Clin Drug Investig
DOI 10.1007/s40261-016-0406-y
ORIGINAL RESEARCH ARTICLE
Evaluation of a Pharmacokinetic Interaction between Telmisartan
and Chlorthalidone in Healthy Male Adult Subjects
Sook Jin Seong1 • Mi-sun Lim2 • Joomi Lee1 • Boram Ohk1 • Mi-Ri Gwon1
Bo Kyung Kim1 • Hyun-Ju Kim1 • Dong Heon Yang3 • Hae Won Lee1 •
Woo Youl Kang1 • Young-Ran Yoon1
Ó Springer International Publishing Switzerland 2016
Abstract
Background and Objective Combination therapy is rec-
ommended for the effective management of hypertension
according to most treatment guidelines, including those of
the US Joint National Committee. Therefore, pharma-
cokinetic drug interactions are an important issue in com-
bination therapy for hypertension. In this study, the
pharmacokinetic properties of telmisartan and chlorthali-
done were evaluated to investigate their pharmacokinetic
interactions in healthy subjects.
Methods Two separate, randomized, multiple-dose, two-
period, one-sequence studies were conducted. In study A,
43 participants received 80 mg of telmisartan orally for
7 days, and were then administered oral chlorthalidone
25 mg for 14 days (days 8–21), coadministered with 80 mg
of telmisartan from day 15. In study B, 14 participants
received oral chlorthalidone (25 mg) for 13 days, followed
S. J. Seong and M. Lim equally contributed to this work.
& Young-Ran Yoon
yry@knu.ac.kr
1
Department of Biomedical Science, BK21 Plus KNU Bio-
Medical Convergence Program for Creative Talent, Cell and
Matrix Research Institute and Clinical Trial Center,
Kyungpook National University Graduate School and
Hospital, Daegu, Republic of Korea
2 healthy volunteers are presented.
College of Pharmacy, Yeungnam University, Kyungsan,
Kyungpook, Republic of Korea
3
Division of Cardiology, Department of Internal Medicine,
Kyungpook National University School of Medicine, Daegu,
Republic of Korea
•
by coadministration with 80 mg of telmisartan orally for
7 days.
Results The geometric mean ratios (GMRs) (90 % confi-
dence intervals [CIs]) of the maximum plasma concentra-
tion (Cmax,ss) and area under the concentration-time curve
for the dosing interval at steady state (AUCs,ss) of telmis-
artan (with and without chlorthalidone) were 1.018
(0.861–1.203) and 1.099 (1.015–1.190), respectively. For
chlorthalidone (with/without telmisartan), the GMRs
(90 % CIs) for Cmax,ss and AUCs,ss were 0.996
(0.922–1.075) and 0.992 (0.925–1.064), respectively. The
GMRs and 90 % CIs for telmisartan and chlorthalidone
were all within the 0.80–1.25 range.
Conclusion Thus, in this study, there was no significant
pharmacokinetic interaction between telmisartan and
chlorthalidone.
ClinicalTrial.gov identifier NCT01806363.
Key Points
No pharmacokinetic drug interaction was identified
between 80 mg telmisartan and 25 mg
chlorthalidone.
Although chlorthalidone was approved as an
antihypertensive agent more than 50 years ago,
information on the pharmacokinetics of
chlorthalidone in humans is limited. In this study, the
pharmacokinetic characteristics of chlorthalidone in
Safety and tolerability of telmisartan and
chlorthalidone were similar and acceptable, whether
administered alone or in combination.

