Expert Opinion on Pharmacotherapy
`
`Thürmann
`Valsartan: a novel angiotensin Type 1 receptor antagonist
`
`Cardiovascular & Renal
`Valsartan: a novel angiotensin Type 1
`receptor antagonist
`
`Petra A Thürmann
`
`http://www.ashley-pub.com
`
`Philipp Klee-Institute of Clinical Pharmacology, Hospital Wuppertal GmbH,
`Arrenberger Str. 20, 42117 Wuppertal, Germany
`
`Drug Evaluation
`Introduction
`
`1.
`
`2. Rationale for the
`development of
`AT1 receptor antagonists
`3. Chemistry of valsartan
`
`4. Pharmacology
`
`5. Clinical pharmacology
`
`6. Clinical trials in patients
`with essential
`hypertension
`
`7. Clinical trials with
`valsartan in heart failure
`
`8. Adverse drug reactions of
`valsartan
`
`9. Expert opinion
`
`Acknowledgement
`
`Bibliography
`
`Valsartan is a highly selective, orally available antagonist of the angiotensin
`Type 1 (AT1) receptor. It is indicated for treatment of mild to moderate
`essential hypertension. Experimental studies have confirmed the abolition
`or
`attenuation of
`angiotensin II
`(AII)-related effects,
`such as
`vasoconstriction, cell growth promotion and aldosterone release.
`In
`humans, valsartan is rapidly absorbed with maximal plasma concentrations
`occurring 1 - 2 h after oral administration. The elimination half-life comes to
`about 7 - 8 h, valsartan is metabolised to a negligible extent and most of the
`drug is excreted via the faeces. There is no dose adjustment required for
`patients with a creatinine clearance > 10 ml/min. The dose should not
`exceed 80 mg o.d. in patients with hepatic dysfunction, valsartan is not
`recommended for patients with severe hepatic dysfunction and/or biliary
`cirrhosis. At present, no clinically relevant pharmacokinetic drug interac-
`tions have been observed. Valsartan produces persistent blood pressure
`reductions
`in patients with mild to moderate hypertension,
`the
`recommended starting dose is 80 mg o.d. If required, the dose may either be
`increased to 160 mg o.d. or hydrochlorothiazide may be added. In compar-
`ison to other antihypertensive drugs valsartan therapy leads to similar blood
`pressure reductions, while exhibiting a favourable tolerability profile.
`Preliminary studies suggest beneficial effects in patients with hypertensive
`end-organ damage such as renal disease and left ventricular hypertrophy.
`Furthermore, the drug is evaluated for its efficacy in heart failure and
`patients post-myocardial infarction.
`
`Keywords: angiotensin receptor antagonist, heart failure, hypertension, target
`organ disease
`
`Exp. Opin. Pharmacother. (2000) 1(2):337-350
`
`1. Introduction
`
`High blood pressure remains a serious health problem leading to heart
`disease, stroke, end stage renal failure and retinopathy [1,2]. Heart disease
`and stroke are the first and third leading causes of death in the USA.
`Awareness and adequate treatment of hypertension have increased steadily
`during the last 20 years [3], contributing to a decline in stroke and coronary
`artery disease mortality. According to the most recent JNC VI guidelines [4]
`hypertension is defined by a systolic blood pressure above 140 mmHg or a
`diastolic blood pressure above 90 mmHg. Depending on additional risk
`factors, e.g., diabetes, dyslipidaemia, smoking, older age and gender, and
`pre-existing target organ disease (e.g.,
`left ventricular hypertrophy,
`coronary heart disease, nephropathy, congestive heart failure) drug therapy
`
`337
`2000 © Ashley Publications Ltd. ISSN 1465-6566
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1011, p. 001
`
`

