Clinical and Experimental Hypertension, 28:631–643, 2006Copyright © Informa HealthcareISSN: 1064-1963 print / 1525-6006 onlineDOI: 10.1080/10641960600946171

631

LCEH1064-19631525-6006Clinical and Experimental Hypertension, Vol. 28, No. 7, August 2006: pp. 1–28Clinical and Experimental Hypertension

Pharmacokinetics and Safety of Olmesartan Medoxomil in Combination with Glibenclamide

in Healthy Volunteers

Olmesartan Medoxomil Combined with GlibenclamideM. Huber et al. MATTHIAS HUBER, JULIANE BOLBRINKER, AND REINHOLD KREUTZ

Department of Clinical Pharmacology and Toxicology, Campus BenjaminFranklin, Charité—Universitätsmedizin Berlin, Berlin, Germany

Objective. To investigate the pharmacokinetic interactions, safety, and tolerability ofthe combination of olmesartan medoxomil with glibenclamide. Methods. In an open,three-way crossover, phase I trial, 18 healthy adults entered three randomly ordered,seven-day treatment periods. The three treatments comprised once daily administra-tion of (1) olmesartan 20 mg, (2) olmesartan 20 mg plus glibenclamide 3.5 mg, or (3)glibenclamide 3.5 mg. Results. The combination of olmesartan with glibenclamide didnot influence the bioequivalence of the area under the plasma-concentration timecurve at steady state during one dosing interval 0 to t = 24 hours (AUCss,t) or the max-imum steady-state concentration (Css,max) of both substances. Mean AUCss,t values forolmesartan were 2594.8 ng h/ml for olmesartan alone and 2443.7 ng h/ml in combina-tion with glibenclamide; the corresponding Css,max values were 479.3 ng/ml and 462.7ng/ml, respectively. For glibenclamide, the mean AUCss,t values were 525.7 ng·h/mlfor monotherapy and 518.7 ng·h/ml for its combination with olmesartan. The mediantime to reach Css,max (tmax) for glibenclamide was shifted from 2.0 h to 1.0 h when com-bined with olmesartan, whereas the median tmax values for olmesartan remainedunchanged at 1.5 h. During combined treatment with olmesartan plus glibenclamide,no adverse event occurred, and the medications were well tolerated. Conclusion. Withthe exception of a slight shift of tmax values for glibenclamide, the concomitant admin-istration of olmesartan medoxomil with glibenclamide had no significant effects on thesteady-state pharmacokinetics of either agent. This provides the pharmacokineticrationale for clinical studies to test the combination therapy of patients with hyperten-sion and type-2 diabetes mellitus with both compounds.

Keywords pharmacokinetics, safety, olmesartan medoxomil, glibenclamide

Introduction

Hypertension and type-2 diabetes mellitus are widespread conditions that are each esti-mated to affect more than 1 billion people worldwide (1,2). There is significant overlap

Address correspondence to Prof. Dr. Reinhold Kreutz, Department of Clinical Pharmacologyand Toxicology, Charité—Universitätsmedizin Berlin, Campus Benjamin Franklin,Hindenburgdamm 30, 12200 Berlin, Germany; E-mail: reinhold.kreutz@charite.de

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y O

ndok

uz M

ayis

Uni

v. o

n 05

/05/

14Fo

r pe

rson

al u

se o

nly.

632 M. Huber et al.

between the two conditions, and the frequency of hypertension is higher in patients withdiabetes than in those without (3). Thus, at some point in their therapy, hypertensive patientswith diabetes are likely to require concurrent treatment with anti-hypertensive and anti-diabetic agents. For this reason, it is important to determine whether there are any pharmaco-kinetic interactions resulting from the concomitant administration of such agents.

Olmesartan medoxomil is a potent non-peptidergic angiotensin AT1 receptor blocker(ARB) that is both effective and well tolerated in the treatment of arterial hypertension(4–7). Olmesartan has also been shown to have equal or superior antihypertensive efficacycompared with amlodipine, atenolol, or captopril (5,8–11). In addition, the pharmacoki-netic and pharmacodynamic profile of olmesartan is favorable, both in terms of providingeffective 24-hour blood pressure (BP) control with once-daily dosing and in restricting thelikelihood of pharmacokinetic interactions with other drugs (12). Olmesartan is not metab-olized by cytochrome P-450 isoenzymes, and its pharmacokinetic profile is not affected byage or gender. Moreover, clinical studies have shown that there were no pharmacokineticinteractions between olmesartan and antacids, digoxin, or warfarin (12).