1 Introduction
Telmisartan, an angiotensin II receptor antagonist, inhibits
angiotensin II-induced vasoconstriction and aldosterone-
releasing activity by selective binding to the AT1 receptor
in a variety of tissues, including the heart, kidneys, adrenal
gland, and arteriolar smooth muscle [1–8].
The bioavailability of telmisartan has been reported to
be 40–60 % [5, 9], and dose dependent [3]. The maxi-
mum plasma concentration for telmisartan is achieved
0.5–2 h after oral administration [9, 10]. Telmisartan is
metabolized to a pharmacologically inactive acyl glu-
curonide by conjugation [3, 7]. It has been established
that telmisartan metabolism is not cytochrome P450
(CYP) dependent [3, 9, 10]. In contrast, other angiotensin
receptor blockers (ARBs), including losartan, irbesartan,
valsartan, and candesartan cilexetil, are CYP enzyme
substrates [10]. Thus, telmisartan has a low probability of
interrupting the metabolism of substances that are
metabolized by CYP enzymes [3, 9]. The long-duration
blood-pressure-lowering effects of the drug compared
with other ARBs may be owing to its long elimination
half-life (24 h) and high AT1 receptor affinity [11]. Bil-
iary excretion is the major elimination pathway of
telmisartan and its metabolite [3, 7, 9].
Favorable properties of telmisartan, such as a long
elimination half-life (24 h) and low potential for drug
interactions by CYP enzymes, provide clinical benefits,
including considerable and long-lasting (*24 h) antihy-
pertensive effects, which protect against cardiovascular
disease [11]. For these reasons, telmisartan has been rec-
ommended as a treatment of choice and as the primary
ARB for combination regimens [11].
Recently, the published outcomes of large trials, such as
the Antihypertensive and Lipid-Lowering Treatment to
Prevent Heart Attack Trial, Multiple Risk Factor Inter-
vention Trial, Hypertension Detection and Follow-up Pro-
gram, and Systolic Hypertension in the Elderly Program,
have supported the use of chlorthalidone over other thi-
azide diuretics [12, 13].
Chlorthalidone is a thiazide-like diuretic that leads to
diuresis, with enhanced excretion of Na? and Cl- ions. It
has been demonstrated to be effective in reducing blood
pressure and ameliorating cardiovascular disease morbidity
and mortality [14, 15]. Chlorthalidone has a prolonged
action compared with hydrochlorothiazide and with a 24-h
dosing interval, it is more effective in terms of reducing
blood pressure [14–16].
To the best of our knowledge, limited data are available
regarding the inhibition or induction of the CYP enzymes,
the degree of hepatic uptake, or the influence of trans-
porters on the pharmacokinetics of chlorthalidone, even
S. J. Seong et al.
though chlorthalidone was approved as an antihypertensive
agent more than 50 years ago [17].
The latest guidelines for the management of hyperten-
sion, such as the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood
Pressure 8, are anticipated to increase the focus on the
prescription of multiple medications, including initial
combination treatment in appropriate populations [18].
Furthermore, beneficial combination regimens have been
identified and are being increasingly recommended in the
guidelines [12]. In addition, in the relevant European
guidelines, preferred combination treatments are suggested,
which include an ARB or angiotensin-converting enzyme
inhibitor combined with a thiazide-like diuretic or a cal-
cium channel blocker [12].
Therefore, telmisartan and chlorthalidone may be given
to hypertensive patients at the same time. Because the
pharmacokinetic interactions of chlorthalidone with an
ARB have not yet been studied, our study was warranted.
This study was performed to ascertain whether the
coadministration of chlorthalidone and telmisartan can
influence the pharmacokinetic characteristics of either drug
in healthy male subjects.
2 Methods
This study was conducted in accordance with the Decla-
ration of Helsinki, the International Conference on Har-
monization-Good Clinical Practice standards, and all
related laws [19, 20]. The study protocol was reviewed and
approved by the Institutional Review Board of Kyungpook
National University Hospital (KNUH, Daegu, Republic of
Korea) before the study began. All volunteers received a
full explanation regarding the study and submitted a writ-
ten informed consent before a screening test for eligibility
in the study.
2.1 Subjects
Healthy adult male volunteers, aged 20–50 years, who met
the following inclusion criteria participated: no clinically
significant findings, determined by medical history, phys-
ical examination, clinical laboratory tests (complete blood
cell count, biochemistry, urinalysis), and 12-lead electro-
cardiogram. Exclusion criteria included a known allergy to
any drug, any disease and/or abnormal diet that might
affect the pharmacokinetic properties (absorption, distri-
bution, metabolism, and excretion) of the drugs, levels of
aspartate transaminase, alanine transaminase, or total
bilirubin [1.59 the upper limit of normal, creatinine
clearance, using the Cockcroft–Gault equation, of\80 mL/
Pharmacokinetic Interaction between Telmisartan and Chlorthalidone
min. Subjects who had a congenital or chronic disease, or a
history of drug abuse were also excluded.
2.2 Study Design and Procedures
The A and B studies had a single-center, randomized,
open-label, multiple-dose, two-period, one-sequence
design (Fig. 1). Eligible participants were enrolled and
randomized into study A or B according to the random-
ization schedule. Subjects were hospitalized on the day
before the last dosing in each period to ensure an overnight
fast and they remained throughout the pharmacokinetic
sampling.
Study A was designed to investigate the influence of
chlorthalidone on the pharmacokinetics of telmisartan at
steady state. In total, 43 subjects received oral telmisartan
(Boehringer Ingelheim Korea, Seoul, Republic of Korea)
80 mg for 7 days, and were then administered 25 mg of
chlorthalidone (Hanlim Pharm. Co., Ltd., Seoul, Republic
of Korea) for 14 days (from day 8 to 21), coadministered
with 80 mg of telmisartan from day 15 in a fasting state.
Blood samples were drawn at the following time points for
the measurement of telmisartan concentrations; 0 h (pre-
dose on days 7 and 21) and at 0.5, 0.75, 1, 1.25, 1.5, 2, 4, 8,
12, and 24 h after last dosing.
Study B was conducted to assess the effects of telmis-
artan on the pharmacokinetics of chlorthalidone at steady
state. In total, 14 participants received chlorthalidone for
13 days, followed by coadministration with telmisartan for
7 days in a fasting state. Venous blood samples for the
determination of chlorthalidone concentrations were taken
Fig. 1 Study design to evaluate
the PK interactions between
telmisartan and chlorthalidone.
PK pharmacokinetic, PSV post-
study visit
at the following time points: 0 h (prior to the last dose) and
at 4, 8, 9, 10, 11, 12, 13, and 24 h after the last dosing.
Within 30 min of sampling, samples were centrifuged
(3000 rpm, 10 min, 4 °C) to prepare plasma. Then, the
supernatant was transferred to microcentrifuge tubes and
aliquots were frozen at -70 °C until measurement of the
drug.
2.3 Drug Concentration Measurements
2.3.1 Telmisartan
Drug concentrations were quantified by a certified analyt-
ical laboratory (Biocore, Seoul, Republic of Korea) using a
validated high-performance liquid chromatography cou-
pled to a tandem mass spectrometry method.
Telmisartan quantification was performed on a Shiseido
nanospace SI-2 (Shiseido Co., Tokyo, Japan) and TSQ
Quantum Ultra triple-stage quadrupole mass spectrometer
(Thermo Fisher Scientific Inc., Waltham, MA, USA) by a
single reaction monitoring method. Telmisartan standard
material (lot number F0I345) was purchased from United
States Pharmacopeia (Rockville, MD, USA), and the
internal standard telmisartan-d3 (lot number 9-SHG-14-1)
was purchased from Toronto Research Chemicals Inc.
(Toronto, ON, Canada). Chromatographic separation was
achieved with a C18 column (2.0 9 75 mm, 3-lm particle
size) using 10 mM ammonium acetate/methanol/formic
acid at 15/85/0.1 (v/v/v) as the mobile phase at a flow rate
of 0.2 mL/min. The linearity of the calibration curve for
telmisartan was examined in the concentration range of

