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In Search of an Ideal Drug:
Emerging Roles ofLOSARTAN inCardiovascular Diseases
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9.5
3.3 2.45
23.5
2.1
45.4
21.3
12.4
6.2
9.9
7.3
13.9
6.3
22.7
0
10
20
30
40
50
Men Women Men Women Men Women Men Women
Normotensive
Hypertensive
Risk Ratio 2.0 2.2 3.8 2.6 2.0 3.7 4.0 3.0
Excess Risk 22.7 11.8 9.1 3.8 4.9 5.3 10.4 4.2
Coronary Disease Stroke Peripheral Artery
Disease Cardiac Failure
Bienn
ialAge-A
djus
tedRa
teper
1000
Kannel WB JAMA 1996;275(24):1571-1576.
Risk of CV Events by Hypertensive StatusFramingham Heart StudyPatients Aged 35-64 Years; 36-Year Follow-Up
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Hypertension Treatment SignificantlyReduced Mortality and Morbidity
Estimated Cumulative Incidence of AllMorbid Events Over 5 Years
Veterans Administration Cooperative Study Group on antihypertensive agents JAMA 1970;213(7):1143-1152.
0
10
20
30
40
50
60
0 1 2 3 4 5
Years
EstimatedCumulative
Incid
enceofAllMorbidE
vents(%)
Control - Placebo
Active Treatment Groups -
Diuretic-based regimen
and hydralazine
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* SciSearch Medline-Current Contents Database (Institute for Scientific Information) Updated
9//02
AII Antagonist Scientific/ClinicalPublications
0
1000
2000
3000
4000
5000
1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002
Losartan
Candesartan
Irbesartan
Valsartan
Eprosartan
Telmisartan
Cumulative Total
4948
797
494
464
147
121
Cumul
ativeTotalPublications*
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Classical "circulating" system (RAAS):
Renin-Angiotensin Systems (I)
Angiotensin II
Angiotensin I
Angiotensinogen
Aldosterone
Na+-retentionK+-loss
glomerular zone
ACE
Renin
Blood pressure
Na+
Sympathetic
system
Renin
maculadensa
adrenalglands
adapt. from Dominiak & Unger (eds.) in Ang II-AT1-Receptor Antagonists, Steinkopff (1997)
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t-PA = tissue plasminogen activatorCAGE = chymostatin-sensitiveangiotensin generating enzyme
Local "tissue-bound" system (RAS):
Renin-Angiotensin Systems (II)
AT1 AT2
Bradykinin
inactive fragments
B2B1
Angiotensin II
Angiotensin I
Angiotensinogen
ACE
Renin
specific cellular response
ChymasesCathepsin G
CAGE
t-PACathepsin G
Tonin
specific cellular response
adapt. from Dominiak & Unger (eds.) in Ang II-AT1-Receptor Antagonists, Steinkopff (1997)
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Distribution of ACE:
Renin-Angiotensin Systems (III)
mod. from Dzau V, Arch Intern Med 153 (1993)
R A S
circulating (plasma) local (tissue)
10 % 90 %
Acute and short-term effectscardiovascular/
renal homeostasis
Long-term effectslocal "organ adaptation"
renal-independent activation
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Angiotensin II generating systems/organs:
Local Renin-Angiotensin-Systems
Tissue/Compartment
HeartBrain
KidneyBlood vessels
atherosclerotic plaquesTestisUterus
Adrenal gland
Cell systems (e.g.)
MyocytesNeurons
Mesangium,TubuleEndothelium
Macrophages?Smooth muscle?Glomerulosa cells
mod. from Dzau V, Arch Intern Med 153 (1993)
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Growth factors: TGF, PDGF, CTGFCytokines: IL-6, TNFa
Chemokines: MCP-1, RANTES, OPN
Other: PA1, Metalloproteinases
ECM production and degradation
ECM accumulationProteinuria Cell proliferation Inflammation
Activation and recruitment of
inflammatory cells
Renal Cells
(mesangial, tubuloepithelial
interstitial fibroblasts)
Ang Il
ChemotaxisInflammatory Cells
Chemokines
- MCP-1, RANTES
Adhesion molecules
- VCAM-1Cytokines, growth factors
Ang II Induced Renal Fibrosis
Renal FibrosisMezzano, S.A. Hypertension 2001; 38(2) 635-638.