`

`338 Valsartan: a novel angiotensin Type 1 receptor antagonist
`
`Figure 1: Differences and similarities between angiotensin converting enzyme-inhibition and AT1-receptor antagonist.
`
`ACE-inhibition
`
`Alternative
`pathways !
`
`Decrease of angiotensin II
`concentrations
`
`@ ?
`
`AT1-blockade
`- inhibition of smooth muscle cell
`contraction
`- diminished myocyte contractility
`- decrease of aldosterone
`- attenuation of sympathetic stimulation
`- decrease of growth hormone stimulation
`
`Cumulation of bradykinin
`
`AT2-stimulation
`- regulation of cell growth/
`differentiation
`- apoptosis
`
`- in addition to lifestyle modifications - should be
`initiated soon after the diagnosis of essential
`hypertension has been confirmed.
`
`In the absence of relevant co-morbidity initial
`treatment is generally recommended using diuretics
`or b -blockers, based on randomised clinical trials
`showing the benefit of these drugs [5]. In diabetic
`patients and those with heart failure, angiotensin
`converting enzyme (ACE)-inhibitors should be
`considered preferentially, [6-8] whereas patients with
`isolated systolic hypertension may benefit
`from
`long-acting dihydropyrimidine calcium antagonists [9]
`or diuretics [10]. The goal of antihypertensive therapy
`is to keep blood pressure below 140/90 mmHg, and if
`tolerated, even lower [11]. However, diabetic patients
`should achieve a blood pressure below 130/85 mmHg
`[12].
`
`Compliance with antihypertensive therapy remains a
`problem, since most people do not suffer from
`symptoms of high blood pressure, but rather fear and
`experience drug-induced side effects as well as an
`impact of drugs on their quality of life [13]. Optimal
`treatment and control is therefore maintained only in
`about one third of hypertensive patients.
`
`Consequently, some of the prerequisites for optimal
`antihypertensive therapy are [4]:
`
`• sufficient information for the patient about the aims
`and benefits of therapy
`
`2. Rationale for the development of AT1
`receptor antagonists
`
`Experience with ACE inhibitors has shown, that drugs
`interfering with the renin-angiotensin-system (RAS)
`are useful
`for treatment of hypertension [14,15],
`regression of left ventricular hypertrophy as a major
`risk factor [16], prevention and treatment of heart
`failure [6,17,18], treatment of patients with left ventric-
`ular dysfunction following myocardial
`infarction
`[7,19] and prevention of nephropathy in diabetic
`patients [8].
`
`As demonstrated below, ACE inhibitors do not only
`attenuate the unwanted actions of AII,
`they also
`increase the levels of bradykinin. The latter substance
`may be responsible for the ACE inhibitor-related
`cough, which disturbs about 5% - 10% of treated
`patients [20]. A more selective approach, namely the
`direct blockade of the angiotensin receptor, seemed
`to be a promising way to treat high blood pressure as
`well as other cardiovascular diseases [21] (Figure 1).
`
`ACE inhibitors block the conversion of angiotensin I
`(AI) to the active AII and thereby attenuate the effects
`of AII, which are mediated mainly via the
`AT1-receptor subtype:
`
`• vasoconstriction
`
`• release of aldosterone
`
`• a simple drug dosing regimen (o.d.)
`
`• activation of sympathetic nervous system
`
`• low incidence of side effects
`
`© Ashley Publications Ltd. All rights reserved.
`
`• stimulation of growth
`
`Exp. Opin. Pharmacother. (2000) 1(2)
`
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`
`

