医薬品相互作用研究

Vol.41, No. 1（2017）35（35）

医薬品相互作用研究
一
般論
文
41（1） 35-42 （2017）

Relationship between drug dosage and antihypertensive eﬀect
in clinical trials.
Kazushi OSADA*1,2）, Eriko KOBAYASHI1）, and Nobunori SATOH1）
1）

Department of Social Pharmacy, Graduate School of Pharmaceutical Sciences, Chiba University
2）
Division of Clinical Pharmacy, Nagano Matsushiro General Hospital（Received June 28, 2016 ; Revised October 13, 2016 ; Accepted November 14, 2016）

It is important to determine the dose adjustment of alternative drugs that patients have taken before
hospitalization, therefore the aim of this study was to derive regression equations between drug dosage andpharmacological effect based on clinical trial data in angiotensin II receptor antagonists (ARB). We investigated thecharacteristics of 3 ARB: candesartan (CND), valsartan (VAL), and azilsartan (AZL). Using data on the daily dose of
ARB and the mean blood pressure (BP) before and after ARB administration, we applied Emax model and derived a
regression equation between the daily dose and the predicted BP in each ARB. For CND, VAL and AZL, regression
equations between drug dosage and predicted BP reduction were derived in systolic BP and diastolic BP. Predicted
BP reduction was nearly equivalent between CND 2 mg/day and VAL 20 mg/day, between CND 4 mg/day and VAL
40 mg/day, between CND 4 mg/day and VAL 80 mg/day, between CND 8 mg/day and VAL 160 mg/day, and between
CND 12 mg/day and AZL 10 mg/day. These regression equations enable comparison of how BP reduction occurs
with these drugs; it is useful for choosing alternative drugs and their appropriate dosage when switching from thedrugs the patients have been taken before hospitalization.
Key Words: Medication reconciliation, Alternative drug, Angiotensin II receptor antagonist, Regression equation,
Emax model

Introduction

drugs, physicians often prescribe alternative drugs

Medication reconciliation by a pharmacist makes it

proposed by pharmacists without modification 4）. In

possible to confirm and assess more precisely notsome case reports, the patientʼs values of blood

only the drug name that patients have taken before

pressure and pulse were varied after thehospitalization but also content specification,

antihypertensive drug was switched from the one thedirections for use and dosage1,2）. This is an importantpatient had taken before hospitalization to anrole for the hospital pharmacist, in addition toalternat ive drug 4 ）. Therefore, it is crit ical that

dispensation and patient compliance instruction.

pharmacists choose alternative drugs that have

Moreover, when the drug that the patient was taking

clinical effects equivalent to the drugs that the

before hospitalization is not adopted in the hospital,patient was taking before hospitalization in order topharmacists are expected to propose an alternative

maintain the proper drug therapy.

drug and appropriate dosage as part of the proposal

Angiotensin II receptor antagonists (ARBs) arefor administration planning. This proposal

first-line drugs for antihypertensive therapy in the3）contributes to the continuation of drug therapy .

guidelines for the management of hypertension

When the drugs that patients have taken before

published by the Japanese society of hypertension in

hospitalization need to be switched to alternative2014 (JSH 2014)5）. To date, seven ARBs are clinicallyDepartment of Social Pharmacy, Graduate School of Pharmaceutical Sciences, Chiba University 1-8-1 Inohana, Chuo-ku, Chiba City,
Chiba 260-0856, Japan.
2）
Division of Clinical Pharmacy, Nagano Matsushiro General Hospital 183 Matsushiro, Matsushiro-machi, Nagano City, Nagano 381-1231,
Japan.
*連絡著者：Kazushi Osada（E-mail: kazosa.pc@gmail.com）1）

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Vol.41, No. 1（2017）

available in Japan. Ant ihypertensive drugs are

Methods

compared among the categories, such as ARBs andWe investigated the characteristics of 3 ARB: CND,

Ca blockers, in JSH 2014. Comparison of the

VAL, and azilsartan (AZL), that we could derive

antihypertensive effects among ARBs have not been

regression equation between the daily dose anddescribed in detail. However, the pharmacologicalantihypertensive effect using literature of clinicaleffects, w ith the except ion of ant ihypertensive

trials from the references of the interview forms andeffects, have been described, such as the uricosuric