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Angiotensin II and Atherosclerosis
Stimulation of superoxide-production,lipid-peroxidation and inactivation of NO(oxidative stress)
Expression of adhesion molecules (VCAM-1,ICAM-1) and chemoattractant proteins (MCP-
1)
Involvement of Ang II in inflammatory processes:
adapt. from Gibbons GH, Clin Cardiol 20 (1997)
Activation and migration of macrophages
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Angiotensin II and Atherosclerosis
Proliferation, migration and hypertrophyof smooth muscle cells
Stimulation of growth factors, cytokines
and metalloproteinases
Involvement of Ang II in inflammatory processes:
Matrix-expansion and interstitial fibrosis
adapt. from Gibbons GH, Clin Cardiol 20 (1997)
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AII Receptor Blockers
Bridging the Gap for MaximalTarget Organ DamageProtection via AII inhibition
i i l Sh S i i
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Mega-trials CAPPP NORDIL STOP-2
ComparatorTreatments
ACE IVs
B-blockers/Diur
CCBVs
B-blockers/Diur
ACE Is/CCBsVs
B-bockers/DiurNumber of
Patients 10985 10881 6614Number of
PrimaryEnd points
698 803 659
Composite primaryendpoint
MI,
Stroke, CV
Death
MI,
Stroke, CV Death
Fatal MI, Fatal
Stroke, Fatal
CV Disease
Differences onprimary end point
NSP = 0.52
NSP = 0.97
NSP = 0.89
No Hypertension Trial Has Shown Superiorityon Combined CV Morbidity and Mortality vs.Active comparator
These data were from 3 independent, non-comparative studies.
Hansson L et al, Lancet1999;353:611-616; Hannson L et al Lancet2000;356:359-365; Hannson L et al,Lancet1999;354(9192):1751-1756.
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m
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Clin Ther. 1995 Sep-Oct;17(5):911-23.Efficacy and tolerability of losartan versus enalaprilalone or in combination with hydrochlorothiazide inpatients with essential hypertension.
Townsend R, Haggert B, Liss C, Edelman JM.
Department of Medicine, Universityof Pennsylvania, Philadelphia,USA.
Am J Hypertens. 1995 Jun;8(6):578-83.Efficacy and tolerabilityof losartan potassium and atenolol in patients with mildto moderate essential hypertension.
Dahlof B, Keller SE, Makris L, Goldberg AI, Sweet CS,Lim NY.
Department of Medicine, University of Goteborg, Ostra Hospital,Sweden.
Losartan Efficacy
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GENERIC BRAND MANUFACTURER T/P RATIO
Losartan COZAAR Merck 65%Valsartan DIOVAN Novartis 54-76%
Temisartan MICARDIS Boehringer
Ingelheim66-100%
Telmisartan PRITOR GSK 66-100%
Candesartan BLOPRES Boie Takeda 76-87%
Irbesartan APROVEL Sanofi 60-70%
Eprosartan TEVETEN Solvay 67%
TROUGH TO PEAK RATIO
Source : Acta Cardiol Sin 2002, 18:1-10
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The Losartan Intervention
For Endpoint Reductionin Hypertension Study
Dahlf B et al Lancet2002;359:995-1003.
Steering Comm ittee
Chair: Co-chair:
B . Dah lf R.B. Devereux
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LIFE: A Landmark Study
RCT of 9193 hypertensive patients with LVH,aged 55-80 years
Mean 4.8-year follow-up
44,119 patient-years of follow-up
945 study sites in 7 countries
1096 patients with primary endpoints
Dahlf B et al Lancet2002;359:995-1003.
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* Titration encouraged if SiDBP >90 mmHg or SiSBP >140 mmHg but was mandatory if SiBP >160 / 95 mmHg
**Other antihypertensives excluding ACEIs, AII antagonists, beta blockers
HCTZ=hydrochlorothiazide, SiDBP= sitting diastolic blood pressure, SiSBP=sitting systolic blood pressureDahlf B et alAm J Hypertens 1997;10:705713.