10–10000 ng/mL (r2 = 0.9994) and the lower limit of
quantification was 10 ng/mL.
The intra- and inter-day accuracy values for telmisartan
ranged from 98.80 to 101.63 % and from 98.55 to
102.64 %, respectively. The intra-batch precision %CVs
ranged from 0.36 to 7.45 % and the inter-batch preci-
sion %CVs ranged from 2.13 to 8.49 %. These results met
the acceptable ranges of accuracy and precision for the
validation of bioanalytical methods [21].
2.3.2 Chlorthalidone
Quantification of chlorthalidone was performed on an
ACQUITYTM UPLC (Waters Corp., Milford, MA, USA)
coupled with API 4000 (AB Sciex, Redwood City, CA,
USA) by a multiple reaction monitoring method.
Chlorthalidone (lot number I1L127) was purchased from
United States Pharmacopeia and the internal standard
hydrochlorothiazide (lot number 602111127) was pur-
chased from Polpharma (Nowa De˛ba, Tarnobrzeg County,
Poland). Chromatographic separation was achieved on a
C18 column (2.0 9 150 mm, particle size, 3.0 lm) using
1 mM ammonium formate/acetonitrile at 50/50 (v/v) as the
mobile phase at a flow rate of 0.2 mL/min. The lower limit
of quantification was 50 ng/mL, which was determined
from a standard curve of a chlorthalidone with a concen-
tration range of 50–2000 ng/mL (r2 = 0.9988).
The intra- and inter-day accuracy values for chlorthali-
done ranged from 89.48 to 100.17 and from 96.42 to
104.31%, respectively. The intra-batch precision %CVs
ranged from 1.62 to 2.96 % and the inter-batch preci-
sion %CVs ranged from 3.84 to 8.50 %. These fell within
the acceptable ranges of accuracy and precision for the
validation of bioanalytical methods [21].
2.4 Pharmacokinetic Evaluation
Pharmacokinetic variables for telmisartan and chlorthali-
done were calculated using a non-compartmental pharma-
cokinetic model and the WinNonlin Professional software
(ver. 5.3; Pharsight, Mountain View, CA, USA).
The primary pharmacokinetic variables measured were
the maximum steady-state plasma concentration during a
dosing interval (Cmax,ss) and area under the plasma con-
centration-time curve during a dosing interval at steady
state (AUCs,ss). Other pharmacokinetic parameters, such as
time of maximum observed concentration following
administration at steady state (Tmax,ss), apparent total body
clearance for oral administration (CL/F), and volume of
distribution (Vd/F), were also calculated.
Cmax,ss and time to Cmax,ss were determined from the
observed concentrations. AUCs,ss was calculated by the
trapezoidal method and CL/F was estimated by dividing
S. J. Seong et al.
the drug amount by AUCs,ss. The Vd/F was calculated using
the equation Vd/F = CL/F/ke. ke is the elimination rate
constant estimated by linear regression of the log-linear
decline of the final data points.
Pharmacokinetic variables are presented as means ±
standard deviation (SD), with the exception of Tmax,ss,
which is reported as the median and range.
2.5 Safety Analysis
Results from vital signs (blood pressure, pulse rate, and body
temperature), physical examinations, 12-lead electrocardio-
gram, hematology, biochemistry, urinalysis, and self-report-
ing of participants were included in the safety assessment.
Clinical laboratory examinations were performed at an
accredited Department of Laboratory Medicine (KNUH).
Systolic and diastolic blood pressure (BP) and pulse rate were
measured at screening, pre-dose at each outpatient visit and 0,
2, 4, 6, 12, and 24 h after administration of the last dose, and at
the post-study visit. BP and pulse rate were recorded using an
automated device (BP-203 RV III; Omron Matsusaka Co.,
Ltd, Matsusaka, Japan) or a mercury sphygmomanometer
after a 5-min rest in the sitting position. Because the study was
conducted in healthy normotensive subjects, a single BP
reading at one time was taken for safety assessment.
Adverse events (AEs) occurring on or after administra-
tion of the investigational drug were included in the safety
evaluation. According to the International Conference on
Harmonization-Good Clinical Practice guidelines, the
defined conditions of what constitutes an AE and a serious
AE were described in the protocol [20]. An AE or a serious
AE was determined by the investigator.
2.6 Statistical Analysis
According to the currently accepted guidelines for drug
interaction studies, assessment of drug interactions in
studies A and B were made on the basis of point estimates
and 90 % confidence intervals (CIs) of the ratio for com-
bination therapy to monotherapy of the primary pharma-
cokinetic parameters [22].
The 90 % CIs of the concomitant treatment/single
treatment ratios for log-transformed Cmax,ss and AUCs,ss
were assessed with a mixed-effects model analysis of
variance using SAS version 9.3 (SAS Institute Inc., Cary,
NC, USA).
Pharmacokinetic variables between the treatment groups
were compared using descriptive statistics. Differences in
pharmacokinetic and safety parameters of the investiga-
tional products between combination therapy and
monotherapy were evaluated using a paired-t test or Wil-