STEDs. Clinical trials of ARB monotherapy on mild toaction of losartan (LOS) 6） and, the insulin-sensitizing

moderate essential hypertension Japanese patientsand lipid metabolism-improving effect via thewere included. Selection criteria of study design wereactivating action of peroxisome proliferator-activated

a fixed-dose study and a forced titration study with areceptor (PPARγ) of telmisartan ( TLM) and

fixed dose for more than 4 weeks. We gathered7）

irbesartan (IRB) . Little information is available inliterature of clinical trials from the references of the

JSH2014 on the antihypertensive effects to base ainterview forms of ARBs and on combination drugs

decision of an alternative antihypertensive drug withcomposed of ARB and other antihypertensive drug. In

an equivalent clinical effect to that of the drug thethe case of these combinat ion drugs, since thepatient had taken before hospitalization.

clinical trials were carried out in ARB monotherapy

Some reports are available that comparegroup and combination therapy group, we used dataa n t i h y p e r t e n s i ve e f f e c t s a m o n g A R B s . LO S 5 0

of ARB monotherapy group. For literature not listed

mg/day was reported to be equivalent to valsartan

as references in interview forms, we collected STEDs

8）(VAL) 80 mg/day . However, it is reported that there

from the website of pharmaceuticals and medical

are differences in the antihypertensive effects amongdevices agency in Japan 17）. We excluded the clinical

ARBs at approved moderate doses or high doses intrials in which participants were non-responders of

Japan

9-16）

. Therefore, the dose of an alternative

hypertensive drug should be adjusted based on theprevious antihypertensive therapy, or had renal or
hepatic impairment.

power of the antihypertensive effect. Since theseIn an international conference on thereports were mainly carried out in foreign countries,

harmonisation of technical requirements forthere are few reports which compare the clinicalregistration of pharmaceuticals for human use (ICH)

effects of ARBs at low dose, such as LOS 25 mg/day,harmonized tripart ite guideline: dose-response

candesartan (CND) 4 mg/day and VAL 40 mg/day;information to support drug registration (ICH-E4) 18）,

these are the doses which are approved in Japan.

it was indicated that titration studies cannot

In combination tablets of CND anddistinguish the response to an increased dose fromhydrochlorothiazide (HCTZ), CND and amlodipine

the response to increased time on drug therapy or a

(AML) and TLM and HCTZ, the polynomial

cumulative drug dosage effect. It was also indicatedexpressions of response surface model have been

in ICH-E4, however, if most patients completed all

described as a clinical response model for predicting

doses, and if the study was controlled with a parallel

the antihypertensive effect in their summary

placebo-group, the forced titration study allowed atechnical documentation (STED). However, it is notseries of comparisons of an entire randomized group

possible to use these model formulae to predict theg i ve n s e ve r a l d o s e s o f d r u g w i t h a c o n c u r r e n t

antihypertensive effects of ARBs expect for CND andplacebo, just as the parallel fixed dose trial did. Since

TLM, since these model formulae were described

it is rare for hypertension to be improved

only in CND and TLM.

spontaneously, prolonged administrat ion of

Currently, there is no criteria for the selection andantihypertensive drug could not increase thedose adjustment of alternative ARBs based on theantihypertensive effect after steady state. Therefore,

comparison of antihypertensive effects among ARBs.

if there is a sufficient fixed-dose period in which the

The aim of this study was to derive reg ression

antihypertensive effect of ARB reaches the steadyequations between drug dosage and antihypertensive

state, the antihypertensive effect could be estimatedeffect based on clinical trials data of ARBs.

by a forced titration study. The antihypertensive
effect of ARB nearly reached the steady state in 4

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37（37）

weeks 15,19）. Therefore, both fixed-dose studies and

PreBP, and SBP and DBP of ΔBPo. The literature

forced titration studies (fixed dose for more than 4from which data were extracted were all in-house

weeks) are included in this research.

documents of the pharmaceutical companies orData was extracted on the subject drug,

STED. Four trials are available on CND, 5 on VAL andinformation sources, daily dose of the drug, the3 on AZL. Mean SBP of PreBP was 148.5 to 159.6

number of participants, mean blood pressure (BP)mmHg in CND, 150.5 to 162.7 mmHg in VAL andbefore ARB administration (PreBP), and mean