`

`the vasodilator
`the inactivation of
`In addition,
`bradykinin is prevented. Since alternative pathways
`exist for the production of AII [22], ACE inhibitors do
`not completely abolish all the unwanted AII-mediated
`effects; in contrast, substances, which bind to the
`AT1-receptor, are able to prevent these deleterious
`effects. Following blockade of the AT1-receptor AII
`may preferably bind at the AT2-receptor, moreover,
`AT2-receptors may be upregulated in certain disease
`states. However, the role of the AT2-receptor subtype
`is not fully understood. It has been associated with
`release of NO and subsequent vasodilation, regula-
`tion of cell growth as well as apoptosis [21,23].
`
`3. Chemistry of valsartan
`
`Valsartan (CGP48933) is the S-enantiomer of
`N-valeryl-N-[[2¢ -(1H-tetrazol-5-yl)biphenyl-4-yl]methy
`l]-valine (C24H29N5O3) and has a molecular weight of
`435.5 g [24] (Figure 2). The R-enantiomer has been
`reported to have a 170-fold less activity in terms of
`AT1-receptor binding. Valsartan is available as a
`microcrystalline powder with a melting point of 105 -
`110°C. It is soluble in water at 25°C and in phosphate
`buffer at pH 8.0. The hydrophilic character of the
`compound is indicated by the partition coefficient P
`with 0.033 (n-octanol/aqueous phosphate buffer pH
`7.4) [24] (Figure 2).
`
`4. Pharmacology
`
`4.1 In vitro experimental studies
`AT1 and AT2 receptors are expressed by human
`myometrium membranes as well as vascular smooth
`muscle cells in rats and are used for binding experi-
`ments. Valsartan competes with radiolabelled
`[125I]-AII at
`the AT1-receptor with an inhibitory
`constant (Ki) of 2.38 ± 0.31 nmol/l and at
`the
`AT2-receptor with a Ki of 57.7 ± 9.4 m mol/l, showing a
`more than 30-fold higher affinity to the AT1-receptor
`than to the AT2-receptor [25]. Due to differences in
`AT1-receptors in different tissues, affinity of valsartan
`was also shown in human adrenal gland with a Ki of
`2.6 ± 0.9 nmol/l, suggesting that the rat tissue experi-
`ments are suitable models [26]. Binding of valsartan to
`the AT1-receptors achieves steady-state after about 60
`min, stability has been proven for 3 h. The dissocia-
`tion half-life has been calculated to 56 ± 7 min [26].
`Affinity and density of AT1-receptors were unchanged
`after administration of valsartan to rats and marmosets
`
`Figure 2: Chemical structure of valsartan.
`
`Thürmann 339
`
`O
`
`N
`
`COOH
`
`N
`
`N
`
`N
`
`NH
`
`over 13 weeks, receptor desensitisation following
`chronic therapy with valsartan seems therefore not to
`be the case.
`
`In isolated rabbit aortic rings, serving as a functional
`assay, valsartan inhibited AII-induced contractions
`with an IC50 of 1.4 nmol/l [26] showing a typical
`sigmoidal concentration-effect curve.
`
`4.2 In vivo studies
`
`Intravenous application of valsartan to renovascular
`hypertensive rats resulted in a dose-dependent fall in
`blood pressure. A decrease of 30 mmHg was achieved
`with a dose of 0.06 mg/kg, higher doses produced
`persistent blood pressure reduction lasting for 24 h.
`The effect of 3 mg/kg valsartan was comparable to the
`effect of 3 mg/kg of the ACE inhibitor enalaprilat [24].
`
`Oral doses of 1 - 30 mg/kg valsartan were given to
`conscious,
`freely-moving, sodium-depleted
`marmosets controlled via a telemetric device [24]. The
`maximum blood pressure lowering response
`occurred within 1 h after dosing and persisted longer
`than 24 h after the largest dose. In this model, the
`hypotensive action of the AT1-antagonist losartan was
`markedly shorter. This is due to the fact, that primates
`are poor metabolisers for the hepatic activating step
`required for losartan. Neither of the AT1-antagonists
`exhibited an influence on heart rate.
`
`Following clipping of the left renal artery hyperten-
`sive rats were given 0.3, 3 or 10 mg/kg per day
`intraperitoneally of the ACE inhibitor benazeprilat or
`valsartan over 12 weeks [27]. Both drugs produced
`similar effects on blood pressure as well as on left
`ventricular volumes, wall stress and ejection fraction.
`Increase in mRNA for atrial natriuretic factor (ANF) as
`well as a decrease in the mRNA for the sarcoplasmatic
`calcium-ATPase are indicators for the development of
`heart failure. Benazeprilat and valsartan were able to
`achieve values for these two prognostic markers
`
`© Ashley Publications Ltd. All rights reserved.
`
`Exp. Opin. Pharmacother. (2000) 1(2)
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1011, p. 003
`
`