Oral antidiabetic drugs like sulfonylurea are commonly used in the treatment of type-2diabetes, with an increasing importance in the future due to the increasing prevalence oftype-2 diabetes (13). As a second generation sulfonylurea, glibenclamide is a hypoglyce-mic agent with a 24-hour duration of action that lowers blood glucose levels by stimulatinginsulin release from the pancreas and promoting the uptake of glucose from the circulation(14,15). Glibenclamide is widely used as initial therapy in patients with type-2 diabetes.However, due to the high frequency of comorbidity of type-2 diabetes and arterial hyper-tension, glibenclamide is often co-administered with antihypertensive drugs, includingARBs. The authors therefore conducted a phase I trial to evaluate the effects of combina-tion therapy with olmesartan medoxomil and glibenclamide on pharmacokinetics, safety,and tolerability in healthy, adult subjects.

Materials and Methods

Study Design

This was a randomized, open-label, phase I study with a three-way crossover design, carriedout at a single center in Görlitz, Germany. Three treatment periods were conducted, eachwith a duration of seven days. The three treatment periods were separated by 14-daywashout periods. Subjects received seven days of treatment with olmesartan alone (A),olmesartan plus glibenclamide (B), and glibenclamide alone (C).

The trial was conducted in accordance with the Declaration of Helsinki and the Inter-national Conference on Harmonisation guidelines for Good Clinical Practice and was approvedby an ethics committee. All subjects provided written informed consent before entering the trial.

The primary objectives of the trial were to investigate any possible influence ofolmesartan medoxomil on the steady-state plasma pharmacokinetics of glibenclamide andany possible influence of glibenclamide on the steady-state plasma pharmacokinetics ofolmesartan, the pharmacologically active metabolite of olmesartan medoxomil. Safety andtolerability were also assessed.

Subjects

Healthy, adult male subjects aged 18–45 years were included in the study if they hadnormal BP (systolic BP < 140 mmHg and diastolic BP < 90 mmHg); displayed no

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y O

ndok

uz M

ayis

Uni

v. o

n 05

/05/

14Fo

r pe

rson

al u

se o

nly.

Olmesartan Medoxomil Combined with Glibenclamide 633

clinically relevant abnormality in physical examination, electrocardiogram (ECG), orlaboratory findings; and were negative for human immunodeficiency virus antibody,hepatitis B surface antigen, and hepatitis C virus tests.

Subjects who showed clinical evidence of renal disease or clinically significantlaboratory abnormalities or who had taken any medication during the seven days prior tothe start of the study were excluded. Subjects were excluded if they had a history or clini-cal evidence of cerebrovascular, cardiovascular, gastrointestinal, hematological, or hepaticdisease, a history of alcohol or drug abuse, or any serious underlying disease that couldinterfere with the study. In addition, subjects that smoked more than 15 cigarettes per dayor smoked cigars/pipes, and individuals with a body mass index <19 or >28 kg/m2 orweight <45 kg or >95 kg, were excluded from the study.

Interventions

Subjects began active treatment within four weeks of being screened. On day 1 of the firsttreatment period, subjects were randomly allocated to one of six possible treatmentsequences (ABC, ACB, BAC, BCA, CAB, or CBA) using a randomization list generatedby Sankyo Pharma GmbH using SAS version 6.12 software. Thus, in the first treatmentperiod, subjects received treatment A, B, or C as follows:

A: olmesartan medoxomil 20 mg once daily (Sankyo Pharma, Munich, Germany);B: olmesartan medoxomil 20 mg once daily plus glibenclamide 3.5 mg once daily

(Aventis Pharma Deutschland GmbH, Germany); orC: glibenclamide 3.5 mg once daily.

In the second treatment period, subjects received one of the other two treatments, and inthe final treatment period they received the treatment they had not already received. Eachtreatment period lasted seven days; after the last dose of study medication in the first andsecond treatment periods, there was a 14-day treatment-free washout before the nexttreatment period.

During each treatment period, all doses of medication were taken orally with 200 mlwater at 08:00 (± one hour) after an overnight fast. On days 1–6, subjects received astandardized breakfast immediately after intake of study medication, a standardized lunchapproximately 4 hours after dosing, and another standardized meal 8–10 hours after dosing.On day 7, subjects were given breakfast approximately 4 hours after dosing (following thefour-hour blood sample), lunch approximately 7 hours after dosing, and the last mealapproximately 11 hours after dosing. Following a case of convulsion that was probably dueto hypoglycemia, on day 7 of treatment period 1, oral glucose (19.4 g) was administered toall patients at 15 minutes, 1, 2, and 3 hours after dosing on day 7 of treatment periods 2 and3 to prevent hypoglycemia. Subjects were admitted to the trial center approximately 12hours before dosing on day 1 of each treatment period and remained at the site until allassessments had been carried out on day 8. Subjects were permitted to leave the trial centerduring the washout periods. After the end of the third treatment period, subjects remained atthe center until a final examination had been carried out on day 9.