coxon signed rank-sum test after confirming that the data
followed a normal distribution using a normality test.
Pharmacokinetic Interaction between Telmisartan and Chlorthalidone
Statistical analyses were conducted using the PASW soft-
ware (version 18.0; SPSS Korea, Seoul, Republic of
Korea). P values \0.05 were considered to indicate sta-
tistical significance.
3 Results
3.1 Subjects
In total, 57 eligible male volunteers entered the study and
50 subjects (Study A: n = 37, Study B: n = 13) completed
the study. One subject withdrew from the study because of
an AE, and six subjects withdrew consent from the study.
The mean ± SD values for age, height, and weight of
subjects who completed the Study A were 26 ± 3 years,
175.1 ± 5.9 cm, and 70.2 ± 8.3 kg, respectively. The
mean (SD) values for the age, height, and weight of sub-
jects who completed Study B were 26 ± 5 years,
172.1 ± 3.8 cm, and 68.8 ± 6.1 kg, respectively.
3.2 Pharmacokinetic Data
3.2.1 Telmisartan
Figure 2a shows a graph of the arithmetic mean plasma
telmisartan concentrations vs. time after administration of
an oral dose of 80 mg of telmisartan with or without
chlorthalidone 25 mg. The pharmacokinetic parameters of
telmisartan are summarized in Table 1.
The mean Cmax,ss and AUCs,ss values of telmisartan were
similar (P = 0.96, P = 0.07, respectively) with or without
chlorthalidone administration (Table 1). The point estimates
(90 % CIs) of the ratio for combination therapy to
monotherapy of the variables Cmax,ss and AUCs,ss for telmis-
artan were 1.018 (0.861–1.203) and 1.099 (1.015–1.190),
respectively (Table 2). The Cmax,ss and AUCs,ss for telmisar-
tan increased by 1.8 and 9.9 %, respectively, when taken with
chlorthalidone compared with monotherapy. In addition, as
shown in Fig. 3a, b, plasma telmisartan concentrations dis-
played considerable inter-individual differences [expressed
as % coefficient of variation (CV)] in Cmax,ss and AUCs,ss after
repeated administration of telmisartan alone (61.4 and
61.8 %, respectively) and combined with chlorthalidone (69.5
and 66.0 %, respectively).
3.2.2 Chlorthalidone
A plot of plasma chlorthalidone concentration vs. time
after administration of chlorthalidone 25 mg with or
without telmisartan 80 mg is presented in Fig. 2b, and the
pharmacokinetic parameters of chlorthalidone are sum-
marized in Table 1. Comparable values for chlorthalidone
mean Cmax,ss (P = 0.91) and AUCs,ss (P = 0.94) were
found between concomitant and single treatments
(Table 1). The point estimates (90 % CIs) of the variables
Cmax,ss and AUCs,ss ratios for coadministration treatment
to chlorthalidone monotherapy were 0.996 (0.922–1.075)
and 0.992 (0.925–1.064), respectively (Table 2). The
Cmax,ss and AUCs,ss for chlorthalidone decreased by 0.4
and 0.8 % with combination therapy compared with
monotherapy, respectively. The inter-individual variabili-
ties (presented as %CV) for Cmax,ss and AUCs,ss for
chlorthalidone alone were 24.0 and 24.6 %, respectively,
and 26.9 and 30.2 %, respectively, when combined with
telmisartan. Therefore, pharmacokinetic data for
chlorthalidone showed relatively small inter-individual
variability (Fig. 3a–d).
Both the point estimates and 90 % CIs of Cmax,ss and
AUCs,ss ratios for coadministration treatment to single
treatment of telmisartan and chlorthalidone were within the
acceptable range of 0.80–1.25. These results indicate that
the bioavailability of telmisartan was not affected by
combination therapy with chlorthalidone and vice versa.
3.3 Safety
Safety evaluations were performed in the 57 subjects
(Study A: n = 43, Study B: n = 14) who received at least
one dose of the study medication.
No serious AEs or deaths occurred during the entire
study, with the exception of one subject.
In study A, a subject experienced severe nausea after
administration on day 2 of period 2. The subject was
referred to the emergency room of KNUH and was
immediately dropped from the trial. The symptom resolved
without any additional occurrences after conservative
management with hospitalization for 9 days. It was con-
sidered related to the drug being studied and was reported
to the KNUH Institutional Review Board according to the
protocol.
In both studies, mild decreased blood sodium was the
predominant sign observed (Study A: eight events, Study
B: five events). Other AEs included increased blood uric
acid (Study A: five events, Study B: four events), increased
total bilirubin (Study A: seven events), sinus tachycardia
(Study A: five events), and decreased blood potassium
(Study B: five events). These AEs were all considered to be
related to the study agent.
No clinically relevant changes in blood pressure were
observed, and the mean systolic blood pressure decreased
more with treatment with telmisartan plus chlorthalidone
than with telmisartan or chlorthalidone monotherapy (all
P \ 0.05, Table 3).
The influence of the medications studied on serum
potassium, sodium, and uric acid levels was evaluated and
 S. J. Seong et al.