`

`340 Valsartan: a novel angiotensin Type 1 receptor antagonist
`
`Table 1: Pharmacokinetic parameters of valsartan in healthy volunteers (n = 12) after iv. administration of 20 mg and oral
`application of the 80 mg capsule [34]. Data are given as mean ± SD and median for Tmax.
`
`20 mg iv.
`80 mg capsule
`
`Cmax (mg/l)
`4.02 ± 0.43
`1.64 ± 0.63
`
`Tmax (h)
`-
`2
`
`t½el (h)
`9.45 ± 3.83
`7.05 ± 1.58
`
`Ae (% of dose)
`28.95 ± 5.82
`7.34 ± 3.02
`
`f (AUC oral/iv.)
`-
`0.23 ± 0.07
`
`Ae: Urinary recovery; Cmax: Maximum plasma concentration; f: Oral bioavailability; t½el: Terminal elimination half-life;
`Tmax: Time of occurrence of Cmax.
`
`which were comparable to those obtained in healthy
`control animals.
`
`Furthermore, treatment with valsartan in genetically
`hypertensive rats induced not only significant regres-
`sion of left ventricular hypertrophy but also reversal of
`vascular structural alterations as measured by the
`media to lumen ratio in resistance arteries [28].
`
`Given to spontaneously hypertensive rats over 48
`weeks valsartan significantly reduced urinary protein
`excretion and prevented development of
`nephrosclerosis over the dose range from 3, 10 and 30
`mg/kg/d p.o.
`[29]. Furthermore, stroke-related
`behaviour was observed significantly less under
`valsartan (vs. vehicle control) and survival improved:
`14 vs. 0 deaths from a total of 30 controls and treated
`animals, respectively.
`
`The effect of valsartan on haemodynamics after
`myocardial
`infarction was compared with that of
`enalapril in rats following coronary artery ligation [30].
`Left ventricular end-diastolic pressures decreased
`significantly after valsartan, suggesting a beneficial
`effect on left ventricular dilation following myocardial
`infarction.
`
`failure 3 months
`In dogs with moderate heart
`treatment with valsartan 400 mg b.i.d. ejection fraction
`was preserved in comparison to control animals
`receiving no therapy, however, in animals receiving
`800 mg b.i.d., ventricular pump function deteriorated
`[31]. In a pig model of heart failure valsartan treatment
`prevented the development of pacing-induced left
`ventricular dysfunction [32], however, significant
`effects on myocardial collagen content were not
`observed.
`
`5. Clinical pharmacology
`
`5.1 Pharmacokinetics
`The disposition and metabolism of valsartan were
`studied after oral administration of 80 mg of the
`
`[14C]-radiolabelled substance [33]. Maximal concentra-
`tions (Cmax) of valsartan were observed after 1 h and
`declined with an elimination half-life of about 6 ± 1 h.
`Only one pharmacologically inactive metabolite
`(valeryl-4-hydroxy-valsartan) was identified in plasma
`and represented only 11% of the area under the
`plasma concentration/time curve (AUC0-24h) of the
`radioactivity.
`
`At least 51% of the dose was absorbed, 99% of the
`radioactivity was recovered within 7 days, where the
`most was excreted in the faeces (86 ± 5%).
`
`investigated the absolute
`[34]
`Flesch et al.
`bioavailability of valsartan after administration of a 80
`mg single oral dose (capsule and solution) in compar-
`ison to 20 mg given intravenously. The
`pharmacokinetic parameters derived are shown in
`Table 1. The volume of distribution was calculated to
`be 16.91 ± 6.90 l, the renal clearance came to 0.62 ±
`0.12 l/h. The relatively low volume of distribution of
`the drug may be explained by the protein binding
`properties of valsartan. About 96 ± 2% of the drug is
`bound to plasma proteins, preferentially to albumin
`(92%), only a small percentage is bound to a 1-acid
`glycoprotein (22%), binding to g
`globulins is
`negligible [35].
`
`The area under the plasma concentration vs.
`time-curve increases in a linear and dose-proportional
`manner in the dose range of 80 - 320 mg [24].
`
`After repeated oral dosing of 200 mg o.d. over 8 days
`Cmax increased slightly from 3.46 ± 1.44 mg/l to 3.94 ±
`1.38 mg/l and AUC0-24h increased from 21.33 ± 10.22
`mg/l.h to 25.75 mg/l.h suggesting only little accumu-
`lation with a cumulation factor of 1.21 [36]. The
`bioavailability of valsartan when given with food is
`reduced by 46% [24], however, this did not influence
`the antihypertensive effect in patients.
`
`Mean Cmax and AUC0-24h increased by 53% and 24%,
`respectively, in elderly subjects with a mean age of 76
`years in comparison to younger volunteers aged 23
`years [37]. However, these differences could not be
`
`© Ashley Publications Ltd. All rights reserved.
`
`Exp. Opin. Pharmacother. (2000) 1(2)
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`
`

