Fimasartan cardiology

Recent Advances in the
Management of
Hypertension
1

Effect of renal function on the
pharmacokinetics of Fimasartan: a single-dose,
open-label, Phase I study
 Objective:
 To evaluate the effect of renal function on the PK of fimasartan in
patients with renal impairment and healthy volunteers
 Methods:
 A single centre, single-dose, open-label
 Healthy volunteer controlled trial was conducted in patients with
renal impairment (RI) (estimated glomerular filtration rate lower
than 30 mL/min/1.73 m2)
 Received a single oral dose of fimasartan 120 mg
3
 Drug Design, Development and Therapy 2014:8 1723–1731

Effect of renal function on the pharmacokinetics of
Fimasartan: a single-dose, open-label, Phase I study
4
Mean plasma fimasartan concentration-time profiles after a single
oral administration of fimasartan 120 mg to healthy volunteers (n=8,
solid circle) or renal impairment (RI) patients (n=8, open triangle)
The relative bioavailability
of fimasartan from the
population PK analysis
was 77% higher in the RI
patients than in the
healthy volunteers
The increased drug exposure of fimasartan in RI patients was
explained by the increased relative bioavailability
Drug Design, Development and Therapy 2014:8 1723–1731

Efficacy and tolerability of once-daily oral Fimasartan 20 to 240
mg/d in Korean patients with hypertension: Findings from two
phase II, randomized, double-blind, placebo-controlled studies
 Objectives:
 To determine its dose-response relationship and minimum effective dose,
and to characterize its blood pressure (BP)-reduction profile over the dosing
interval
 Methods:
 Two studies
 Phase II, randomized, double blind, placebo-controlled, parallel-group, and
dose-response
 Receive fimasartan 20, 60, 120, or 180 mg (study 1) or 20, 60, 120, or 240
mg (study 2) or placebo in the same ratio
5
Clin Ther. 2012 Jun;34(6):1273-89

-4.6
-3.3
-5.8-5.8
†
-9.4*
-9.7†
-11.5
*
-12*
-14.4*
-8.7*
-11.9* -14.1*
-8.9*
-12*
-12.7*
-16
-14
-12
-10
-8
-6
-4
-2
0
2 week 4 week 8 week
ΔDBP(mmHg) Dose response of fimasartan in office blood pressures
(DBP) (study 2)
Placebo 20mg 60mg 120mg 240mg
* p<0.005, † p<0.001, versus placebo
Clin Ther. 2012 Jun;34(6):1273-89

4.4
2.7
8.1
-14.7* -15.1‡
-13.5†
-14.1* -14.7‡
-12.2†
-19.6† -19.1* -20.2†
-25
-20
-15
-10
-5
0
5
10
24Hour Day time Night time
ChangefrombaselineBP(mmHg)
24-h ambulatory systolic blood pressure monitoring
(study 1)
Placebo 20mg 60mg 180mg
* p<0.005, † p<0.001, ‡p< 0.01 versus placebo
Once-daily oral administration of fimasartan was well tolerated and
efficacious in reducing BP in hypertensive patient populations
Clin Ther. 2012 Jun;34(6):1273-89

Efficacy and safety of 30-mg fimasartan for the
treatment of patients with mild to moderate
hypertension – phase III CT
 Objective:
 To compare the efficacy and safety of low-dose (30 mg) fimasartan and placebo
or valsartan (80 mg) for 8 weeks in patients with mild to moderate hypertension
 Methods:
 Randomised study
 N= 293 with mild to moderate hypertension
 30mg fimasartan (n = 115), placebo (n = 117), or 80-mg valsartan (n = 61) for 8
weeks
 Primary endpoint is improvement in SiDBP
 The secondary end point was the overall efficacy and safety of low-dose
fimasartan
8
 Clinical Therapeutics/Volume 36, Number 10, 2014

