186

Thai J. Pharm. Sci. 37 (2013) 186-193

Original article

Bioequivalence study of 300 mg irbesartan film-coated tablets

preparations in healthy Thai volunteers
Porranee Puranajoti1,*, Peerawong Werarak2, Burapat Intawong1,
Jarunee Hongrapipat1, Rungrudee Talubsri1, Soravee Sangsuriyawong1
and Temsiri Kuamsuk1
1International Bio Service Co. Ltd., Golden Jubilee Medical Center, Mahidol University,

Nakhon Pathom 73170, Thailand

2Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University,

Bangkok 10600, Thailand

*Corresponding author: Tel: +66 024415211, Fax: +66 024415220,

E-mail address: porranee.pur@mahidol.ac.th

Abstract:
Irbesartan, an angiotensin II receptor antagonist, is indicated for the treatment of essential hypertension
alone or in combination with other antihypertensive agents. The purpose of this study was to compare
the bioavailability of two formulations of irbesartan 300 mg film-coated tablets administered orally in Thai
healthy volunteers. One formulation was a generic product named irbesartan 300 mg film-coated tablet which
was a representative of a test drug in this study. Another was an innovator product of irbesartan 300 mg
tablet commercially available in the market which was a representative of a reference drug. An open-label,
single dose, randomized crossover study was designed and conducted in 26 healthy Thai volunteers.
Each subject received both formulations of irbesartan 300 mg tablet with respect to either reference drug or
test drug in each period. Blood samples were collected prior to dosing and at various blood collection time
points after dosing up to 72 hours and irbesartan concentrations in plasma samples were determined using a
validated High Performance Liquid Chromatography (HPLC) method with fluorescence. The pharmacokinetic
parameters including Cmax, AUC0-t, and AUC0-inf were statistically compared in order to evaluate the bioequivalence
of the two formulations. Drug safety and tolerability were assessed. Twenty-six volunteers completed both
treatment periods. It was found that 90% confidence intervals for the log-transformed test/reference ratios
of irbesartan were 103.71% (90% CI, 94.86-113.39%) for Cmax, 92.91% (90% CI, 86.27-100.08%) for
AUC0-tlast, and 92.81% (90% CI, 86.11-100.03%) for AUC0-inf. The results of statistical analysis showed
that two formulations were bioequivalent in terms of both rate and extent of absorption according to the
guideline of the Food and Drug Administration of Thailand.
Keywords: Irbesartan; Bioequivalence; Pharmacokinetic; HPLC

P. Puranajoti et al.

187

Introduction

Material and Methods

Irbesartan, 2-butyl-3-[[29-(1H-tetrazole-5-yl)[1,19biphenyl]-4-yl]methyl]-1,3-diazaspiro-[4,4]non-1-en-4-one
(Figure 1), is an angiotensin II (AII) receptor antagonist
indicated for the treatment of essential hypertension
alone or in combination with other antihypertensive
agents. Clinical trials conducted in hypertensive patients
have demonstrated that irbesartan is well tolerated and
effective in reducing blood pressure in a dose-dependent
manner [1-5].
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 60-80% with no food
effect. Following oral administration, peak plasma
concentrations of irbesartan are attained at 1.5-2 hours
after dosing. Irbesartan is 90% bound to serum proteins
with negligible binding to cellular components of blood.
Irbesartan has the longest half-life of all AII receptor
antagonists (11-15 h) [6-9]. Irbesartan is primarily
metabolized by the cytochrome P450, 2C9 isoenzyme.
Its metabolites do not have pharmacological activity [10].
Irbesartan and its metabolites are excreted by both biliary
and renal routes. Total plasma and renal clearances are
approximately 157 mL/min and 3.0 mL/min, respectively [11].
Although the pharmacokinetic (PK) characteristics
of Irbesartan have been studied previously, the studies
were not performed in a Thai population. The purpose
of this study is to compare the bioavailability of two
formulations of irbesartan 300 mg film-coated tablets
administered orally in Thai healthy volunteers. The
bioequivalence study was already approved by the Food
and Drug Administration of Thailand.

Test and reference drugs

Irbesartan 300 mg film-coated tablets of batch
number IRB 019 with expiration date of 05/2012 were
used as the test formulation and Innovator irbesartan
300 mg tablets of batch number 2891 with expiration
date of 02/2013 were used as the reference formulation.