LIFE: Design/Dosing Titration
Day14 Day7 Day1 Mth1 Mth2 Mth4 Mth6 Yr1 Yr1.5 Yr2 Yr2.5 Yr3 Yr3.5 Yr4 Yr5
* Target BP:
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0
2
4
6
8
10
12
14
16
Prop
ortionofpatients
withfirstevent(%
)
Losartan
Atenolol
LIFE: Primary Composite Endpointof CV death, stroke or MI
Study Month0 6 12 18 24 30 36 42 48 54 60 66
Losartan 4605 4524 4460 4392 4312 4247 4189 4112 4047 3897 1889 901Atenolol 4588 4494 4414 4349 4289 4205 4135 4066 3992 3821 1854 876
Adjusted Risk Reduction 13.0%, p=0.021
Unadjusted Risk Reduction 14.6%, p=0.009
Dahlf B et al Lancet2002;359:995-1003.
Number
at Risk
22
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LIFE: Stroke
Losartan
Atenolol
Adjusted Risk Reduction 24.9%, p=0.001
Unadjusted Risk Reduction 25.8%, p=0.0006
Study
Month
0 6 12 18 24 30 36 42 48 54 60 660
1
2
3
4
5
6
7
8
Dahlf B et al Lancet2002;359:995-1003.
Losartan 4605 4528 4469 4408 4332 4273 4224 4166 4117 3974 1928 925
Atenolol 4588 4490 4424 4372 4317 4245 4180 4119 4055 3894 1901 897
Fatal and non-fatal stroke
Proportionofpatientsw
ithfirstevent(%)
Number
at Risk
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Intention-to-Treat
LIFE: New-Onset Diabetes
Losartan
AtenololAtenolol (N=3979)
Losartan (N=4019)
Study Month 0 6 12 18 24 30 36 42 48 54 60 66
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.10
Adjusted Risk Reduction 25 %, p
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0.5 1 1.5
Hazard Ratio (95% CI
Composite 242
Cardiovascular Death 99
Stroke 116
MI 91
Total Mortality 167
Favors L Favors A
Primary Composite Endpoints and
Components in Patients with Diabetes
L H Lindholm et al. Lancet:2002
Baseline Factor #
Events
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0
5
10
15
20
Discontinuation
due to all AEs
Discontinuation due to
drug-related AE
Discontinuation due to
serious drug-related AE
p
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LIFE: Conclusions
Losartan is the only antihypertensive that hasdemonstrated a superior benefit over another activetreatment, atenolol, in reducing the risk of combined CV
morbidity and death in patients with hypertension andLVH*
The superior benefit of losartan therapy on combined CV
morbidity and death* compared to atenolol was: beyond blood-pressure control only partially explained by superior LVH regression
potentially linked to molecule-specific effects
* Defined as composite of CV death, MI, and stroke
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ELITE II - Evaluation ofLosartan In The Elderly II
Study Design:Multicenter, double-blind, randomized, parallel, captopril-controlled involving 2600 patients(>60 years old) withsymptomatic heart failure(NYHA II-IV)Period of Study: 36 months
Primary Objective:To evaluate the effect of losartan vs captopril on TotalMortality in patients with symptomatic congestive heartfailure
Secondary Objectives:1. Evaluate the effects of losartan vs captopril on compositeendpoint of sudden cardiac death and/or resuscitatedcardiac arrest in patients with symptomatic CHF.2. Investigate safety and tolerability of losartan in patientswith congestive heart failure.
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ELITE - II
Study Design
60 yrs; NYHA II - IV; EF 40 %
ACEI naive or 7 days in 3 months prior to entry
Standard Rx ( Dig / Diuretics ), - blocker stratification
Captopril
50 mg 3 times dailyn = 1574
Losartan
50 mg dailyn = 1578
Event Driven
Targeting 510 deaths
estimate 2 yrs
median follow-up 555 days
Primary Endpoint : All-cause Mortality
Secondary Endpoint : Sudden cardiac death and/or Resuscitated Arrest
Other : All-cause Mortality / Hospitalizations
Safety and Tolerability
Lancet 2000; 355:1582-87
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ELITE IIPrimary Endpoint: All-Cause Mortality
0.0
0.2
0.4
0.6
0.8
1.0
Captopril (n-1574) 250 Events 15.9 % over 1.5 yearsLosartan (n-1578) 280 Events 17.7 % over 1.5 years
p=0.16
Probability
ofS
urvival
Days of Follow-up0 100 200 300 400 500 600 700
Pitt, B. et al, Lancet 2000; 355:1582-87
Average Mean Mortality Rate = 11.0 % per year
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ELITE IIWithdrawal for Adverse Experience ( Excluding Death )
0
5
10
15
20
Any adverse
effect
Drug-related
adverse effect
Cough Heart failure
Losartan
Captopril
*
*
*
* p = 0.001 between groups
Patients who died were excluded from any adverse effect and drug-related adverse effects.