 Results:
 At week 8, SiDBP changed by:
–9.93 (8.86) mm Hg in the fimasartan group
–2.08 (9.47) mm Hg in the placebo group (P<0.0001)
 The fimasartan group exhibited more potent antihypertensive efficacy
than the valsartan group both at week 4
SiDBP, –9.96 [7.73] vs –6.53 [9.58] mm Hg [P=0.0123]
SiSBP, –16.18 [14.4] vs –7.65 [12.89] mm Hg [P=0.0002]
 Fimasartan Vs Valsartan at week 8
SiDBP, –9.93 [8.86] vs –5.47 [8.96] mm Hg [P=0.0021]
SiSBP, –15.35 [16.63] vs –7.49 [13.68] mm Hg [P=0.0021]
9
 Clinical Therapeutics/Volume 36, Number 10, 2014

10
The proportion of responders in the fimasartan,
placebo, and valsartan study groups at weeks 4
and 8
The rate of achievement of controlled BP in the
fimasartan, placebo, and valsartan study groups at
wks 4 and 8
Low-dose Fimasartan had an effective blood pressure–lowering effect that was
greater than that of 80-mg valsartan
Low-dose Fimasartan (30 mg) was well tolerated during the study period with
no significant TEAEs
Clinical Therapeutics/Volume 36, Number 10, 2014

Fimasartan for independent reduction of blood
pressure variability in mild-to-moderate hypertension
 Objective:
 To evaluate whether fimasartan treatment for 3 months affects clinical and home BP
variability in addition to reducing BP
 Methods:
 N= 1,396 (mean age 56.2±10.0 years; males 53.6%) with mild-to-moderate
hypertension
 Treatment:
 Fimasartan daily dose of 30–120 mg for 3 months
 Clinical and home BP measurements were performed before and after the 3-month
treatment
 BP variability included beat-to-beat variability (clinical) and day-to-day variability
(home)
11
Drug Design, Development and Therapy 2016:10 1573–1580

12
Changes in BPV and BP after fimasartan treatment
Changes in clinical BP and home (morning) BP after 3
months of fimasartan treatment

pressure variability in mild-to-moderate
hypertension
13
Correlation between standard deviation (sd) of clinical systolic blood pressure (SBP) and sd of morning
home SBP at baseline and after 3 months of fimasartan treatment
(A) sd of morning home SBP versus sd of clinical SBP at baseline
(B) sd of morning home SBP versus sd of clinical SBP after fimasartan treatment.
b_SBPsd, sd of baseline SBP; m3_SBPsd, sd of clinical SBP after 3 months of fimasartan treatment; b_am_hSBPsd, sd
of baseline morning home SBP; b_pm_hSBPsd, sd of baseline evening home SBP

pressure variability in mild-to-moderate
hypertension
14
Correlation between standard deviation (sd) of clinical systolic blood pressure (SBP) and sd of morning
home SBP at baseline and after 3 months of fimasartan treatment
(C) sd of evening home SBP versus sd of clinical SBP at baseline.
(D) sd of evening home SBP versus sd of clinical SBP after fimasartan treatment
b_SBPsd, sd of baseline SBP; m3_SBPsd, sd of clinical SBP after 3 months of fimasartan treatment; b_am_hSBPsd, sd
of baseline morning home SBP; b_pm_hSBPsd, sd of baseline evening home SBP

Results:
 Fimasartan reduced BP after 3 months of treatment
 The average reduction of:
Clinical systolic BP (c-SBP) was 15.08±18.36 mmHg (P<0.0001)
Morning home SBP (m-SBP) was 11.49±19.33 mmHg (P<0.0001)
15
This study indicated that 3 months of fimasartan treatment
reduced day-to-day BP variability independent of BP
reduction in patients with hypertension

Ambulatory Blood Pressure Response to Once-Daily Fimasartan: An 8-
Week, Multicenter, Randomized, Double- Blind, Active-Comparator,
Parallel-Group Study in Korean Patients With Mild To Moderate Essential
Hypertension
 Objective:
 To evaluate the 24-hour blood pressure (BP) profiles before and after 8-week
treatment with Fimasartan and to compare them with those of valsartan
 Methods:
 Multicenter, randomized, double-blind, active-controlled, parallel-group using
ABPM
 Treatment:
Once-daily oral fimasartan 60 or 120 mg or valsartan 80 mg
 Duration: 8 wks
 ABPM (Ambulatory Blood Pressure Monitoring) was performed before and after
8-week treatment, and clinic BP was also measured
 Based on ABPM data, trough-to-peak ratio and smoothness index derived
16
Clinical Therapeutics/Volume 35, Number 9, 2013