Assessments

Pharmacokinetics. The pharmacokinetic parameters that were evaluated for olmesartanand glibenclamide were the maximum steady state concentration (Css,max), the time toreach Css,max (tmax), the area under the plasma concentration time curve at steady state

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y O

ndok

uz M

ayis

Uni

v. o

n 05

/05/

14Fo

r pe

rson

al u

se o

nly.

634 M. Huber et al.

during one dosing interval 0 to τ = 24 hours after the last dose on day 7 of each treatmentperiod (AUCSS,τ), and the apparent steady state volume of distribution (VSS/f). In eachtreatment period, blood samples (6 ml) for pharmacokinetic analysis were taken on day 7immediately before dosing and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 20, and 24 hours afterdosing. Urine was collected at 4 h intervals between 0–4 h, 4–8 h, and 12–24 h after thelast dose of medication on day 7 of each treatment period, and a 10 ml sample from eachperiod was frozen until assay.

Subjects were not permitted to use any other medication, including over-the-counterpreparations, from 7 days before the first day of the first treatment period until the end ofthe trial. Subjects were also asked to refrain from smoking, drinking coffee or alcohol,physical exercise, and exposure to cold for at least 30 minutes before BP and pulse ratemeasurements.

Blood samples were collected in lithium-heparin tubes and separated by centrifuga-tion into plasma, which was frozen at −20°C and stored until assay. Concentrations ofolmesartan, the active metabolite of olmesartan medoxomil, were determined using a vali-dated high performance liquid chromatography system with a lower limit of quantificationof 0.41 ng/ml in plasma and 5.12 ng/ml in urine. Glibenclamide concentrations weredetermined using a validated reverse phase liquid chromatography/tandem massspectrometry system, with a lower limit of quantification set at 1.04 μg/L, the lowest cali-bration standard concentration for both plasma and urine. The accuracy and precision ofvalidation plasma samples had intra-assay ranges of −12.60% to +1.98% and 1.48% to5.81%, respectively, and inter-assay ranges of −6.45% to +1.38% and 2.62% to 7.64%.Specificity testing revealed no interference with olmesartan (RNH-6270), and the storagestability of glibenclamide in plasma at less than −18°C was confirmed for up to 18 weeks.All analytical procedures were conducted in accordance with the Food and Drug Adminis-tration and European Commission guidelines. Concentrations of olmesartan were mea-sured by Simbec Research Ltd. (Mid Glamorgan, South Wales, UK) and glibenclamide byA&M Labor für Metabolismusforschung, Service GmbH (Bergheim, Germany).

Other Assessments. At the screening visit, demographic and anthropometric data wererecorded and subjects provided medical histories. Checks on the use of concomitant medi-cation were made at screening and on days 1–8 of each treatment period, and checks onthe dispensing of medication and compliance were made on days 1–7.

Safety and Tolerability

Subjects underwent physical examinations at screening and at the final examinationor premature termination. Trough BP and pulse rates were measured at screening, on days1–8, and at the final examination or premature termination. In addition, peak BP and pulserates were measured 4 ± 1 hours after administration of medication on days 1 and 7.Routine laboratory tests and 12-lead ECG recordings (except on day 7) were performed atscreening, on days 1 and 7, and at the final examination. Information on adverse eventswas collected by questioning or by subjects’ spontaneous reports on days 1–8, at the finalexamination or premature termination visit, and, where required, for up to 14 days aftereach study. As part of the laboratory safety test, samples of venous blood (2 ml) weretaken to determine fasting blood glucose levels on days 1 and 7 of each treatment period at2 and 4 hours after dosing. Following the convulsive episode of one subject in period 1,samples of capillary blood were also taken at 45, 60, 75, and 90 minutes, and 2, 3, and 4hours after dosing on day 7 of treatment periods 2 and 3.

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y O

ndok

uz M

ayis

Uni

v. o

n 05

/05/

14Fo

r pe

rson

al u

se o

nly.

Olmesartan Medoxomil Combined with Glibenclamide 635

Statistical Analysis

No formal sample size calculations were carried out, but it was intended that a total of 18subjects would be used in each of the three treatment periods. Pharmacokinetic parameterswere calculated from plasma concentrations measured in the samples taken on days 7 and8 of each treatment period for olmesartan and glibenclamide using a non-compartmentalmodel. The parameter AUCSS,τ was calculated using the linear trapezoidal rule, with VSS/fderived from

where CLSS/f is the steady-state oral clearance calculated as CLSS/f = dose/AUCSS,τ, f isthe unknown fraction of dose absorbed, and the steady state mean residence time (MRTSS)is extrapolated to infinity using the following equation:

In this equation, AUMCSS,τ is the area under the time curve from dosing until τ andAUCSS,0–∞ is the steady-state AUC extrapolated to infinity using

in which AUCSS,0–tz is the area under the concentration-time curve at steady state up to thelast time point tz for which there is a measurable serum concentration (Cz ≥ limit ofquantification), and λz is the terminal rate constant derived by log-linear regression on theterminal elimination phase of the plasma concentration-time profiles.