Fig. 2 Mean (standard

deviation) plasma a telmisartan
concentration time after
multiple oral administration for
7 days without chlorthalidone
and coadministration with
chlorthalidone (25 mg) for
7 days (n = 37),
b chlorthalidone concentration
time after 13-day multiple doses
of oral 25 mg chlorthalidone
without telmisartan and
coadministration of 80 mg
telmisartan for 7 days (n = 13)

presented in Table 3. In Study A, telmisartan monotherapy
caused reductions in serum potassium, sodium, and uric
acid levels (P = 0.36, P \ 0.001, and P \ 0.001, respec-
tively). Co-administration of telmisartan and chlorthali-
done presented significant decreases in serum potassium
and sodium levels and increases in uric acid levels
compared with the baseline (all P \ 0.001). Differences
between combination treatment and telmisartan
monotherapy were significant (all P \ 0.001).
In Study B, serum potassium, sodium, and uric acid
levels all decreased after administration of chlorthalidone
alone and chlorthalidone plus telmisartan compared with
Pharmacokinetic Interaction between Telmisartan and Chlorthalidone

the baseline (all P \ 0.05). The difference in the change in

Table 1 Summary of pharmacokinetic characteristics of telmisartan and chlorthalidone following multiple-dose oral administration of telmisartan (80 mg) and chlorthalidone (25 mg) alone or

P value

Cmax,ss maximum plasma concentration at steady-state, Tmax,ss time to reach Cmax,ss, AUCs,ss area under the plasma concentration-time curve for the dosing interval at steady state, CL/F apparent
0.911
0.938

0.674
0.152
serum potassium levels between combination therapy and
chlorthalidone monotherapy was significant (P = 0.046),
but differences in serum sodium and uric acid levels were
not significant (all P [ 0.05).
Chlorthalidone ? telmisartan
All subjects (Study A: n = 30, Study B: n = 9) with
drug-related AEs recovered completely (Table 4).

4.00 (4.00–4.00)
Telmisartan and chlorthalidone were well tolerated in
3967.65 (1202.37) these studies.
255.43 (72.02)

279.59 (94.52)
6.83 (2.00)
4 Discussion

Recently, combination therapy with ARBs, such as

Chlorthalidone (n = 13)

telmisartan, and thiazide-related diuretics, such as

Chlorthalidone alone

4.00 (4.00–4.00)

chlorthalidone, has been increasingly prescribed for the

3952.50 (967.73)

340.59 (160.60)

effective management of hypertension. Thus, it is clinically

253.93 (59.78)

6.71 (1.79)

meaningful to identify the drug–drug interactions between

telmisartan and chlorthalidone. To determine the potential
for pharmacokinetic interactions between telmisartan and
chlorthalidone, both agents were administered at high
therapeutic doses. Following US Food and Drug Admin-
Values are presented as mean (standard deviation) except for Tmax,ss, which is shown as the median and range

istration interaction guidance, there was no washout period

P value

in the studies [22].

0.958
0.069
0.623
0.069
0.934

No pharmacokinetic drug–drug interactions were found

when examining the 90 % CIs for log-transformed Cmax,ss,
and AUCs,ss ratios for the combination with telmisartan and
chlorthalidone vs. monotherapy (telmisartan or chlorthali-
Telmisartan ? chlorthalidone

done) were within the no-effect boundaries of 80–125 %

[22]. Statistical analyses revealed that the point estimates
0.75 (0.50–4.00)

and 90 % CIs for Cmax,ss and AUCs,ss were all within the
3854.42 (2537.20)
1053.82 (732.06)

451.80 (329.44)
28.51 (18.94)

predefined range. The results of these repeated-dose studies

showed no evidence for any interaction between 80 mg
telmisartan and 25 mg chlorthalidone in healthy male
adults.
These results are consistent with those of previous
studies of combination treatment with ARBs and thiazide
as a combination treatment in healthy adult male subjects

diuretics [1, 2, 9, 10, 23].

Telmisartan (n = 37)

0.75 (0.50–2.00)

Studies in healthy subjects have indicated no significant

3526.60 (2181.31)

615.16 (1032.66)
Telmisartan alone

1012.28 (615.15)

total body clearance, Vd/F volume of distribution

31.29 (18.38)

modulation of the pharmacokinetic variables of telmisartan

when it was coadministered with hydrochlorothiazide
[10]. Additionally, the pharmacokinetic profiles of
hydrochlorothiazide were unaffected by telmisartan, and
further, an enhanced therapeutic effect has been noted
when telmisartan and hydrochlorothiazide are coadminis-
tered [10]. When telmisartan 160 mg and hydrochloroth-
Pharmacokinetic variable

iazide 25 mg were given together to healthy subjects for

7 days, there was no clinically significant pharmacokinetic
AUCs,ss (ng
h/mL)

drug interaction between telmisartan and hydrochloroth-

Cmax,ss (ng/mL)

iazide [1]. Keating and McCrea et al. reported the absence

CL/F (L/h)
Tmax,ss (h)

of pharmacokinetic interactions between losartan and

Vd/F (L)

hydrochlorothiazide [2, 24]. Furthermore, it has been

reported that the pharmacokinetics of valsartan were not
 S. J. Seong et al.