158.5 to 160.2 mmHg in AZL. Mean DBP of PreBP

observed BP reduction after 8 weeks of ARB

was 99.6 to 101.0 mmHg in CND, 99.3 to 102.5

administration (ΔBPo). The observed BP reduction

mmHg in VAL and 100.2 to 101.5 mmHg in AZL.

after 8 weeks of ARB administration was used for

Mean of ΔBPo in CND 4mg/day was 8.1 mmHg inassessment of BP reduction because the

DBP, and no data was obtained in SBP. Mean of ΔBPoantihypertensive effect was mainly evaluated after 8in CND 8mg/day was 14.8 to 17.3 mmHg in SBP andweeks of medication.

7 . 7 t o 1 2 . 2 m m H g i n D B P, a n d t h a t i n C N D 1 2
20）,

mg/day was 17.5 to 19.9 mmHg in SBP and 9.8 tofollow ing equat ion 1, and derived a reg ression

12.1 mmHg in DBP. Mean of ΔBPo by VAL was 7.6

equation between the daily dose and the predicted

to 13.9 mmHg for SBP and 6.5 to 9.3 mmHg for DBP

BP reduct ion (ΔBPp) for systolic BP (SBP) andin 40 mg/day, and 9.4 to 17.1 mmHg for SBP and 6.0

diastolic BP (DBP), based on daily dose and ΔBPo of

to 9.7 mmHg for DBP in 80 mg/day. Mean of ΔBPoeach clinical trial. When ΔBPo was not clearly

by AZL was 18.0 mmHg for SBP and 12.4 mmHg fordescribed, ΔBPo was calculated by PreBP minus BP

DBP in 5 mg/day, 18.1 mmHg for SBP and 10.7

at 8 weeks after of ARB administration. Since themmHg for DBP in 10 mg/day, 19.9 to 21.5 mmHg for

Emax model has two coefficients (Emax and ED50),

SBP and 11.0 to 13.9 mmHg for DBP in 20 mg/day,three or more points of data of daily dose and ΔBPo

21.8 to 22.5 mmHg for SBP and 12.4 to 13.7 mmHg

are required to derive a regression equation. The

for DBP in 40 mg/day, and 22.5 mmHg for SBP anddrugs with less than three points of data of daily

13.9 mmHg for DBP in 80 mg/day. The number ofd o s e a n d Δ B Po w e r e e x c l u d e d . We c a l c u l a t e dpoints of data of daily dose and ΔBPo to derive theprediction error (PE) and absolute prediction error

regression equation were 4 (daily dose range: 8(APE) to validate predictability of a reg ression

mg/day to 12 mg/day) for SBP and 6 (daily dose

equation, following equations 2 and 3. Furthermore,range: 4 mg/day to 12 mg/day) for DBP in CND.

we calculated ΔBPp at the approved dose for each

These data for VAL were 9 (daily dose range: 40

ARB in Japan based on the following regression

mg/day to 80 mg/day) for SBP and 9 (daily dose

equations:range: 40 mg/day to 80 mg/day) for DBP; the data

For each drug, we applied an Emax mo delΔBPp = D ×Emax / (D + ED50) … Equation 1

for AZL were 8 (daily dose range: 5 mg/day to 80

PE = ΔBPp ‒ ΔBPo ………………… Equation 2

mg/day) for SBP and 8 (daily dose range: 5 mg/day

APE = |ΔBPp ‒ ΔBPo| …………… Equation 3

to 80 mg/day) for DBP.

ΔBPp: Predicted BP reduction (mmHg), ΔBPo:
Observed BP reduction (mmHg), D: Daily dose (mg),

The values of Emax and ED50 of regression

Emax: Maximum drug effect (mmHg), ED50: Median

equation between daily dose and ΔBPp in CND, VAL

effective daily dose (mg/day).

and AZL are shown in Table 2. The largest Emax in

Statistical analyses were performed by R version
21）

22）

SBP, 27.920 mmHg was obtained for CND, followed. We derived the Emax model

by AZL of 22.681 mmHg and VAL of 16.625 mmHg.

regression equation between the daily dose and Δ

In DBP, Emax for CND and AZL were almost theBPp by using nonlinear least squares regression.

same, 13.186 mmHg and 13.142 mmHg,

3.0.2

and EZR

respectively. Emax for VAL was the smallest among

Results
For CND, VAL and AZL, table 1 summarizes thename of the drug, information sources, trial name,daily dose, number of participants, SBP and DBP of

the 3 drugs, 8.105 mmHg.