Participants and study design

The present study was designed as an open-label,
single dose, randomized, two-way crossover study with
a 7-day washout period between periods 1 and 2. Both
formulations of irbesartan 300 mg tablets were
administered orally to each subject with one formulation
in period 1 and another in period 2 depending on the
randomization code of administration of each period.
The study protocol, informed consent form, and consent
methods were approved by the ethics committee of the
Institute for Development of Human Research Protection
(IHRP), Thailand. All clinical work has been carried out
in compliance with GCP [12] and guidelines according
to the ethical standards for studies in humans of the
Declaration of Helsinki [13]. The clinical part of the study
was conducted at the Clinical Research Department,
International Bio Service Co., Ltd., Nakhonpathom,
Thailand.
During the study, twenty-six healthy Thai volunteers
were confined for both periods 1 and 2. The participants
in this study had the age range of 18-55 years (27.08
5.04 years) with BMI range of 18-25 kg/m2 (the mean
body weight of 59.69 8.60 kg and the mean height of
1.64 0.09 meters). All participants in the study had to
be in compliance with the inclusion / exclusion criteria

N
N

(CH2)3CH3

N
N

N N H

Figure 1 The chemical structure of irbesartan

188
defined in the study protocol and were considered eligible
based on the screening process including completion
of the informed consent form with each volunteers
signature, demographic data, medical histories, physical
examination, concomitant medication checking, vital
signs and blood pressure measurements, clinical
laboratory tests with respect to haematology and
blood biochemistry. The consumption of alcohol was
not permitted at least 14 days prior to the study until
the last blood sample collection in each period.
In addition, the consumption of grapefruit juice or
grapefruit-related citrus fruits (e.g. seville orange, pomelo)
was not allowed at least 7 days prior to the study until
the last blood sample collection in each period. Subjects
were also instructed to abstain from taking any medication
for at least 1 week prior to and during the study period.
All participants were informed consent prior to the study.
For each period, subjects were confined to the Clinical
Research Department from at least 10 hours prior to
drug administration and were fasted overnight. After
drug administration with drinking water of 240 mL, water
intake was allowed from 1 hour after dosing onward.
Consequently, a controlled meal was served at 4 hours
post-dosing and standard meals were given to all
volunteers according to the time schedule. Data obtained
from subjects who completed the study for both periods
were used for pharmacokinetic and statistical analysis.
Inclusion and exclusion criteria
The study recruited male or female aged between
18-55 years with body mass index (BMI) range of 18-25
kg/m2. The volunteers were determined to be healthy
by assessment of physical examination, drug abuse,
medical history, and vital signs. The screening tests
composed of complete blood count (CBC), fasting
blood sugar (FBS), aspartate aminotransferase (AST),
alanine aminotransferase (ALT), alkaline phosphatase
(ALP), total bilirubin, blood urea nitrogen (BUN), serum
creatinine (Cr), HBsAg test and EKG. The female must
be non-pregnant woman (negative pregnancy test) or
using appropriate contraceptive method or must not
currently breast feeding. In addition, the subjects must
be willingly to participate and sign the informed consent

Thai J. Pharm. Sci. 37 (2013) 186-193

form.
Exclusion criteria included history of allergic reaction
to irbesartan and/or related molecular structure materials
and/or any of the components of the product as well as
history of concurrent symptoms of allergy, cardiovascular,
liver, kidney, gastro-intestinal, hematological disorders
and/or any diseases that may affect the bioavailability
of drug. The exclusion criteria also meant regularly alcohol
consumption (more than 1 times/week), drug addict,
ex-smoker less than 30 days prior to study. They also
excluded ones who used any medications within 14
days, used food supplements, vitamins, mineral, herbal
remedies and/or contraceptives hormonal within 14 days
prior to drug administration. The subjects who participated
in other clinical studies within the last 30 days were
excluded. In addition, pregnant women (positive
pregnancy test) or women in breast feeding period, as
well as ones with history of hypotension were also
excluded.
Drug administration and sample collection
After an overnight fasting of phase I, volunteers
were given a single dose of either test or reference
formulation in accordance with a web-base randomization
scheme with 240 mL of water and a mouth check was
performed to ensure consumption of the drug. The
volunteers were continuously monitored by the Clinical
Research Department staffs throughout the confinement
period of the study. Approximately 6 mL of blood sample
for irbesartan assay was drawn into heparinized tube
through an indwelling cannula before (0 hour baseline)
and at 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12, 24, 48 and
72 hours after dosing. Blood samples were centrifuged
at 3,000 rpm at 4C for 10 min. The plasma was separated
and kept frozen at -70 5C until assayed. After a
washout period of 7 days the study was repeated in the
same manner to complete the cross-over design.
Safety evaluation
Adverse events (AEs) were monitored and recorded
in case report forms (CRF) based on volunteer interview
and physical examination. The safety of patients, adverse
events and concomitant drug assessment were performed