Pitt, B. et al, Lancet 2000; 355:1582-87
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ELITE IIStudy Endpoint Summary
P Value
1.13 (0.95-1.35) P = 0.16 NS
1.25 ( 0.98, 1.60 ) P = 0.08 NS
1.07 ( 0.97, 1.19 ) P = 0.18 NS
228 ( 14.5 ) P = 0.001149 ( 9.4 )
Losartan n = 1578
number ( % )Captopril n = 1574
number ( % )
752 ( 47.7 ) 707 ( 44.9 )
115 ( 7.3 )142 ( 9.0 )
280 ( 17.7 ) 250 ( 15.9 )
Hazards
Ratio ( 95% CI )*
Withdrawal forAdverse
Experiences
Combined total mortalityor hospitalizations
for any reason
Sudden death or/resuscitated cardiac
arrest
All-cause mortality
(primary endpoint)
Pitt, B. et al, Lancet 2000; 355:1582-87
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Acronym Diagnosis Randomization PrimaryEndpoint Duration
IDNT
N=1715
Type 2 DM withnephropathy
Irbesartan/amlodipine/placebo + AHT*
ESRD2x creatininemortality
2.6 yrs
IRMA 2 Type 2 DM withmicroalbuminuria
Irbesartan (150 mg)/irbesartan (300 mg)/placebo + AHT
Progressionto proteinuria
2 yrs
RENAAL Type 2 DM withnephropathy
Losartan/placebo + AHT
ESRD2x creatinine
mortality
3.4 yrs
MARVAL Type 2 DM withmicroalbuminuria
Valsartan/amlodipine
UAER 6 mos
*AHT=other antihypertensive therapy (excluding ACEIs, ARBs, and CCBs).AHT=other antihypertensive therapy (excluding ACEIs, ARBs, and DHP CCBs).
AHT=other antihypertensive therapy (excluding ACEIs and ARBs).
ARBs and Diabetic Nephropathy
N=590
N=1513
N=332
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0
5
10
15
20
25
30
Losartan Placebo
Doublingofserumcre
atinine
conce
ntration(%o
fpatients)
ARBs in preventing renal disease progression
Brenner et al. N Engl J Med2001;345:861869
Lewis et al. N Engl J Med2001;345:851860
RENAAL IDNTp=0.003
p
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IDNT and RENAAL Trial Results
Doubling of Creat, 16 (P=0.02) 20 (P=0.02) 23 (P=0.006) -4 (P=0.69)
ESRD, or death
Doubling of Creat 25 (P=0.006) 33 (P=0.003) 37 (P
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ARBs and ACE inhibitors areestablished renoprotective therapies
JNC 7. JAMA 2003;289:25602572
The renal protection trials
ARBs are first-line treatment in type 2diabetic patients with nephropathy
ARBs have shown superior efficacycompared with placebo and calciumchannel blockers
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Compelling indications for specific
antihypertensive classes JNC 7
Diabetes Chronic kidney
disease
Diuretic Beta blocker ACE inhibitor ARB CCB Aldosterone
antagonist
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ARBs & ACE Inhibitors: Do theycomplement each others clinical effects?
Maximal inhibition of AII effects not possible
with ACE inhibitors due to non-ACEpathways of AII production
ARBs capable of complete blockade of AII
effects on the AT1 receptor
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ARBs & ACE Inhibitors: Do theycomplement each others clinical effects?