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Vol.41, No. 1（2017）

Table 1. Characteristics of clinical trials of angiotensin II antagonist monotherapy in mild to moderate Japanese essential
hypertension patients.

PreBP: Blood pressure before angiotensin II antagonist administration, BPo: Observed blood pressure reduction at the time of after 8 weeks angiotensin II
antagonist administration, N: Number of participants, SBP: Systolic blood pressure, DBP: Diastolic blood pressure, CND: Candesartan, VAL: Valsartan, AZL:
Azilsartan, HCTZ: Hydrochlorothiazide, AML: Amlodipine, CLN: Cilnidipine, TCTZ: Trichlormethiazide, STED: Summary technical documentation, IHD:
In-house document of the pharmaceutical companies, ND: No data, *1: Mean (95% confidence interval). *2: Calculated by standard error times the square rootof number of participants.

Table 2. Estimated the values of Emax and ED50 on regression equationof Emax model.

Emax: Maximum drug effect, ED50: Median effective daily dose

Based on these values of Emax and ED50 for CND,

ΔSBPp: Predicted SBP reduction (mmHg), ΔDBPp:

VAL and AZL, regression equations between drug

Predicted DBP reduction (mmHg), D: Daily dose (mg)dosage and ΔBPp were derived in SBP and DBP,

The relationships between the daily dose and Δ

following equations 4 to 9. Predicted SBP reduction

SBP or ΔDBP in CND, VAL and AZL are shown in

w a s d e s c r i b e d a s “ Δ S B P p”, a n d p r e d i c t e d D B P

Figs. 1, 2 and 3, respectively. PE (mean ± SD) of

reduction was described as “ΔDBPp”.

regression equations in SBP and DBP were 0.001 ±CND

1.415 mmHg and −0.006 ± 1.658 mmHg in CND,

ΔSBPp = D × 27.920 / (D + 5.916) … Equation 40.000 ± 3.017 mmHg and 0.000 ± 1.393 mmHg in

ΔDBPp = D × 13.186 / (D + 2.717) … Equation 5

VAL, and −0.003 ± 0.825 mmHg and −0.001 ±VAL

1.149 mmHg in AZL, respectively. On the other hand,

ΔSBPp = D × 16.625 / (D + 21.688) … Equation 6

APE (mean ± SD) of regression equations in SBP and

ΔDBPp = D × 8.105 / (D + 1.166) … Equation 7

DBP were 1.225 ± 0.029 mmHg and 1.318 ± 0.813

AZL

mmHg in CND, 2.593 ± 1.242 mmHg and 1.219 ±ΔSBPp = D × 22.681 / (D + 1.637) … Equation 80.519 mmHg in VAL, and 0.617 ± 0.496 mmHg and

ΔDBPp = D × 13.142 / (D + 0.730) … Equation 90.955 ± 0.527 mmHg in AZL, respectively.

医薬品相互作用研究

Vol.41, No. 1（2017）

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Candesartan
Systolic blood pressure (N=4)

25
20

15
10
PE (mean SD): 0.001 1.415
APE (mean SD): 1.225 0.029

5

Diastolic blood pressure (N=6)

20
Blood pressure reduction(mmHg)

Blood pressure reduction(mmHg)

30

0

15
10
5

PE (mean SD): -0.006 1.658
APE (mean SD): 1.318 0.813

0
0

5
10
15
Daily dose (mg/day)

0

20

5
10
15
Daily dose (mg/day)20

Fig 1. Emax model regression line of relationship between daily dose and blood pressure reduction in candesartan.
PE: Prediction error, APE: Absolute prediction error. Solid circles represent observed reduction of blood pressure. Curved lines represent predicted
reduction of blood pressure.