P. Puranajoti et al.
throughout the study. Vital signs were measured
at screening and during the entire study period.
No abnormalities were observed in terms of blood
pressure, heart rate, respiratory rate and body
temperature.
All of the 26 healthy adult volunteers enrolled in
the study completed the study. No death or serious
adverse events occurred during the conduct of the study.
Both test and reference formulations were generally well
tolerated by the study volunteers. A total of 4 post-dose
adverse events were reported by 3 out of 26 volunteers.
The adverse events were reported in 2 (7.7%) out of 26
subjects receiving the test formulation compared with 1
(3.85%) out of 26 subjects receiving the reference
formulation. The most frequent adverse events reported
were nausea and vomiting, dizziness and hypotension.
All of the adverse events were assessed to be mild in
intensity and most of them were possibly related to the
study drugs.
Chromatographic condition
The analytical method of irbesartan in human
plasma was applied from previous study with some
modification by the analytical investigator [14].
The analysis of irbesartan was successful by using
validated HPLC with fluorescence measurement at
259 nm (excitation) and 385 nm (emission).
Chromatograms were obtained on a Zorbax Eclipse
XDB C18 column (1.6 150 mm, 5 micron) with the
column temperature of 25 C. The mobile phase
composed of 62% of acetic acid (0.2% v/v) containing
0.06% triethylamine (v/v) and 38% of acetronitrile
delivered at the flow rate 1 mL/min with isocratic
elution system. The injection volume was 10 microliters
with the total run time was 12 minutes. Retention
time of Irbesartan and internal standard were
shown at 8.9-9.9 minutes and at 4.4-5.4 minutes,
respectively.
Plasma sample preparation
Extraction of irbesartan and losartan (internal
standard, I.S.) from human plasma was performed by
employing optimized protein precipitation using

189
acetonitrile plus saturated NaCl [14, 15]. Briefly, 180
microliters of human blank plasma were added into a
microcentrifuge tube containing either 20 microliters
of irbesartan calibration standards at concentration of
20-8,000 ng/mL or QC samples at 60 ng/mL (LQC),
4,000 ng/mL (MQC) and 6,000 ng/mL (HQC) and
100 L internal standard (150,000 ng/mL losartan).
The plasma protein was precipitated with 500 microliters
of acetonitrile plus 200 microliters of saturated NaCl
and then vortex-mixed for 30 seconds. After centrifugation
at 13,000 rpm for 12 minutes, 200 microliters of upper
phase were transferred to insert-HPLC vial. The 10
microliters of the resulting solution was injected into the
HPLC system.
Calculation of pharmacokinetic parameter and
statistical analysis
Irbesartan bioequivalence between the two
treatments were compared with respect to AUC0-,
AUC0-tlast, Cmax, Tmax, t1/2 and z. The definition of
each is shown below:
1. AUC 0-tlast is the areas under the plasma
concentration-time curves (AUC) from 0 to the last
quantifiable concentration. The AUC0-tlast is calculated
by taking the average of two subsequent plasma
concentrations (Ci and Ci-1) and multiplying that
average by the time difference between the
consecutive measuring points (ti and ti-1). All these
outcomes are then summed to render the AUC
from 0 to the last quantifiable concentration. This
approach is called the linear-log trapezoidal approach.
The formulation is;
t
Ci + Ci -1
(ti - ti-1)
AUC0-tlast =
l
n(C
/
C
)
i
i
-1
i=1

(1)

2. z is the terminal rate constant or the slope of the

regression line. To obtain z the log (ln) transformation
is applied to make it possible to draw a straight line
through the elimination phase.
3. AUC0- is an extrapolation of AUC0-tlast to extend
the plasma concentration-time profile to infinity.
This parameter is an estimate of the total mass of

190

Thai J. Pharm. Sci. 37 (2013) 186-193

drug present in the blood. To obtain AUC0-, z is of

the most logical parameter. The formulation is;
C
AUC 0-inf = AUC 0-tlast + last
z

(2)

Results

4. Cmax is the maximum observed plasma concentration

that is presented on the curves.
5. T max is the time taken to achieve maximum
concentration that can be detected directly from the
curves.
6. t1/2 is the plasma concentration half-life. The t1/2
can be calculated by simply divided 0.693 by the z.
The term 0.693 is derived from ln(2) = 0.693. The
formulation is;
t 1/2 = 0.693

Reference (T/R) for AUC and Cmax were calculated based

on least squares means from the ANOVA of logtransformed data.