Statistical analysis was carried out by calculating arithmetic means and standarddeviations; geometric means, medians, and maximum and minimum values for continuousdata; and absolute and relative frequencies for categorical data. Treatments were com-pared on a test versus reference basis as follows: olmesartan plus glibenclamide versusolmesartan; and olmesartan plus glibenclamide versus glibenclamide. For AUCss,τ andCss,max, treatment comparisons involved two one-sided equivalence hypothesis testingwith a significance of α = 0.05 in conjunction with an analysis of variance model appro-priate for the crossover design using log-transformed values. Equivalence was establishedif the geometric mean ratios lay within the range 80–125% with 90% confidence. For tmax,a non-parametric approach was used on untransformed data, and equivalence wasestablished if the 90% confidence interval (CI) for the median difference between test andreference treatments was entirely within ±20% of the median reference tmax.

Pharmacokinetic analyses were evaluated in all subjects for whom analysis of bloodand urine samples were carried out (pharmacokinetic set). An analysis of safety and toler-ability data was carried out in all subjects randomized to treatment who had received atleast one dose of study medication (safety set). Summary statistics were tabulated toassess safety and tolerability for adverse events, laboratory tests, ECG results, BP, andpulse rate.

V f CL f MRTSS SS SS/ / ,= ×

MRT AUMC AUC AUC AUCSS SS SS SS SS= + −−∞[ ( )] ., , , ,/τ τ ττ 0

AUC AUC CSS SS tz z z, , / ,0 0−∞ −= + λ

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y O

ndok

uz M

ayis

Uni

v. o

n 05

/05/

14Fo

r pe

rson

al u

se o

nly.

636 M. Huber et al.

Results

Subjects

Of 40 subjects screened, 18 were randomized and received at least one dose of study med-ication (safety set). During treatment, three subjects were withdrawn, one because of aserious adverse event and two after withdrawing consent. Thus, 15 subjects completed thetrial (the pharmacokinetic set). The demographic and baseline characteristics of the phar-macokinetic set are shown in Table 1.

Pharmacokinetics

The plasma concentration versus time profiles for olmesartan were very similar forolmesartan medoxomil monotherapy and olmesartan medoxomil in combination withglibenclamide (see Figure 1). Similarly, the glibenclamide concentration versus timeprofiles for glibenclamide administered alone and in combination with olmesartan medox-omil were comparable (see Figure 2). For olmesartan, geometric mean AUCss,τ and Css,maxvalues were similar when olmesartan medoxomil was administered alone and in combina-tion with glibenclamide (see Table 2). The 90% CIs for the ratios of geometric means fellwithin the acceptance ranges, indicating bioequivalence for both of these parameters.Bioequivalence was also established for tmax, where the median values were identical andthe 90% CI values fell within the acceptance range.

For glibenclamide, bioequivalence was established for AUCss,τ and Css,max, butmedian tmax values differed between monotherapy and combination therapy. Bioequiva-lence could not be established, as the 90% CI did not lie within the acceptance range andtmax was significantly earlier for glibenclamide in combination therapy compared tomonotherapy.

The co-administration of olmesartan with glibenclamide had no effect on the amountof olmesartan excreted in urine. The average amount of administered dose of olmesartanexcreted in urine during olmesartan monotherapy was 9.5%, compared with 8.6% during

Table 1Demographic and baseline characteristics of subjects in the pharmacokinetic

analysis (n = 15)

Parameter Value

Age (years) 30.5 ± 7.0 [31.0, 22.0–44.0]Weight (kg) 70.8 ± 8.8 [71.0, 58.5–86.0]Height (cm) 174.5 ± 4.7 [174.0, 165.0–183.0]BMI (kg/m2) 23.3 ± 3.0 [23.6, 19.4–27.7]Alcohol consumption, n (%)None 1 (6.7)Sporadic 14 (93.3)Smoking status, n (%)Yes 9 (60.0)No 4 (26.7)Ex-smoker 2 (13.3)

Continuous data are means ± standard deviations [medians, minimum–maximum].

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y O

ndok

uz M

ayis

Uni

v. o

n 05

/05/

14Fo

r pe

rson

al u

se o

nly.

