following
either oral or intravenous administration of 14C-labeled
irbesartan, about 20% of radioactivity is recovered in the urine and the remainder
in the feces, as irbesartan or irbesartan glucuronide.
In
vitro studies of irbesartan oxidation by cytochrome P450 isoenzymes
indicated irbesartan was oxidized primarily by 2C9; metabolism by 3A4 was
negligible. Irbesartan was neither metabolized by, nor did it substantially
induce or inhibit, isoenzymes commonly associated with drug metabolism (1A1,
1A2, 2A6, 2B6, 2D6, 2E1). There was no induction or inhibition of 3A4.
Hydrochlorothiazide
Hydrochlorothiazide
is not metabolized but is eliminated rapidly by the kidney. At least 61% of
the oral dose is eliminated unchanged within 24 hours.
Distribution
Irbesartan
Irbesartan
is 90% bound to serum proteins (primarily albumin and α1-acid
glycoprotein) with negligible binding to cellular components of blood. The
average volume of distribution is 53 to 93 liters. Total plasma and renal
clearances are in the range of 157 to 176 mL/min and 3.0 to 3.5 mL/min, respectively.
With repetitive dosing, irbesartan accumulates to no clinically relevant extent.
Studies
in animals indicate that radiolabeled irbesartan weakly crosses the blood-brain
barrier and placenta. Irbesartan is excreted in the milk of lactating rats.
Hydrochlorothiazide
Hydrochlorothiazide
crosses the placental but not the blood-brain barrier and is excreted in breast
milk.
Pediatric
Irbesartan-hydrochlorothiazide pharmacokinetics
have not been investigated in patients <18 years of age.
Gender
No gender-related differences in pharmacokinetics
were observed in healthy elderly (age 65 to 80 years) or in healthy young
(age 18 to 40 years) subjects. In studies of hypertensive patients, there
was no gender difference in half-life or accumulation, but somewhat higher
plasma concentrations of irbesartan were observed in females (11% to 44%).
No gender-related dosage adjustment is necessary.
Geriatric
In elderly subjects (age 65 to 80 years),
irbesartan elimination half-life was not significantly altered, but AUC and
Cmax values were about 20% to 50% greater than those
of young subjects (age 18 to 40 years). No dosage adjustment is necessary
in the elderly.
Race
In healthy black subjects, irbesartan
AUC values were approximately 25% greater than whites; there were no differences
in Cmax values.
Renal Insufficiency
The pharmacokinetics of irbesartan were
not altered in patients with renal impairment or in patients on hemodialysis.
Irbesartan is not removed by hemodialysis. No dosage adjustment is necessary
in patients with mild to severe renal impairment unless a patient with renal
impairment is also volume depleted. [See
Warnings and Precautions
.]
Hepatic Insufficiency
The pharmacokinetics of irbesartan following
repeated oral administration were not significantly affected in patients with
mild to moderate cirrhosis of the liver. No dosage adjustment is necessary
in patients with hepatic insufficiency.
Drug-Drug Interactions
No significant drug-drug pharmacokinetic
(or pharmacodynamic) interactions have been found in interaction studies with
hydrochlorothiazide, digoxin, warfarin, and nifedipine.
In
vitro studies show significant inhibition of the formation of oxidized
irbesartan metabolites with the known cytochrome CYP 2C9 substrates/inhibitors
sulphenazole, tolbutamide, and nifedipine. However, in clinical studies the
consequences of concomitant irbesartan on the pharmacodynamics of warfarin
were negligible. Concomitant nifedipine or hydrochlorothiazide had no effect
on irbesartan pharmacokinetics. Based on in vitro data, no
interaction would be expected with drugs whose metabolism is dependent upon
cytochrome P450 isoenzymes 1A1, 1A2, 2A6, 2B6, 2D6, 2E1, or 3A4.
In
separate studies of patients receiving maintenance doses of warfarin, hydrochlorothiazide,
or digoxin, irbesartan administration for 7 days had no effect on the pharmacodynamics
of warfarin (prothrombin time) or the pharmacokinetics of digoxin. The pharmacokinetics
of irbesartan were not affected by coadministration of nifedipine or hydrochlorothiazide.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Irbesartan-Hydrochlorothiazide
No
carcinogenicity studies have been conducted with the irbesartan-hydrochlorothiazide
combination.