Table 2 Geometric mean ratio (GMR) and 90 % confidence intervals (CIs) for the log-transformed Cmax,ss and AUCs,ss of telmisartan and
chlorthalidone after repeated oral administration of telmisartan and/or chlorthalidone in healthy adult male subjects
Pharmacokinetic variable GMR (telmisartan ? chlorthalidone/telmisartan or chlorthalidone alone; 90 % CIs)
Telmisartan (n = 37) Chlorthalidone (n = 13)

Cmax,ss 1.018 (0.861–1.203) 0.996 (0.922–1.075)

AUCs,ss 1.099 (1.015–1.190) 0.992 (0.925–1.064)
Cmax,ss maximum plasma concentration at steady state, AUCs,ss area under the plasma concentration-time curve for the dosing interval at steady
state

Fig. 3 Individual plots of plasma concentrations for telmisartan after multiple oral doses of 25 mg chlorthalidone alone for 13 days (c) and
multiple oral doses of 80 mg telmisartan alone for 7 days (a) and in in combination with 80 mg telmisartan (d)
combination with 25 mg chlorthalidone (b), for chlorthalidone after

affected by concomitant administration of hydrochloroth-
iazide [23].
Hydrochlorothiazide and chlorthalidone are structurally
different and they have quite different pharmacokinetic
properties, including half-life and volume of distribution
[13–15]. Several studies have reported the pharmacokinetic
characteristics of hydrochlorothiazide-based combination
therapy; however, pharmacokinetic data regarding
chlorthalidone or chlorthalidone-based combination ther-
apy are lacking. Thus, the results of this study, which
Pharmacokinetic Interaction between Telmisartan and Chlorthalidone

P value
compares telmisartan/chlorthalidone combination therapy

0.046
1.000
0.760
0.001
0.002
with monotherapy (telmisartan or chlorthalidone), may be
useful.
Although both drugs were administered repeatedly at

Chlorthalidone ? telmisartan
high therapeutic doses, their safety and tolerability were
Table 3 Sitting blood pressure and serum biochemical levels after repeated oral administration of 80 mg telmisartan and/or 25 mg chlorthalidone in healthy male subjects

generally similar and acceptable, whether administered

alone or in combination. The decreased blood sodium and
increased blood uric acid were frequently reported in the
110.38 ± 7.61
62.23 ± 5.88
3.82 ± 0.35
138.23 ± 2.65
7.04 ± 1.36

Statistical significance of the differences between combination therapy and telmisartan or chlorthalidone monotherapy was calculated and expressed as P values
current study, and were likely owing to the pharmaco-
dynamic effects of controlling electrolytes with diuretics
in healthy male subjects. Sinus tachycardia might occur as
a result of the pharmacological effects of the antihyper-
tensive and/or depletion of Na? and fluid volume in
Chlorthalidone

122.54 ± 8.70
71.38 ± 9.31
3.63 ± 0.28
138.23 ± 1.30
7.08 ± 1.29

subjects.
McGill and Reilly reported that combination therapy of
telmisartan and hydrochlorthiazide tended to blunt the
adverse effects of thiazide diuretics, especially hypokale-
Study B (n = 13)

mia [25]. Although in our studies, combining telmisartan

129.85 ± 8.86
74.92 ± 7.04
4.21 ± 0.20
141.08 ± 1.04
5.72 ± 0.94

with chlorthalidone did not appear to reduce the adverse

Baseline

effects of chlorthalidone on potassium, sodium, and uric

acid, these findings are not enough to conclude that the
combination does not reduce these effects. The reasons are
as follows. After multiple administrations of chlorthalidone
P value

\0.001
0.001
\0.001
0.038
0.673

alone, mean potassium levels decreased from 4.21 to

3.63 mmol/L. However, levels increased significantly
(?0.19 mmol/L; P \ 0.05) after co-administration with
Telmisartan ? chlorthalidone

telmisartan. In addition, after chlorthalidone monotherapy,

serum potassium levels of less than 3.5 mmol/L were seen
in 38.5 % of subjects (5/13 subjects), whereas only 7.7 %
of subjects (1/13 subjects) had levels below 3.5 mmol/L
108.51 ± 10.28
63.03 ± 8.32
3.99 ± 0.37
138.03 ± 1.95
6.77 ± 1.22

after combination therapy with telmisartan. This observa-

tion may support that co-administration of telmisartan and
chlorthalidone offsets the adverse effect of chlorthalidone
on serum potassium levels. Furthermore, decreased or
increased levels of serum potassium, sodium, and uric acid
111.97 ± 9.79
61.73 ± 8.02
4.28 ± 0.21
139.35 ± 1.03
5.36 ± 1.04

were all within the acceptable range and no clinically

Telmisartan

significant changes were reported. More large-scale studies

SBP systolic blood pressure, DBP diastolic blood pressure

to confirm the effect of the telmisartan plus thiazide

diuretics combination therapy on potassium, sodium, and
Values are presented as mean ± standard deviation
Study A (n = 37)

uric acid levels are required.