Olmesartan Medoxomil Combined with Glibenclamide 637

combination therapy. The effect of co-administration on the urinary excretion of glib-enclamide could not be assessed because the urinary concentrations of glibenclamide werebelow the limit of quantification.

Figure 1. Mean plasma concentration versus time curve for olmesartan during the administration ofolmesartan medoxomil monotherapy and olmesartan medoxomil plus glibenclamide. Data arepresented as mean ± standard deviation.

0 4 8 12 16 20 240

200

400

600Olmesartan monotherapy

Combination therapynatrase

mlo fo noitartnecnoc naeM

)Lm/gn( a

msalp ni )0726-H

NR(

Time after dosing on day 7 (hours)

Figure 2. Mean plasma concentration versus time curve for glibenclamide during the administra-tion of glibenclamide monotherapy and olmesartan medoxomil plus glibenclamide. Data arepresented as mean ± standard deviation.

0 4 8 12 16 20 24

0

50

100

150

200

Glibenclamide monotherapyCombination therapyfo noitartnecnoc nae

M)L

m/gn( amsalp ni edi

malcnebilg

Time after dosing on day 7 (hours)

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y O

ndok

uz M

ayis

Uni

v. o

n 05

/05/

14Fo

r pe

rson

al u

se o

nly.

638

Tab

le 2

Mea

n va

lues

for

pri

mar

y ph

arm

acok

inet

ic p

aram

eter

s fo

r ol

mes

arta

n an

d gl

iben

clam

ide

give

n as

mon

othe

rapy

an

d co

mbi

nati

on th

erap

y w

ith

the

resu

lts

of b

ioeq

uiva

lenc

e te

stin

g (n

=15

)

Para

met

erSu

bsta

nce

Tre

atm

ent

Poi

nt e

stim

ate

(com

bina

tion/

mon

othe

rapy

)*90

% C

IA

ccep

tanc

e ra

nge

Equ

ival

ence

Mon

othe

rapy

Com

bina

tion

ther

apy

AU

CS

S,τ (

ng •

h/m

L)†

Olm

esar

tan

2594

.8 [

20.2

]24

43.7

[26

.3]

0.94

0.85

, 1.0

50.

80, 1

.25

Yes

Gli

benc

lam

ide

525.

7 [2

8.1]

518.

7 [3

0.7]

0.99

0.92

, 1.0

60.

80, 1

.25

Yes

CS

S,m

ax (

ng/m

L)†

Olm

esar

tan

479.

3 [1

8.4]

462.

7 [3

0.7]

0.97

0.83

, 1.1

30.

80, 1

.25

Yes

Gli

benc

lam

ide

147.

1 [2

3.6]

164.

7 [2

6.8]

1.12

1.01

, 1.2

50.

80, 1

.25

Yes

t max

(h)

‡O

lmes

arta

n1.

50 (

1.0,

2.0

)1.

50 (

1.0,

2.0

)0.

000.

00, 0

.25

−0.3

0, 0

.30

Yes

Gli

benc

lam

ide

2.00

(1.

0, 3

.0)

1.00

(1.

0, 2

.0)

−0.7

5−0

.75,

−0.

50−0

.40,

0.4

0N

o

Abb

revi

atio

ns: A

UC

SS,

τ = A

rea

unde

r th

e pl

asm

a-co

ncen

trat

ion

time

curv

e at

ste

ady

stat

e du

ring

one

dos

ing

inte

rval

0 to

τ =

24

hour

s, C

SS,m

ax=

max

imum

ste

ady

stat

e co

ncen

trat

ion,

t max

= ti

me

to r

each

CSS

,max

, CI

= c

onfi

denc

e in

terv

al.

*rat

io o

f th

e ge

omet

ric

mea

ns f

or A

UC

SS,

τ an

d C

SS,

max

; med

ian

of a

ll po

ssib

le p

air-

wis

e di

ffer

ence

s be

twee

n tr

eatm

ent r

egim

ens

for

t max

.† ge

omet

ric

mea

n [g

eom

etri

c co

effi

cien

t of

vari

atio

n, %

].‡ m

edia

n (m

in, m

ax).

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y O

ndok

uz M

ayis

Uni

v. o

n 05

/05/

14Fo

r pe

rson

al u

se o

nly.

Olmesartan Medoxomil Combined with Glibenclamide 639

Safety and Tolerability

Three subjects experienced adverse events, as summarized in Table 3. One individual treatedwith olmesartan monotherapy showed an increase in alanine aminotransferase from 28.8 U/L at day 1 to 86.4 U/L at day 7 that may be related to treatment. One subject who receivedglibenclamide monotherapy experienced headache and another experienced dizziness,although the glucose values of both subjects were within the reference range. Each of theseevents was of mild intensity, and all subjects recovered spontaneously, but the two subjectswho experienced dizziness and headache withdrew their consent and were withdrawn fromthe trial. No adverse events were reported with combination therapy.