ACE inhibition and AII Receptor Blockade(AT2 receptor) both reduces PAI-1 activity
(
anti-thrombotic effect)
Bradykinin and NO production via ACEinhibition and AII Receptor Blockade (AT2
receptor) improves endothelial function
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OPTIMAALOptimal therapy in post MI
patients withAALosartan
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Relative risk = 1.13 (o.99 to 1.28:p=0.069)
All-cause Mortality
OPTIMAAL
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OPTIMAAL: Summary
Losartan (50 mg/day) compared withcaptopril (150 mg/day) in high risk MIwas associated with:
Non-significant trend in all-cause mortalityin favor of captopril
Higher incidence of CV mortality (p=0.032)
Essentially identical results for:
Re-infarction, stroke, revascularization, all-cause re-hospitalization and NYHA class
Better tolerability with significantly fewerdiscontinuations for adverse effects
ACE I hibit ARB
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Captopril Losartan Hazard pratio value
ACE Inhibitors vs ARBs
in Multicenter Trials
OPTIMAAL 447/2733 499/2744 1.13 .07(post-MI CHF) (0.99, 1.28)
ELITE II 250/1574 280/1578 1.13 .16(Chronic HF) (.95, 1.35)
Dickstein et al. Lancet 2002. 360, 752-760. Pitt et al. Lancet 2000. 355; 1582-87
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New treatment modalities
Are as effective with fewer side effects
Will improve patient compliance Will Target organ protection
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Side Effects of CurrentAntihypertensive Agents
Some patients suffer from troublesome sideeffects that:
Interfere with quality of life
Negatively affect compliance
lead to more frequent visits to the physicianand more frequent lab tests
ultimately increase the cost of medical care
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Efficacy: Adverse Effects Ratio
100%
50%
0%EFFICAY
/ADVERSE
EFFECTS
Gang
lion
bloc
kers
Reserp
in
Hy
dra
laz
ine
Guane
the
dine
Thiaz
ides
a-me
thyl-
dopa
Clon
idine
Proprano
lol
Prac
tolol
Verapam
il
Nife
dipine
Diltiazem
Captopri
l
Ace
Inhibitor
1950 1960 1970 1980 1990 YEAR
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(Adapted from Hollenberg NK, Higginbotham MB. Therapeutic Options to Preserve
Target Organs. Parsippany, NJ: Applied Clinical Communications; Case 3 of 5)
Muscle cramps
Impotence
Gout
Glucose intolerance
Hypokalemia
Hyperuricemia
Hypomagnesemia
Hypercalcemia
DIURETICS
Depression
Sleep disorders
Exerciseintolerance
Dyslipidemia
Glucoseintolerance
Impotence
BBs
Edema
Flushing
Headache
Dizziness
GI disorders
Changes inheart rate
CCBs
Cough
Rash
Hyperkalemia
Angioedema
Altered Taste
ACEIs
Hyperkalemia
Dizziness
Fatigue
ARBs
EVOLUTION OF ADVERSE EVENT
PROFILE
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We may have lofty goals in treating
hypertension, particularly with regard totarget-organ protection and compliance,
but we will never be able to accomplishthem unless our patients are willing totake their medication
Target Organ Protection & Compliance
THE RISK FACTOR
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THE RISK FACTOR
CARDIOVASCULAR
CONTINUUM
Risk Factors
Diabetes
Hypertension
Atherosclerosis
and LVH
Myocardial
Infarction
RemodelingVentricular
Dilation
Congestive
Heart Failure
End-Stage
Heart Disease
and Death
DeathRENAAL
ELITE II
OPTIMAAL
LIFE
LIFE
Adapted from Dzau V, Braunwald E.Am Heart J. 1991;121:1244-1263.
because endpoint mattersLosartan
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BIOEQUIVALENCE STUDY
The bioavailability ofUnilabs Lifezar 50 mg Tabletwas compared to that of the innovatorMSDsCozaar 50 mg Tablet
Eighteen (18) male adult volunteers with normalphysical findings participated in the study.
The clinical phase of the study was done at Dr. Victor R.
Potenciano Medical Center and approved by the MedicalEthics Committee.
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BIOEQUIVALENCE STUDY
RESULTSLosartan plasma concentrations (ng/mL)
PARAMETERS DRUG A
ULs Lifezar 50 mg
Tablet
DRUG B
MSDs Cozaar 50 mg
Tablet1. Tmax (hour) 0.5 1.5
2. Cmax + S.D.
(ng/mL)
> % of Reference
206.23 + 234.103
120%
171.75 + 112.72
Reference
3. AUC0-36hr + S.D.
(ng-hr/mL)
> % of Reference
526.19 + 151.11
93%
566.37 + 180.22
Reference
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BIOEQUIVALENCE STUDY
Semilogarithmic plots ofthe mean losartan plasmaconcentration versussampling time of
ULs Losartan and MSDsCozaar 50mg Tablets.
The lower and upper limits ofthe 90% CI for thelogarithmically-transformed datalie within the bioequivalence
criteria of 80-125%.
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Thank You