`

`attributed solely to differences in creatinine clearance
`(ClCR), liver function, weight or concomitant medica-
`tion and appear not to be of any clinical relevance.
`
`The pharmacokinetics of valsartan were studied in 3
`patients with mild renal impairment (ClCR: 78 ± 15
`ml/min), 4 patients with moderate dysfunction (ClCR:
`48 ± 8 ml/min), 5 patients with severe renal impair-
`ment (ClCR: 18 ± 7 ml/min) and compared with 7
`patients with normal renal function (ClCR: 126 ± 35
`ml/min) [38]. The corresponding AUC0-48h-values
`came to 10,722 ± 4,862 m g/l.h, 6,123 ± 769 m g/l.h,
`14,274 ± 10,880 m g/l.h and 7923 ± 3,703 m g/l.h,
`respectively. There were no significant correlations
`between AUC and ClCR (r = -0.2675) or Cmax and ClCR
`(r = -0.1249). Since renal clearance contributes to <
`30% of
`the total excretion, dose adjustment of
`valsartan is not necessary in patients with a creatinine
`clearance above 10 ml/min.
`
`Biliary excretion is the primary elimination route of
`valsartan, therefore, prolongation of the half-life is
`expected in patients with hepatic impairment. The
`pharmacokinetics of valsartan 160 mg orally were
`studied in 6 patients each with mild to moderate
`hepatic dysfunction (Child-Pugh grade A and B) and
`compared with 12 matched healthy volunteers [39].
`The AUC was almost twice as high in patients with
`liver impairment with 46 mg/l.h when compared to
`healthy controls with 21 mg/l.h. Therefore, the dose
`of 80 mg should not be exceeded in patients with mild
`to moderate hepatic dysfunction and valsartan should
`not be given to patients with severe hepatic failure
`and biliary cirrhosis.
`
`5.2 Pharmacokinetic-pharmacodynamic
`investigations in healthy volunteers
`
`After single dose administrations of 40 - 80 mg
`valsartan, respectively,
`in 6 healthy volunteers
`dose-response curves for the inhibition of
`the
`AII-induced blood pressure increase were established
`[40]. 2 h after administration of placebo the dose of AII
`required to achieve a blood pressure increase of 30
`mmHg (D30) came to 5.2 ± 4.0 m g. After valsartan 40
`and 80 mg, respectively, the D30 came to 47.4 ± 43.8
`m g and 68.2 ± 49.6 m g, respectively. The maximal
`effect was observed 2 h after dosing of valsartan and
`lasted up to 24 h. Concentration/effect analysis
`performed by an Emax-model revealed an Emax of
`about 74% inhibition of blood pressure increase and
`an EC50 of 0.37 ± 0.37 m mol/l.
`© Ashley Publications Ltd. All rights reserved.
`
`Thürmann 341
`
`Plasma renin activity (PRA) peaked at 4 and 6 h after
`application and returned to baseline after 24 h.
`
`Mazzolai et al. [40] compared the pressure response to
`exogenous AII after the recommended starting doses
`of losartan (50 mg), valsartan (80 mg) and irbesartan
`(150 mg) in healthy volunteers. At 4 h, losartan attenu-
`ated the ANG-induced pressure increase by 43%,
`valsartan by 51% and irbesartan by 88% (p < 0.01
`between drugs).
`
`In a repeated dose study with 200 mg valsartan o.d.
`over 8 days plasma AII levels were measured [36]. The
`maximum increase in AII concentrations occurred 6 h
`after dosing, at steady-state, a significant (2- to 3-fold)
`cumulation of plasma AII concentrations was
`observed.
`
`The effect of valsartan 80 mg on the pressure response
`induced by exogenous AII was comparable after
`single dosing and on the 8th day of once daily dosing
`with a combined EC50 of 85.6 ± 42.3 ng/ml and a
`corresponding Emax of 104% ± 15% [42]. This confirms
`the experimental findings, that receptor desensitisa-
`tion does not occur [26].
`
`5.3 Pharmacokinetic interaction studies
`The absence of clinically relevant pharmacokinetic
`interactions with the following drugs has been
`confirmed: atenolol [43], cimetidine [44], furosemide
`[45], amlodipine, hydrochlorothiazide (HCTZ),
`digoxin, warfarin, glibenclamide and indomethacin
`[Data on file, Novartis, Basle, Switzerland].
`
`6. Clinical trials in patients with essential
`hypertension
`
`6.1 Clinical trials comparing valsartan and
`placebo
`The safety and efficacy of valsartan in patients with
`mild to moderate essential hypertension at different
`dose levels was compared to placebo in several trials
`(Table 2). Pool et al. [46] treated 122 patients with
`placebo, 10, 40, 80 and 160 mg valsartan, respectively,
`over 4 weeks. Responder rates, as defined by a sitting
`diastolic blood pressure below 90 mmHg or a
`decrease in diastolic blood pressure by more than 10
`mmHg, came to 16%, 24%, 33%, 46% and 54%, respec-
`tively, indicating a clear dose-response relationship
`(Figure 3). The effects observed after the 80 and 160
`mg dose were significantly different from placebo for
`diastolic and systolic blood pressure. The
`
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`