A serious adverse event occurred during glibenclamide monotherapy in one subjectwho experienced a mild convulsion most likely due to hypoglycemia. This subject recov-ered after receiving oral glucose and was subsequently withdrawn from the study andfurther analysis. This event was judged to be probably related to study medication; for thisreason, oral glucose was administered to all subjects and increased blood glucose testingwas implemented post-dosing on day 7 of treatment periods 2 and 3. No clinically relevantchanges in ECG readings, hematology parameters, or vital signs were observed duringthe trial.

Discussion

The current study demonstrated that the pharmacokinetic parameters AUCss,τ, Css,max, andtmax remain bioequivalent when olmesartan is combined with glibenclamide in healthysubjects. This finding is not unexpected, as olmesartan medoxomil is metabolized viaan enzymatic reaction that is not common to the metabolism of glibenclamide. That is,the hydrolysis of the ester bond of olmesartan medoximil to olmesartan by intestinalwall esterases, which activates the prodrug to olmesartan and enables its absorption (16).In this context, it is also important that olmesartan is neither a substrate, inducer, norinhibitor of CYP 450 isoenzymes. This is in contrast to glibenclamide, which is extensively

Table 3Adverse events and serious adverse events and their relationship to treatment

in the safety set of the study (n = 18)

Number ofreports

Classification ofadverse event

Relationship totreatment

Adverse eventsOlmesartan monotherapy 1 Increased alanine

aminotransferasePossible

Glibenclamide monotherapy 1 Headache Unlikely1 Dizziness Unlikely

Olmesartan and glibenclamidecombination

0

Serious adverse eventsOlmesartan monotherapy 0Glibenclamide monotherapy 1 Convulsion ProbableOlmesartan and glibenclamide

combination0

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y O

ndok

uz M

ayis

Uni

v. o

n 05

/05/

14Fo

r pe

rson

al u

se o

nly.

640 M. Huber et al.

metabolized in the liver and which involves the CYP2C9 enzyme (17). Indeed, it has beenshown that decreased activity of CYP2C9 due to genetic polymorphisms can lead to con-siderable reductions in hepatic clearance of the sulfonylurea tolbutamide and the ARBlosartan (18,19). In addition, other factors such as body weight, plasma protein binding,sex, age, food intake, and overall liver function may contribute to the large interindividualvariations in glibenclamide pharmacokinetics that make it difficult to predict the optimalindividual dose (17,20,21). In this regard, an important result of this trial shows bioequiv-alence for AUCss,τ and Css,max for glibenclamide in combination therapy with olmesartan.If this result can be validated in diabetic and hypertensive patients, a significant interac-tion of both drugs during combination therapy can be ruled out. As a consequence, thedosage can be adjusted to blood pressure and blood glucose without the risk of interfer-ence, thus making the combination therapy practicable.

Nevertheless, a minor difference in pharmacokinetics was detected in this study bythe shift of the median tmax for glibenclamide to an earlier time point during co-administrationwith olmesartan medoxomil than during monotherapy (1.00 vs. 2.00 h). Statisticalanalysis revealed no bioequivalence for this parameter. Although this difference reachedstatistical significance, a visual inspection of Figure 2 reveals only a minor differencebetween AUC curves for glibenclamide monotherapy and combination therapy witholmesartan. An underlying mechanism could be that the absorption of glibenclamide hasbeen enhanced by olmesartan via the inhibition of intestinal drug efflux transporters. Thiseffect, already well described for other combination therapies, might be more pronouncedin patients who receive many other drugs (22). Thus, it appears questionable whether thiscould be of clinical importance during the treatment of patients with diabetes. One poten-tial benefit of this shift to an earlier concentration maximum in combined therapy could bea reduction of post-prandial glucose peak levels in patients, which has been recentlyshown to be of prognostic relevance for the reduction of both macrovascular andmicrovascular complications in diabetic patients (23–25).

Another important result of this trial showed that the combined treatment of olme-sartan medoxomil with glibenclamide was well tolerated and safe. All adverse eventsreported in this study were associated with glibenclamide or olmesartan monotherapy andnot with the combination.