Hypertension
-14.4
-15.6
-11.7-11.7 -11.9
-11.3
-10.7
-11.7
-9.2
-18
-16
-14
-12
-10
-8
-6
-4
-2
0
24 h mean Day time (7am-10pm) Night time (10pm-7am)
Least-squaremeanreductionfrombaseline
(mmHg)
Systolic Blood Pressure
Fimasartan 60 mg Fimasartan 120mg Valsartan 80mg

Hypertension
-10.3
-10.7
-9.2
-7.1
-8.2
-5
-6.7
-7.5
-5.2
-12
-10
-8
-6
-4
-2
0
24 h mean Daytime (7am-10pm) Night time (10pm-7am)
Least-squaremeanreductionfrombaseline
(mmHg)
Diastolic blood pressure
Fimasartan 60mg Fimasartan 120mg Valsartan 80mg
18

Hypertension
19
Parameters Fimasartan Valsartan
60mg 120mg 80mg
T/P Ratio
SBP 0.51 0.71 0.44
DBP 0.74 0.81 0.51
Smoothness Index (SI)
SBP 1.52 0.99 0.99
DBP 1.38 0.82 0.82
Once-daily fimasartan effectively maintained a BP-reduction
profile over the full 24-hour dosing interval comparable to or
slightly better than that of once-daily valsartan

Safety and efficacy of fimasartan in
Mexican patients with grade 1-2 essential
hypertension
 Objective:
 To evaluate efficacy and safety of 60mg and 120mg Fimasartan (FMS) alone or
combined with 12.5mg hydrochlorothiazide (HCTZ) in a Mexican population
 Methods:
 Open study with grade 1-2 hypertension (N=272)
 Six month study
 60mg FMS once daily
 In week 8, DBP ≥90mmHg randomised to either 120mg FMS or 60mg FMS +
12.5mg HCTZ once daily
 In week 12, randomised subjects with DBP ≥90mmHg received 120mg
FMS+12.5mg HCTZ
20
Arch Cardiol Mex. 2017 Oct - Dec;87(4):316-325

Safety and efficacy of fimasartan in Mexican
patients with grade 1-2 essential hypertension
21
149.2
134.72 129.23
* 127.44 126.25 126.07 124.98
93.8
83.08 79.46
* 78.04 77.01 77.08 76.29
0
20
40
60
80
100
120
140
160
Baseline Week 4 Week 8 Week 12 Week 16 Week 20 Week 24
mmHg
Blood pressure lowering effect over time
SBP DBP * P<0.0001

22
0
52.57
64.71
75.74
82.35 81.62
87.13
0
10
20
30
40
50
60
70
80
90
100
Baseline Week 4 Week 8 Week 12 Week 16 Week 20 Week 24
%ofsubjectsachievingtreatmenttarget
(DBP<90mmHgandSBP<140mmHg) Proportion of subjects achieving treatment target
(DBP <90 mmHg and SBP <140 mmHg)

Results:
 Decreased both DBP and Systolic Blood Pressure (SBP) by
11.3±8.9 (p<.0001) and 16.0±14.1 (p<.0001)mmHg
23
Fimasartan is safe and effective in Mexican
subjects with grade 1-2 essential hypertension

Safety and Efficacy of Fimasartan in Patients
with Arterial Hypertension (Safe-KanArb
Study)
 Objective:
 To determine whether age, sex, concomitant disease, and current antihypertensive
medications affect the safety and efficacy of fimasartan in patients with arterial
hypertension
 Methods:
 Large-scale, open-label observational study
 Duration:
 Two months
 Treatment:
 Fimasartan (60 or 120 mg, once daily)
 Data were systematically collected using electronic case report forms
24
Am J Cardiovasc Drugs (2013) 13:47–56

Study)
25
-26.41
-20.98
-12.89
-13.9
-10.34 -11.35
-30
-25
-20
-15
-10
-5
0
Naїve Add-on Switch
MeanChangeinSBP/DBP(mmHg)
Changes in systolic (SBP) and diastolic (DBP) blood pressure
in all patients treated with 60 and 120 mg of fimasartan
SBP DBP