Valsartan
Systolic blood pressure (N=9)

25
20

15
10
PE (mean SD): 0.000 3.017
APE (mean SD): 2.593 1.242

5

Diastolic blood pressure (N=9)

20
Blood pressure reduction(mmHg)

Blood pressure reduction(mmHg)

30

0

15
10
5

PE (mean SD): 0.000 1.393
APE (mean SD): 1.219 0.519

0
0

50
100
150
Daily dose (mg/day)

0

200

50
100
150
Daily dose (mg/day)200

Fig 2. Emax model regression line of relationship between daily dose and blood pressure reduction in valsartan.
PE: Prediction error, APE: Absolute prediction error. Solid circles represent observed reduction of blood pressure. Curved lines represent predicted
reduction of blood pressure.

Azilsartan
Systolic blood pressure (N=8)

25
20

15
10
PE (mean SD): -0.003 0.825
APE (mean SD): 0.617 0.496

50Diastolic blood pressure (N=8)

20
Blood pressure reduction(mmHg)

Blood pressure reduction(mmHg)

30

15
10
5

PE (mean SD): -0.001 1.149
APE (mean SD): 0.955 0.527

0
0

20

40
60
80
Daily dose (mg/day)

100

0

20

40
60
80
Daily dose (mg/day)100

Fig 3. Emax model regression line of relationship between daily dose and blood pressure reduction in azilsartan.
PE: Prediction error, APE: Absolute prediction error. Solid circles represent observed reduction of blood pressure. Curved lines represent predicted
reduction of blood pressure.

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Vol.41, No. 1（2017）

Based on the derived regression equations, ΔSBPp

following: CND 2 mg/day and VAL 20 mg/day, CND 4

and ΔDBPp according to the approved daily dose in

mg/day and VAL 40 mg/day, CND 4 mg/day and VAL

J a p a n a r e s h o w n i n Ta b l e 3 . T h e p r e d i c t e d B P

80 mg/day, CND 8 mg/day and VAL 160 mg/day,

reduction was almost equivalent between theand CND 12 mg/day and AZL 10 mg/day.

Table 3. Daily dose and predicted blood pressure reduction by Emax
model regression in candesartan, valsartan and azilsartan.

BP: Blood pressure, ΔSBPp: predicted systolic blood pressure reduction,
ΔDBPp: Predicted diastolic blood pressure reduction

Discussion
We derived regression equations based on Emax

m g / d a y. A Z L 1 0 m g / d a y c o u l d b e u s e d a s a nalternative to CND 12 mg/day.

model between daily dose and BP reduction using

When switching from VAL, we could switch fromclinical trials data of 3 ARB (CND, VAL and AZL)VAL 20 mg/day to CND 2 mg/day or 4 mg/day, or

monotherapy in Japanese mild to moderate essentialfrom VAL 40 mg/day or VAL 80 mg/day to CND 4

h y p e r t e n s i o n p a t i e n t s . We d e r i ve d r e g r e s s i o n

mg/day or from VAL 160 mg/day to CND 4 mg/day

equations between daily dose and BP reduction foror CND 8 mg/day for successive BP control.

CND, VAL and AZL. Then, we showed values of ΔBPp

When switching from AZL, AZL 10 mg/day could

were estimated in these 3 ARB by the approved daily

be switched to CND 12 mg/day. The previous study23）

dose in Japan. These regression equations enable

has shown that the differences of BP reduction

comparison of the mechanism by which BP reduction

between AZL 40 mg/day and CND 12 mg/day are 4.4

occurs for the drugs, and they are useful for

mmHg (95% confidence interval (CI): 2.20 to 6.53

choosing alternative drugs and the appropriatemmHg) in SBP and 2.6 mmHg (95% CI: 1.22 to 4.08

dosage when switching from the drugs the patientsmmHg) in DBP, and suggested BP reduction by AZL

h a ve b e e n t a k e n b e f o r e h o s p i t a l i z a t i o n . W h e n

40 mg/day was larger than that by CND 12 mg/day.

switching from CND, successive BP control willIn this study, ΔSBPp and ΔDBPp in AZL 40 mg/day

become possible with equivalent BP reduction by

were estimated to be 21.79 mmHg and 12.71 mmHg,

switching from CND 2 mg/day to VAL 20 mg/day, or

respectively. Since the differences of BP reduction

from CND 4 mg/day to VAL 40 mg/day or CND 8

between AZL 40 mg/day and CND 12mg/day were

mg/day to VAL 160 mg/day. On the other hand, Δalso estimated to be 3.09 mmHg for ΔSBPp and 1.96