This phase I trial has been done in healthy volunteers, and its results must now bevalidated in diabetic and hypertensive patients. This is of importance because for suffi-cient control of hypertension or diabetes, multidrug regimens are often recommended(3,26); thus, in clinical practice, it is not unusual that more than three medications arerequired alone for the treatment of diabetes. This can result in a condition known as polyp-harmacy, with the consequence of a higher risk of drug interactions compared to a phase Itrial with healthy volunteers (27,28). There is considerable overlap in the occurrence ofhypertension and diabetes, and the prevalence of both conditions increases with age,making drug interactions between treatments for these conditions a significant concern.Moreover, globally, the proportion of older people in the population is increasing in manycountries, making it likely that the need for concurrent treatment of these conditions willincrease. Current treatment guidelines recommend that hypertensive patients with diabetesshould be managed with an anti-hypertensive agent and an appropriate anti-diabetic (3).For patients with diabetes, using an ARB may be a favorable treatment option, particularlyin patients with microalbuminuria and more advanced diabetic nephropathy, due to therenoprotective benefits of these agents (29). Nevertheless, for these patients, control ofrenal function is necessary to detect renal impairment under AT1-antagonism, whichwould lead if coadministered with glibenclamide to hypoglycemic conditions. There is a

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y O

ndok

uz M

ayis

Uni

v. o

n 05

/05/

14Fo

r pe

rson

al u

se o

nly.

Olmesartan Medoxomil Combined with Glibenclamide 641

strong association between type-2 diabetes and progressive kidney disease, with up to30% of newly diagnosed type-2 diabetes patients showing elevated levels of protein intheir urine (30). ARBs have been shown to slow the development of renal disease in type-2 diabetes (31–33). As a consequence, international guidelines recommend these agentsfor the treatment of hypertensive patients with type-2 diabetes (34).

Conclusions

In this phase I study with healthy volunteers, the pharmacokinetic profiles of olmesartanand glibenclamide remain bioequivalent when they are combined except for a slight shiftin the tmax of glibenclamide toward an earlier time point in combination therapy. Thesefindings provide the pharmacokinetic rationale for clinical studies to test the combinedtreatment with both drugs in the increasing population of patients who suffer from hyper-tension and type-2 diabetes mellitus.

Acknowledgements

This study was supported by Sankyo Pharma GmbH. The experiments described in thisreport complied with the relevant laws of Germany, including ethics approval.

References

1. Sicree R, Shaw J, Zimmet P. The global burden of diabetes. Diabetes Atlas, InternationalDiabetes Federation, 2nd ed. 2003,15–111.

2. World Health Organization. The World Health Report. Geneva, Switzerland: World HealthOrganization, 2004.

3. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW,Materson BJ, Oparil S, Wright JT Jr, Roccella EJ; the National Heart, Lung, and Blood InstituteJoint National Committee on Prevention, Detection, Evaluation, and Treatment of High BloodPressure; National High Blood Pressure Education Program Coordinating Committee. Theseventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treat-ment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560–2572.

4. Brunner HR. Clinical efficacy and tolerability of olmesartan. Clin Ther 2004;26(Suppl. A):A28–A32.

5. Oparil S, Williams D, Chrysant SG, Marbury TC, Neutel J. Comparative efficacy of olmesartan,losartan, valsartan, and irbesartan in the control of essential hypertension. J Clin Hypertens2001;3:283–291, 318.

6. Unger T, McInnes GT, Neutel JM, Bohm M. The role of olmesartan medoxomil in the manage-ment of hypertension. Drugs 2004;64:2731–2739.

7. Warner GT, Jarvis B. Olmesartan medoxomil. Drugs 2002;62:1345–1353; discussion,1354–1356.

8. Ball KJ, Williams PA, Stumpe KO. Relative efficacy of an angiotensin II antagonist comparedwith other antihypertensive agents. Olmesartan medoxomil versus antihypertensives. J Hyper-tens 2001;19(Suppl. 1):S49–S56.

9. Brunner HR, Laeis P. Clinical efficacy of olmesartan medoxomil. J Hypertens 2003;21(Suppl. 2):S43–S46.

10. Brunner HR, Stumpe KO, Januszewicz A. Antihypertensive efficacy of olmesartan medoxomiland candesartan cilexetil assessed by 24-hour ambulatory blood pressure monitoring in patientswith essential hypertension. Clin Drug Invest 2003;23:419–430.

11. Chilman-Blair K, Rabasseda X. Olmesartan, an AT1-selective antihypertensive agent. DrugsToday (Barc) 2003;39(10):745–761.

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y O

ndok

uz M

ayis

Uni

v. o

n 05

/05/

14Fo

r pe

rson

al u

se o

nly.

642 M. Huber et al.

12. Laeis P, Puchler K, Kirch W. The pharmacokinetic and metabolic profile of olmesartanmedoxomil limits the risk of clinically relevant drug interaction. J Hypertens 2001;19(Suppl. 1):S21–S32.