85
87.9
90.1
82
84
86
88
90
92
Naïve Add on Switch
Percentage Responder rate
26
75.6
74.5
79.7
70
72
74
76
78
80
82
Naïve Add on Switch
Percentage
Goal rate
The responder rate means DBP to
<90 mmHg or a reduction of ≥10
mmHg
The goal rate (combined
SBP/DBP < 140/90 mmHg)

Safety and Efficacy of Fimasartan in Patients with
Arterial Hypertension (Safe-KanArb Study)
27
Multiple regression analysis on blood pressure (BP) reductions, using
baseline BP, age, sex, and other co-morbidities
Δ indicates change, BMI body mass index, SE standard error
 Am J Cardiovasc Drugs (2013) 13:47–56

Patients Fimasartan
60 mg
Fimasartan
120 mg
P value
Men and women
Δ SBP, mmHg -18.16 ± 17.97 -20.10 ± 19.14 <.0001
Δ DBP, mmHg -9.57 ± 11.40 -10.17 ± 12.41 0.0103
Δ Pulse rate, beats/min -2.36 ± 7.62 -2.91 ± 8.47 0.0005
Men
Δ SBP, mmHg -18.23 ± 17.37 -19.93 ± 18.22 0.0003
Δ DBP, mmHg -10.00 ± 11.45 -10.17 ± 12.22 0.5796
Women
Δ SBP, mmHg -18.09 ± 18.53 -20.31 ± 20.23 <.0001
Δ DBP, mmHg -9.16 ± 11.32 -10.17 ± 12.65 0.0039
Dose-dependent changes in blood pressure before and after
treatment with fimasartan
Δ indicates change, DBP diastolic blood pressure, SBP systolic blood pressure, * p-value between 60 versus 120 mg
Am J Cardiovasc Drugs (2013) 13:47–56

Study)
1.55
0.52
0
0.5
1
1.5
2
Dizziness Hedache
Percentage
Adverse events
The most frequent adverse events
29
3.42
2.81 3.31
0
2
4
NaїveSwitch overAdd-on
Percentage Adverse events

Study)
30
67
27.5
3.8 1.7
69.2
26.2
3 1.7
68.1
26.9
3.4 1.7
0
10
20
30
40
50
60
70
80
Excellent (100%) Very good
(90~99%)
Good (80~89%) Poor (<80%)
Percentage
Overall global drug compliance
Men Women Men and women

Study)
Results:
 The pulse rate decreased from 74.4 ± 10.3 to 71.9 ± 9.2 beats/min in
comparison with before treatment (p<0.001)
 Administration of 120 mg of fimasartan decreased SBP and DBP were
significantly greater reductions than the 60-mg dose
31
The safety, efficacy, and compliance of fimasartan
were found to be excellent in a large patient
population that included patients potentially at
higher risk for adverse events

Safety and efficacy of Fimasartan with essential hypertension
patients in real world clinical practice: data from a post
marketing surveillance
 Objective:
 To provide an evaluation of the clinical utility of fimasartan in the treatment of patients with
hypertension from the results of post marketing surveillance
 Methods:
 Multi-center, prospective, open-label and non-interventional study.
 N= 3,945
 89 study centers from 9 September 2010 through 8 September 2016
 Results:
 SBP was decreased after administration of fimasartan to 131.3±16.2 mmHg at Week 8 from
the baseline mean value of 142.3±18.1 mmHg, and further decreased to 130 mmHg after
Week 8, and then maintained until the time of long-term prescription
 DBP was also decreased to 78.6±11.1 mmHg at Week 8 from the baseline mean value of
83.8±12.8 mmHg and kept at 80 mmHg or lower until the long-term use
32
Transl Clin Pharmacol 2018;26(3):118-127

Safety and efficacy of fimasartan with essential hypertension
patients in real world clinical practice: data from a post
marketing surveillance
33
87.1 88.9
11.8 10.4
5
15
25
35
45
55
65
75
85
95
Total patients (n= 3473) Patients with long term
follow up (n= 2842)
Percentage
The overall improvement-Efficacy assessment
Improved Unimproved Unassessible Unassessible
Transl Clin Pharmacol 2018;26(3):118-127