(3)

For the purpose of bioequivalence analysis,

AUC0-tlast, AUC0- and Cmax were considered as the
primary variables. The difference between two related
parameters was considered statistically significant for
p-value equal to or less than 0.05. The 90% confidence
intervals (CI) for the ratios of geometric mean of Test to

Irbesartan in human plasma was successfully

determined by a validated HPLC using the standard
calibration curve in the range of 20-8,000 ng/mL. The
mean plasma concentration-time profile over the whole
72-hour pharmacokinetic study is illustrated in Figure 2.
The pharmacokinetic parameters were calculated by
noncompartmental methods using WinNonlin software
version 6.1.0.173 (Pharsight, North Carolina, USA) as
shown in Table 1. The pharmacokinetic parameters
are subjected to a comparative statistical evaluation
by determining the position of the 90% confidence
intervals for the individual ratios test/reference by least
square means of ANOVA of logarithmically transformed
data for Cmax, AUC0-tlast, and AUC0-, to obtain the
residual error. The statistical evaluation of primary
pharmacokinetic parameters for irbesartan after
administration of test and reference formulations is
presented in Table 2.

Table 1 Pharmacokinetic parameters of irbesartan following administration of test and reference formulations from 26 healthy Thai
volunteers
Parameters

Test (Mean SD)

Cmax (ng/mL)
AUC0-tlast (ng.h/mL)
AUC0-inf (ng.h/mL)
Tmax (h)
t1/2 (h) (median)
Kel (h-1)

3324.93 1288.19
14047.88 6473.19
14993.47 6562.97
1.77 0.91
8.38 4.39 (2.00)
0.1015 0.0426

Reference
(Mean SD)
3300.21 1659.86
15264.56 7482.53
16290.89 7587.70
1.40 0.97
7.60 3.60 (1.00)
0.1125 0.0510

Table 2 Statistical evaluation of primary pharmacokinetic parameters for irbesartan following administration of test and reference
formulations from 26 healthy Thai volunteers
Parametric analysis
Cmax (ng/mL)
AUC0-tlast (ng.h/mL)
AUC0-inf (ng.h/mL)

LSM ratio (%)

90% CIs

Power (%)

Intra-subject CV (%)

103.71
92.91
92.81

94.86-113.39
86.27-100.08
86.11-100.03

99.16
99.89
99.88

18.96
15.74
15.88

P. Puranajoti et al.

191

Reference -..-..-..-..-..-Test
5000

Concentration (ng/mL)

4000
3000
2000
1000
0
0

12

24

36

48

60

72

time (hr)

Reference -..-..-..-..-..-Test

Concentration (ng/mL)

100000

10000

1000

100

1
0

12

24

36

48

60

72

time (hr)

Figure 2 Mean plasma concentration-time profiles of irbesartan (n=26); linear plot (top) and semi-logarithmic plot (bottom)

The analytical method of Irbesartan with the use

of losartan as an internal standard was successfully
developed and validated according to the acceptance
criteria of the guideline on bioanalytical method
validation issued by EMEA. In this method, the plasma
concentrations of irbesartan were determined by using
a validated High Performance Liquid Chromatography
(HPLC) method with fluorescence measurement at
259 nm (excitation) and 385 nm (emission) with an
accuracy range of 85-115% and a precision range of
not more than 15% of coefficient of variation (CV).
This method was found to be selective for irbesartan

analysis with no interfering peaks in blank plasma

samples with the limit of quantification of 20 ng/mL of
irbesartan. The calibration curve obtained from irbesartan
standard concentration range of 20-8,000 ng/mL was
constructed using 1/concentration as a weighting factor
for regression analysis. The stock solution stability was
evaluated to ensure the stability of the standard stock
solution used and it was found to be 6 hours at room
temperature and 88 days at -20C with %variations
of -2.41% and 0.94% at room temperature and -0.65%
and -0.67% at -20C for irbesartan and losartan,
respectively. In addition, the dilution process was occurred