SBPp and ΔDBPp in CND 12 mg/day were estimated

mmHg for ΔDBPp in this study, these differences

to be 18.70 mmHg and 10.75 mmHg, respectively.

were consistent with the difference of BP reduction

Because these estimated values of BP reduction were

between AZL 40 mg/day and CND 12 mg/day in thelarger than the estimated Emax of VAL (16.625

previous study. Furthermore, the difference of BP

mmHg in SBP and 8.105 mmHg in DBP), it would be

reduction between AZL 20 mg/day and CND 12

d i f f i c u l t f o r VA L t o b e s u b s t i t u t e d f o r C N D 1 2

mg/day were estimated to be 2.26 mmHg for Δ

医薬品相互作用研究

SBPp. When AZL 20mg/day or AZL 40mg/day was

Vol.41, No. 1（2017）41（41）

50, 865-870, 2014.

switched to CND 12mg/day, patients value of BP

３）Tsuduki Y, Fujii Y, Matsumoto N, Takeuchi T,

might increase due to the weakened antihypertensive

Iwatsuki R, Miyai A, Honda T, Takemura K,

effect. It would be difficult for CND 12 mg/day to be

Furukawa T, Nakamura K, Wada H, Okamura N:

substituted for AZL 20mg/day or AZL 40 mg/day.

Examination of Importance and Problems ofPrevious in vitro study indicated that AZL had a

Medication History Management in Emergency

higher affinity to angiotensin II receptor type 1 andHospitalization as Compared to Scheduled

it bound this receptor more tightly than VAL 2 4 ）.

Hospitalization., Jpn. J. Pharm. Health Care Sci.

Clinical BP reduction by VAL might be weaker than37, 41-47, 2011.

that by AZL, and it would be difficult to use VAL as４）Murakami M, Hoshino T, Tayama R, Shiotsu K,

an alternative drug for AZL, because estimated theMizuno Y: Prescription status of alternativevalues of Emax in VAL, 16.225 mmHg in SBP andagents and change in blood pressure and pulse

8.105 mmHg in DBP, were smaller than ΔSBPp

rate by the use of alternative antihypertensive(19.49 mmHg) and ΔDBPp (12.25 mmHg) in AZLagents., J. Jpn. Soc. Hosp. Pharm. 48,

10mg/day in this study.

1455-1459, 2012.

It was reported that PreBP was correlated with BP５）The Japanese Society of Hypertension: The

reduction after antihypertensive drug administration

Japanese Society of Hypertension Guidelines forwhen the range of PreBP was approximately 100

the Management of Hypertension (JSH 2014).

mmHg

25,26）. This correlation indicated that the greater

Chapter 5. Treatment with antihypertensive

BP reduction was observed by antihypertensive drug

drugs., Hypertension Res. 37, 291‒300, 2014.

when the patientʼs PreBP was higher. Although we６）Iwanaga T, Sato M, Maeda T, Ogihara T, Tamai I:

did not take into account PreBP in derived regression

Concentration-dependent mode of interaction ofequations, the range of PreBP in the trials that weangiotensin II receptor blockers with uric acidused to derive regression equations was narrow, 150

transporter., J. Pharmacol. Exp. Ther. 320,

to 160 mmHg for SBP and 99 to 100 mmHg for DBP,

211-217, 2007.

and means of APE were also small. This range of７）Schupp M, Clemenz M, Gineste R, Witt H, Janke J,

PreBP might little affect prediction ofHelleboid S, Hennuyer N, Ruiz P, Unger T, Staels

antihypertensive effect by regression equations.

B, Kintscher U: Molecular characterization of

We could derive regression equations only in CND,

new selective peroxisome proliferator-activated

VAL and AZL, though 7 ARB were available in Japan.

receptor gamma modulators with angiotensin

Further study is needed to explore the clinical data

receptor blocking activity., Diabetes, 54,

and regression equations for other drugs in order to3442-3452, 2005.

help choose appropriate alternative drugs.

８）Kimura T, Arai M, Masuda H, Iwaki M:
Pharmacist intervention for MUE(medication-use evaluation) in patients who have

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