Irbesartan-hydrochlorothiazide was not
mutagenic in standard in vitro tests (Ames microbial test
and Chinese hamster mammalian-cell forward gene-mutation assay). Irbesartan-hydrochlorothiazide
was negative in tests for induction of chromosomal aberrations (in
vitro—human lymphocyte assay; in vivo—mouse micronucleus
study).
The combination of irbesartan and hydrochlorothiazide
has not been evaluated in definitive studies of fertility.
Irbesartan
No
evidence of carcinogenicity was observed when irbesartan was administered
at doses of up to 500/1000 mg/kg/day (males/females, respectively) in rats
and 1000 mg/kg/day in mice for up to 2 years. For male and female rats, 500
mg/kg/day provided an average systemic exposure to irbesartan (AUC0-24
hours, bound plus unbound) about 3 and 11 times, respectively,
the average systemic exposure in humans receiving the maximum recommended
dose (MRD) of 300 mg irbesartan/day, whereas 1000 mg/kg/day (administered
to females only) provided an average systemic exposure about 21 times that
reported for humans at the MRD. For male and female mice, 1000 mg/kg/day provided
an exposure to irbesartan about 3 and 5 times, respectively, the human exposure
at 300 mg/day.
Irbesartan was not mutagenic in a battery
of in vitro tests (Ames microbial test, rat hepatocyte DNA
repair test, V79 mammalian-cell forward gene-mutation assay). Irbesartan was
negative in several tests for induction of chromosomal aberrations (in
vitro—human lymphocyte assay; in vivo—mouse micronucleus
study).
Irbesartan had no adverse effects on fertility
or mating of male or female rats at oral doses ≤650 mg/kg/day,
the highest dose providing a systemic exposure to irbesartan (AUC0-24
hours, bound plus unbound) about 5 times that found in humans
receiving the MRD of 300 mg/day.
Hydrochlorothiazide
Two-year
feeding studies in mice and rats conducted under the auspices of the National
Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential
of hydrochlorothiazide in female mice (at doses of up to approximately 600
mg/kg/day) or in male and female rats (at doses of up to approximately 100
mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity
in male mice.
Hydrochlorothiazide was not genotoxic in
vitro in the Ames mutagenicity assay of Salmonella typhimurium strains
TA 98, TA 100, TA 1535, TA 1537, and TA 1538 and in the Chinese Hamster Ovary
(CHO) test for chromosomal aberrations, or in vivo in assays
using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes,
and the Drosophila sex-linked recessive lethal trait gene.
Positive test results were obtained only in the in vitro CHO
Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell
(mutagenicity) assays, using concentrations of hydrochlorothiazide from 43
to 1300 μg/mL, and in the Aspergillus nidulans non-disjunction
assay at an unspecified concentration.
Hydrochlorothiazide
had no adverse effects on the fertility of mice and rats of either sex in
studies wherein these species were exposed, via their diet, to doses of up
to 100 and 4 mg/kg, respectively, prior to mating and throughout gestation.
Animal Toxicology and/or Pharmacology
Reproductive Toxicology Studies
When pregnant rats were treated with
irbesartan from Day 0 to Day 20 of gestation (oral doses of 50, 180, and 650 mg/kg/day),
increased incidences of renal pelvic cavitation, hydroureter, and/or absence
of renal papilla were observed in fetuses at doses ≥50 mg/kg/day (approximately
equivalent to the MRHD, 300 mg/day, on a body surface area basis). Subcutaneous
edema was observed in fetuses at doses ≥180 mg/kg/day (about 4 times the MRHD
on a body surface area basis). As these anomalies were not observed in rats
in which irbesartan exposure (oral doses of 50, 150, and 450 mg/kg/day) was
limited to gestation days 6 to 15, they appear to reflect late gestational
effects of the drug. In pregnant rabbits, oral doses of 30 mg irbesartan/kg/day
were associated with maternal mortality and abortion. Surviving females receiving
this dose (about 1.5 times the MRHD on a body surface area basis) had a slight
increase in early resorptions and a corresponding decrease in live fetuses.
Irbesartan was found to cross the placental barrier in rats and rabbits.
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