128.35 ± 11.15
76.14 ± 7.75
4.33 ± 0.34
141.05 ± 0.97
5.82 ± 1.10

Some limitations to the current study should be con-

sidered. First, our pharmacokinetics results were from only
Baseline

healthy normotensive subjects, not hypertension patients.

The pharmacokinetic profiles of the medications in
hypertensive patients, especially after long-term therapy,
Serum potassium (mmol/L)

might differ from those in healthy normotensive subjects.

Serum uric acid (mg/dL)
Serum sodium (mmol/L)

Thus, caution is required in extrapolating these results.

Second, to investigate the drug–drug interactions, small-
scale studies were conducted under experimental condi-
DBP (mmHg)
SBP (mmHg)

tions. Thus, they are unlikely to be typical of real-world

conditions where diet is diverse and hypertensive patients
may drink alcoholic beverages and smoke cigarettes, which
can induce CYP systems and/or drug transporters and alter
 S. J. Seong et al.

Table 4 Summary of treatment-emergent adverse drug reactions after repeated oral administration of 80 mg telmisartan and/or 25 mg
chlorthalidone in healthy male subjects
Adverse drug reaction Study A (n = 43) Study B (n = 14)
Telmisartan Telmisartan ? chlorthalidone Chlorthalidone Chlorthalidone ? telmisartan

Blood sodium decreased 8 (8) 5 (5)

Total bilirubin increased 1 (1) 6 (6) 1 (1)
Blood uric acid increased 5 (5) 4 (4)
Alanine transaminase increased 1 (1) 3 (3)
Blood glucose decreased 3 (3) 1 (1)
Creatinine phosphokinase increased 2 (2) 2 (2)
Blood potassium increased 1 (1)
Blood chloride decreased 1 (1) 2 (2)
Blood potassium decreased 1 (1) 2 (2) 3 (3)
Total cholesterol increased 1 (1)
Aspartate transaminase increased 1 (1)
Eosinophil count increased 1 (1)
Sinus tachycardia 1 (1) 4 (4)
Dizziness 1 (1) 1 (1) 1 (1) 1 (1)
Arrhythmia 1 (1)
Nausea 3 (3) 2 (2)
Acute gastritis 1 (1)
Dyspepsia 1 (1) 1 (1)
Headache 3 (3) 1 (1)
Insomnia 1 (1)
Both leg dermatitis 1 (1)
Abdominal pain 1 (1)
Upper respiratory infection 1 (1)
Values are presented as the number of subjects (number of events)

drug metabolism [23]. Third, the numbers of subjects
participating in the studies were not large enough to detect
possible treatment-emergent AEs. Consequently, additional
larger-scale, longer-term, double-blind research in patients
with hypertension is needed to evaluate the clinical effec-
tiveness and tolerability of combination treatment with
telmisartan and chlorthalidone.
5 Conclusions
Acknowledgment Drs. S.J. Seong and Ms. Lim contributed equally
to this work. This study was supported by a grant of the Korea Health
Technology R&D Project through the Korea Health Industry Devel-
opment Institute, funded by the Ministry of Health and Welfare,
Republic of Korea (HI15C0001, HI14C1731, A070001, HI13C1232),
the Industrial Core Technology Development Program (10051129,
Development of the system for ADME assessment using radiolabeled
compounds) funded by the Ministry of Trade, Industry and Energy
(MOTIE, Korea), and the Bio and Medical Technology Development
Program of the National Research Foundation, funded by the Ministry
of Science, ICT and Future Planning, Republic of Korea (NRF-
2013M3A9B6046416).