13. Smyth S, Heron A. Diabetes and obesity: the twin epidemics. Nature Medicine 2005;12:75–80.14. Luzi L, Pozza G. Glibenclamide: an old drug with a novel mechanism of action? Acta Diabetol

1997;34:239–244.15. Rendell, M. The role of sulphonylureas in the management of type 2 diabetes mellitus. Drugs

2004;64:1339–1358.16. Yoshida K, Kohzuki M. Clinical and experimental aspects of olmesartan medoxomil, a new

angiotensin II receptor antagonist. Cardiovasc Drug Rev 2004;22:285–308.17. Kirchheiner J, Brockmoller J, Meineke I, Bauer S, Rohde W, Meisel C, Roots I. Impact of

CYP2C9 amino acid polymorphisms on glyburide kinetics and on the insulin and glucoseresponse in healthy volunteers. Clin Pharmacol Ther 2002; 71:286–296.

18. McCrea JB, Cribb A, Rushmore T, Osborne B, Gillen L, Lo MW, Waldman S, Bjornsson T,Spielberg S, Goldberg MR. Phenotypic and genotypic investigations of a healthy volunteerdeficient in the conversion of losartan to its active metabolite E-3174. Clin Pharmacol Ther1999;65:348–352.

19. Sullivan-Klose TH, Ghanayem BI, Bell DA, Zhang ZY, Kaminsky LS, Shenfield GM, MinersJO, Birkett DJ, Goldstein JA. The role of the CYP2C9-Leu359 allelic variant in the tolbutamidepolymorphism. Pharmacogenetics 1996;6:341–349.

20. Matsuda A, Kuzuya T, Sugita Y, Kawashima K. Plasma levels of glibenclamide in diabeticpatients during its routine clinical administration determined by a specific radioimmunoassay.Horm Metab Res 1983;15:425–428.

21. Sartor G, Melander A, Schersten B, Wahlin-Boll E. Serum glibenclamide in diabeticpatients, and influence of food on the kinetics and effects of glibenclamide. Diabetologia1980;18:17–22.

22. Tanigawara Y. Role of P-glycoprotein in drug disposition. Ther Drug Monit2000;22:137–140.

23. Bonora E, Muggeo M. Postprandial blood glucose as a risk factor for cardiovascular disease inType II diabetes: the epidemiological evidence. Diabetologia 2001;44:2107–2114.

24. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M; STOP-NIDDM TrialResearch Group. Acarbose treatment and the risk of cardiovascular disease and hyperten-sion in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA2003;290:486–494.

25. Shiraiwa T, Kaneto H, Miyatsuka T, Kato K, Yamamoto K, Kawashima A, Kanda T, Suzuki M,Imano E, Matsuhisa M, Hori M, Yamasaki Y. Postprandial hyperglycemia is a better predictorof the progression of diabetic retinopathy than HbA1c in Japanese type 2 diabetic patients.Diabetes Care 2005; 28:2806–2807.

26. American Diabetes Association. Standards of Medical Care in Diabetes—2006. Diabetes Care2006;29(Suppl. 1):S4–S42.

27. Grant RW, Devita NG, Singer DE, Meigs JB. Polypharmacy and medication adherence inpatients with type 2 diabetes. Diabetes Care 2003;26(5):1408–1412.

28. Grant RW, Cagliero E, Murphy-Sheehy P, Singer DE, Nathan DM, Meigs JB. Comparison ofhyperglycemia, hypertension, and hypercholesterolemia management in patients with type 2diabetes. Am J Med 2002;112:603–609.

29. Schmieder RE. Optimizing therapeutic strategies to achieve renal and cardiovascular risk reductionin diabetic patients with angiotensin receptor blockers. J Hypertens 2005;23:905–911.

30. Tobe SW, McFarlane PA, Naimark DM. Microalbuminuria in diabetes mellitus. CMAJ2002;167:499–503.

31. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G,Snapinn SM, Zhang Z, Shahinfar S, plus the RENAAL Study Investigators. Effects of losartanon renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N EnglJ Med 2001;345:861–869.

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y O

ndok

uz M

ayis

Uni

v. o

n 05

/05/

14Fo

r pe

rson

al u

se o

nly.

Olmesartan Medoxomil Combined with Glibenclamide 643

32. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R,Raz I, Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbe-sartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851–860.

33. Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P, Irbesartan inPatients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan onthe development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med2001;345:870–878.

34. Guidelines Committee. 2003 European Society of Hypertension-European Society ofCardiology guidelines for the management of arterial hypertension. J Hypertens 2003;21:1011–1053.

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y O

ndok

uz M

ayis

Uni

v. o

n 05

/05/

14Fo

r pe

rson

al u

se o

nly.

Clin

Exp

Hyp

erte

ns D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y O

ndok

uz M

ayis

Uni

v. o

n 05

/05/

14Fo

r pe

rson

al u

se o

nly.