192
during the analysis of plasma samples; therefore, the
dilution integrity was performed to ensure the integrity
of the dilution and the results obtained were found to
be 101.16% and 97.71% for two-fold and four-fold
dilution, respectively. The average %recovery of irbesartan
and losartan were found to be 96.47% and 94.20%,
respectively. The plasma samples were well-tolerated
to 3 cycles of freeze-thaw with the changes of -0.76%
and 0.41% for low and high concentration, respectively.
The short-term stability of plasma samples was found
to be 8 hours at room temperature with %change
of -4.07% and 7.67% for low and high concentration,
respectively. The long-term stability was found to be 88
days with %changes of - 8.37% and -11.49% for low
and high concentration, respectively. During the analysis,
samples were stayed in autosampler for some period of
time; hence, the autosampler stability was also performed
and the results indicated that these samples were stable
for 59 hours in autosampler at room temperature with
%changes of -3.05% and 0.51% for low and high
concentration, respectively.
The statistical analysis obtained from this study
showed that the points estimated with 90% confidence
intervals of the geometric mean ratios of test and
reference (T/R) of Cmax, AUC0-tlast and AUC0- were
entirely within the equivalence criteria of 80.00-125.00%.
As can be seen in Table 1, Cmax for the test and reference
formulations were 3,324.93 and 3,300.21 ng/mL with
standard deviations of 1,288.19 and 1,659.86 ng/mL,
respectively. The means of AUC0-tlast for the test
and reference formulations were 14,047.88 and 15,264.56
ngh/mL with standard deviations of 6,473.19 and
7,482.53 ngh/mL, respectively while those of AUC0-inf
for the test and reference formulations were 14,993.47
and 16,290.89 ngh/mL with standard deviations of
6,562.97 and 7,587.70 ng.h/mL, respectively. The point
estimate with 90% confidence intervals of the geometric
mean ratios of test and reference (T/R) in the study
were found to be 103.71% (94.86%-113.39%) for Cmax
with the power of 99.16%, 92.91% (86.27%-100.08%)
for AUC0-tlast with the power of 99.89% and 92.81%
(86.11%-100.03%) for AUC0-inf with the power of 99.88%.
From plasma samples obtained from 26 subjects,

Thai J. Pharm. Sci. 37 (2013) 186-193

irbesartan showed average maximum concentration
(Tmax) at 1.77 0.91 and 1.40 0.97 hours for test and
reference drug, respectively. The median drug plasma
concentration half-life (t1/0) of the test drug was found
to be 8.38 4.39 hours with average terminal rate constant
of 0.1015 0.0426 hour-1 while that of the reference
drug was 7.60 3.60 hours with average terminal rate
constant of 0.1125 0.0510 hour-1.

Discussion
Two drug products are considered to be bioequivalent
if they exhibit a comparable rate and extent of absorption
when administered in the same molar dose and under
similar experimental conditions. Bioequivalent formulations
are usually considered to be therapeutically equivalent.
AUC is accepted as a good indicator of the extent of
absorption, whereas Cmax and Tmax are considered
estimators of the rate of absorption. US FDA generally
accepts that the AUC and Cmax of a test formulation
should lie within 20% deviation of the reference
formulation, so that the ratio of AUC and Cmax should
be between 0.8000 and 1.2500 for logarithm-transformed
data.
The single dose irbesartan Cmax in the present
study was consistent with the previous published data
[7, 16]. For all volunteers, the average AUC0-tlast was a
good representatives of the extent of absorption since
the average %AUC0-72 obtained were found to be greater
than 80% of the average %AUC0-inf for both test and
reference formulations. The Cmax was not observed in
the first sampling time, therefore, the Cmax is considered
to be estimated correctly due to the adequate frequency
of the sampling around Tmax. The 90% confidence interval
of the logarithmic transformed of Cmax, AUC0-tlast and
AUC0- were within 80.00-125.00% with the power of
more than 80% indicating that the study was designed
with sufficient population to acquire the reliable data.
Based on the pharmacokinetic parameters of irbesartan,
the test and reference formulations are considered
bioequivalent with respect to the extent and rate of
absorption. In addition, the Tmax and t1/2 values obtained
from this study were well in line with those previously
published [11-18].

P. Puranajoti et al.

193

Conclusion
The statistical analysis obtained from the study
showed that the points estimated with 90% confidence
intervals of the geometric mean ratios of test and
reference (T/R) of Cmax, AUC0-tlast and AUC0-inf were
entirely within the equivalence criteria (80.00-125.00%).
The study was designed properly to have sufficient blood
collection time point to obtain AUC0-tlast more than 80%
of AUCinf with enough number of subjects to acquire
the power of more than 80% for critical pharmacokinetic
parameters such as Cmax, AUC0-tlast. and AUC0-inf
In summary, it can be concluded that these two irbesartan
tablet formulations established bioequivalence in terms
of rate and extent of absorption.

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