Safety and efficacy of fimasartan with essential hypertension
patients in real world clinical practice: data from a post marketing
surveillance
34
Safety assessment
Transl Clin Pharmacol 2018;26(3):118-127
Fimasartan was well tolerated, with no new safety concerns
identified and an effective treatment in the real world clinical
practice for Korean patients with hypertension
Total patients
(n=3,729)
Patients with long-term follow-up
(n=2,893)
Adverse events Adverse drug
reaction
Adverse events Adverse drug
reaction
Adverse Events
N (%)[events]
724 (19.42%)[1043] 142 (3.81%)[160] 540 (18.67%)[803] 67 (2.32%)[76]
Serious Adverse
Events
N (%)[events]
71 (1.90%)[82] 0 (0.00%)[0] 49 (1.69%)[58] 0 (0.00%)[0]
Unexpected
Adverse Events
N (%)[events]
490 (13.14%)[643] 35 (0.94%)[42] 392 (13.55%)[525] 21 (0.73%)[27]

Efficacy and Tolerability of Fimasartan, a New
Angiotensin Receptor Blocker, Compared With
Losartan (50/100 mg)
 Objective:
 To determine the noninferiority of fimasartan to losartan in mild-to-
moderate hypertension
 Methods:
 A randomized, multicenter, double-blind, parallel group, dose escalation,
Phase III, noninferiority clinical trial
 N=506 (aged 18 to 70 years with mild-to-moderate hypertension)
 Fimasartan 60/120 mg daily or Losartan 50/100 mg daily
 The primary end point:
Improvement in mean siDBP from baseline to week 12
In addition, a 24-week extension study for additional assessment of tolerability and
efficacy
35

36
Effects of fimasartan and losartan on
mean change in sitting diastolic blood
pressure (siDBP)
Effects of fimasartan and losartan on
mean change in sitting systolic blood
pressure (siSBP)

Results:
 At week 12, siDBP was significantly decreased from baseline in both
groups (–11.26 [7.53]mm Hg in the Fimasartan group and –8.56
[7.72] mm Hg in the Losartan group [P<0.0001])
37
The reduction of siDBP after 12 weeks of treatment with
fimasartan 60/120 mg was noninferior to that of losartan
50/100 mg
By post hoc comparison, between-group differences in siDBP
were significant in favor of fimasartan, suggesting superiority to
losartan

Benefit of new angiotensin receptor blocker,
fimasartan, in a porcine model of acute MI
 Objective:
 To evaluate the effect of fimasartan, a new angiotensin receptor blocker
(ARB) in a porcine model of acute MI
 Methods:
 Ten pigs were randomly allocated to 5 groups:
Group 1 (sham operation, n=2),
Group 2 (no angiotensin-converting enzyme inhibitor (ACEI) or ARB, n=2),
Group 3 (perindopril 2 mg daily, n=2),
Group 4 (valsartan 40 mg daily, n=2),
Group 5 (fimasartan 30 mg daily, n=2)
38JACC March 27, 2012 Volume 59, Issue 13

Benefit of new angiotensin receptor blocker,
fimasartan, in a porcine model of acute MI
 Results:
 Histomorphometeric infarct size was well correlated with the number of
segments matched between SPECT and FDG PET (r=0.814, P=0.004)
 The heart/mediastinum count ratios on MIBG images were highest in the
sham operation group (26.4±1.4) and more increased although in groups 3
(17.3±4.8), 4 (19.4±1.1), and 5 (18.9±3.9), compared to group 2 (15.0±2.7)
39
Use of new ARB, fimasartan, following acute MI may
confer additional cardioprotective benefit comparable
to that of other ACEI or ARB by restoring cardiac
sympathetic nerve activity
JACC March 27, 2012 Volume 59, Issue 13

The Effect of Fimasartan on the Proliferation and
Migration of Rat Aortic Vascular Smooth Muscle Cells
with Glucose Fluctuations (Preclinical study)
 Objective:
 To demonstrate that the effect of fimasartan on the proliferation and
migration of VSMCs (Vascular smooth muscle cells) with glucose
fluctuations
 Methods:
 The proliferation of VSMCs, proliferative molecular pathway and apoptotic
pathway were analyzed with fimasartan
40
 Endocrine Society's 97th Annual Meeting and Expo, March 5–8, 2015 - San Diego
Fimasartan decreased the enhanced proliferation and migration
of OLETF rat VSMCs by glucose fluctuations via the MAPK
(ERK1/2) and PI3 kinase pathway