Compliance with Ethical Standards

After repeated doses, the steady-state pharmacokinetic
profile of telmisartan was unaffected when chlorthalidone
was administered concurrently, and it had no clinically
important influence on the pharmacokinetic characteristics
of chlorthalidone at steady state in healthy male subjects.
The results of the present study indicated that once-daily
concurrent administration of telmisartan and chlorthalidone
was relatively well tolerated, with no dosage adjustment
needed for either drug.
Funding This study was funded by HanAll BioPharma Co., Ltd.,
Seoul, Republic of Korea.
Conflict of interest SJS, MSL, JL, BO, MRG, BKK, HJK, DHY,
HWL, WYK and YRY have no conflicts of interest that are relevant to
the content of this manuscript.
Ethical approval All procedures performed in studies involving
human participants were in accordance with the ethical standards of
the institutional and/or national research committee and with the 1964
Pharmacokinetic Interaction between Telmisartan and Chlorthalidone
Helsinki Declaration and its later amendments or comparable ethical
standards.
Informed consent All volunteers received a full explanation
regarding the study and submitted a written informed consent before a
screening test for eligibility in the study.
References
1. Maillard MP, Burnier M. Is the fixed-dose combination of
telmisartan and hydrochlorothiazide a good approach to treat
hypertension? Vascular Health Risk Manage. 2007;3(3):265–78.
2. Keating GM. Losartan/hydrochlorothiazide: a review of its use in
the treatment of hypertension and for stroke risk reduction in
patients with hypertension and left ventricular hypertrophy.
Drugs. 2009;69(9):1239–65.
3. Sharpe M, Jarvis B, Goa KL. Telmisartan: a review of its use in
hypertension. Drugs. 2001;61(10):1501–29.
4. Karlberg BE, Lins L-E, Hermansson K. Efficacy and safety of
telmisartan, a selective AT1 receptor antagonist, compared with
enalapril in elderly patients with primary hypertension. J Hyper-
tension. 1999;17:293–302.
5. Freytag F, Schelling A, Meinicke T, Deichsel G, for the
Telmisartan Hypertension Experience in a Randomized European
Study Versus Atenolol Study Group. Comparison of 26-week
efficacy and tolerability of telmisartan and atenolol, in combi-
nation with hydrochlorothiazide as required, in the treatment of
mild to moderate hypertension: a randomized, multicenter study.
Clin Ther. 2001;23(1):108–23.
6. Stangier J, Su C, Roth W. Pharmacokinetics of orally and intra-
venously administered telmisartan in healthy young and elderly
volunteers and in hypertensive patients. J Int Med Res.
2000;28:149–67.
7. Tatami S, Sarashina A, Yamamura N, et al. Population pharma-
cokinetics of an angiotensin II receptor antagonist, telmisartan, in
healthy volunteers and hypertensive patients. Drug Metab Phar-
macokinet. 2003;18(3):203–11.
8. Stangier J, Su CA, Hendricks MG, et al. The effect of telmisartan
on the steady-state pharmacokinetics of digoxin in healthy male
volunteers. J Clin Pharmacol 2000;40(12 Pt1):1373–9.
9. Israili ZH. Clinical pharmacokinetics of angiotensin II (AT1)
receptor blockers in hypertension. J Hum Hypertens (Suppl).
2000;14:S73–86.
10. Unger T, Kaschina E. Drug interactions with angiotensin receptor
blockers: a comparison with other antihypertensives. Drug Saf.
2003;26(10):707–20.
11. Mallat SG. What is a preferred angiotensin II receptor blocker-
based combination therapy for blood pressure control in hyper-
tensive patients with diabetic and non-diabetic renal impairment?
Cardiovasc Diabetol. 2012;10(11):32.
12. Gradman AH. Rationale for triple-combination therapy for
management of high blood pressure. J Clin Hypertens.
2010;12(11):869–78.
13. Carter BL, Ernst ME, Cohen JD. Hydrochlorothiazide versus
chlorthalidone: evidence supporting their interchangeability.
Hypertension. 2003;43:4–9.
14. Sica DA, Carter B, Cushman W. Thiazide and loop diuretics.
J Clin Hypertens. 2011;13(9):639–43.
15. Sica DA. Chlorthalidone: a renaissance in use? Exp Opin Phar-
macother. 2009;10(13):2037–9.
16. Sica D, Bakris GL, White WB, et al. Blood pressure-lowering
efficacy of the fixed-dose combination of azilsartan medoxomil
and chlorthalidone: a factorial study. J Clin Hypertens.
2012;14(5):284–92.
17. Cheng JW. Azilsartan/chlorthalidone combination therapy for
blood pressure control. Integr Blood Press Control. 2013;6:
39–48.
18. James PA, Oparil S, Carter BL, et al. 2014 evidence-based
guideline for the management of high blood pressure in adults:
report from the panel members appointed to the Eighth Joint
National Committee (JNC 8). J Am Med Assoc. 2014;311(5):
507–20.
19. World Medical Association. World Medical Association Decla-
ration of Helsinki ethical principles for medical research
involving human subjects. J Am Med Assoc. 2013;310(20):
2191–4.
20. ICH harmonised tripartite guideline: guideline for good clinical
practice E6 (R1). International Conference on Harmonisation of
technical requirements for registration of pharmaceuticals for
human use. 1996. Available at: http://www.ich.org/products/
guidelines/efficacy/article/efficacy-guidelines.html. Accessed 12
Apr 2016.
21. Guideline for the validation of bioanalytical method. Ministry of
Food and Drug Safety. Republic of Korea, 2010. Available at:
http://www.mfds.go.kr/index.do?mid=689&pageNo=46&seq=
7560&cmd=v. Accessed 15 Nov 2015.
22. Guidance for industry: Drug interaction studies: study design,
data analysis, implications for dosing, and labeling recommen-
dations [draft guidance]. FDA Center for Drug Evaluation and
Research. Silver Spring, MD: FDA, 2012. Available at: http://
www.fda.gov/drugs/GuidanceComplianceRegulatoryInformation/
guidances/default.htm. Accessed 15 Nov 2015.
23. Wagstaff AJ. Valsartan/hydrochlorothiazide: a review of its use in
the management of hypertension. Drugs. 2006;66(14):1881–901.
24. McCrea JB, Lo MW, Tomasko L, et al. Absence of a pharma-
cokinetic interaction between losartan and hydrochlorothiazide.
J Clin Pharmacol. 1995;35(12):1200–6.
25. McGill JB, Reilly PA. Telmisartan plus hydrochlorthiazide ver-
sus telmisartan or hydrochlorothiazide monotherapy in patients
with mild to moderate hypertension: a multicenter, randomized,
double-blind, placebo-controlled, parallel-group trial. Clin Ther.
2001;23(6):833–50.