A Randomized, Double-blind, Candesartan-controlled, Parallel Group
Comparison Clinical Trial to Evaluate the Antihypertensive Efficacy and
Safety of Fimasartan in Patients with Mild to Moderate Essential
Hypertension
41
Objective:
Investigate the antihypertensive effects of fimasartan 60 and 120
mg and its safety in comparison to 8 mg of candesartan
Methods:
• Multicenter, randomized, double-blind, active comparator, and
parallel group study
• N= 290 patients aged 19 to 75 yrs with mild to moderate
hypertension
• Treatment:
• 60 to 120 mg/d of fimasartan or 8 mg/d of candesartan
• Duration: 12 wks
• Primary end point:
• Differences in DBP changes at week 12
Clin Ther. 2016 Jun;38(6):1485-1497

Hypertension
42
Changes in the mean SiDBP at weeks 4,
8 and 12 from baseline in fimasartan
60 mg, fimasartan 120 mg, and
candesartan 8 mg treatment groups
Changes in the mean SiSBP at weeks 4,
8 and 12 from baseline in fimasartan
60 mg, fimasartan 120 mg, and
candesartan 8 mg treatment groups
Clin Ther. 2016 Jun;38(6):1485-1497

Hypertension
43
85
*
88.2
*
80.781.5 81.5
71.773 75.3
70.8
0
10
20
30
40
50
60
70
80
90
100
Week 4 Week 8 Week 12
Responserate%
The response rates
Fimasartan 60mg Fimasartan 120mg Candesartan 8mg
The antihypertensive effect of fimasartan, a newly available
angiotensin II receptor type 1 blocker, is comparable, although
not superior, to candesartan with a good safety profile
Clin Ther. 2016 Jun;38(6):1485-1497

Effect of high dose fimasartan on changes of daytime
and nighttime blood pressure compared to high dose
Valsartan
44
Objective:
To compare BP lowering effect and variability indices of
FMS with VAL at higher dose
Methods:
 N= 312
 Randomized, double-blind, active-controlled, superiority trial
 Initially given standard starting dose of FMS, VAL (60 mg, 80 mg,
respectively), then forced-titrated to double dose (120 mg, 160
mg, respectively) at week 2 and followed up to week 6
 SiSBP and SiDBP were measured at baseline,
 2 weeks and 6 weeks and ABPM was done at baseline and 6
weeks
Journal of hypertension June 2018 vol 36-Issue P e 149

45
-15.17
-9.49
-14.39
-9.11
-16.73
-10.38
-20
-15
-10
-5
0
Fimasartan Valsartan
ΔSBPmmHg
Changes of day and night time SBP
measured by ABPM
24 Hour Day time Night time
-8.59
-6.13
-8.5
-6.44
-8.75
-5.68
-10
-8
-6
-4
-2
0
Fimasartan Valsartan
ΔDBPmmHg
Changes of day and night time DBP
measured by ABPM
24 Hour Day time Night timeJournal of hypertension June 2018 vol 36-Issue P e 149

Effect of high dose fimasartan on changes of daytime
and nighttime blood pressure compared to high
dose Valsartan
46
 FMS showed strong BP lowering effect than VAL all
day long
 FMS treated group showed greater blood pressure
lowering effect on both day and night-time SBP
 FMS showed more BP changes at night which
suggests possibility of restoring dipping pattern in
non-dipping hypertensive patients
Journal of hypertension June 2018 vol 36-Issue P e 149

Summary
 Double digit BP reduction observed in SBP and DBP (Safe KanARB Study)
 Once daily fimasartan smooth BP reduction over a period of 24Hr
 Maximum response achieved in one month and maintained upto six
month
 Excellent response rate (>85%) (Safe KanARB Study)
 Excellent safety and tolerability
 Easy dose titration
 Proved superior to LOSARTAN and non inferior to VALSARTAN as
evidenced in CT
 Exhibits pleiotropic properties as shown in preclinical data
47

Fimasartan cardiology

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