`

`342 Valsartan: a novel angiotensin Type 1 receptor antagonist
`
`Figure 3: Dose-response relationship of the antihypertensive effect of valsartan in patents with mild to moderate essential hyperten-
`sion (adapted from [79]). *p < 0.05 versus placebo.
`
`*
`
`*
`
`*
`
`Reduction in diastolic blood pressure
`
`Reduction in systolic blood pressure
`after at least 4 weeks of treatment.
`
`10
`
`20
`
`40
`
`80
`
`160
`
`320
`
`0
`
`-2
`
`-4
`
`-6
`
`-8
`
`-10
`
`-12
`
`-14
`
`BPreduction(mmHg)
`
`Valsartan (mg)
`peak/trough ratio was ‡
`6.2 Clinical trials comparing valsartan with
`50%, the maximal blood
`other antihypertensive drugs
`pressure lowering effect was observed about 4 h after
`dosing. Plasma renin activity increased in a
`dose-dependent manner, whereas AII plasma levels
`exhibited no dose-linearity.
`
`In short-term studies over 8 - 12 weeks the blood
`pressure-lowering activity of valsartan was compared
`with amlodipine, HCTZ, enalapril,
`lisinopril and
`losartan (Table 3a and b).
`
`Oparil et al. [47] treated 736 patients with essential
`hypertension with valsartan 20, 80, 160 and 320 mg
`o.d., respectively, over 8 weeks in a randomised,
`placebo-controlled double-blind trial. Responder
`rates were significantly different from placebo with
`the exception of the 20 mg dose. The incremental
`blood pressure lowering effect with doses above 80
`mg o.d. was relatively small.
`
`A dose-ranging trial with forced titration of valsartan
`of 20 - 320 mg o.d. in 121 essential hypertensive
`patients with valsartan doses of 80 and 160 mg,
`respectively, demonstrated statistically significant
`blood pressure reductions in comparison to placebo
`[48].
`
`Another forced titration study by Strödter et al. [49]
`showed a clinically relevant antihypertensive effect
`after the 40 mg valsartan dose.
`
`In a randomised, placebo-controlled double-blind
`study 217 hypertensive patients received once-daily
`valsartan 20, 80, 160 and 320 mg, respectively, over 8
`weeks [50]. 24 h ambulatory blood pressure record-
`ings revealed significant blood pressure reductions
`with the doses of 80 mg and higher, producing persis-
`tent day and night blood pressure control without loss
`of the diurnal variation.
`
`In the study by Holwerda et al. [51], valsartan 80 mg
`o.d. was compared with enalapril 20 mg o.d. and
`placebo. After both treatments, blood pressure was
`significantly reduced, no differences were observed
`between valsartan and enalapril.
`
`In the trial by Mallion et al. [52] the same doses of
`valsartan and enalapril were compared, however, 12.5
`mg HCTZ could be added at week 8 if blood pressure
`was not adequately controlled. The results for
`monotherapy were similar when compared to the
`study above. Co-medication with HCTZ was required
`in 20% of patients in both treatment groups and blood
`pressure reductions from baseline were comparable
`after 12 weeks.
`
`In the study by Black et al. [53] treatment was started
`with valsartan 80 mg o.d., lisinopril 10 mg o.d. or
`placebo. After 4 weeks the dose of the drugs could be
`doubled, valsartan could then be given as 160 mg o.d.
`or 80 mg b.i.d. With all active treatments blood
`pressure decreased significantly in comparison to
`placebo, but to a similar degree and no differences
`were observed between valsartan 80 mg b.i.d. or 160
`mg o.d.
`
`© Ashley Publications Ltd. All rights reserved.
`
`Exp. Opin. Pharmacother. (2000) 1(2)
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1011, p. 006
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`

`

`Thürmann 343
`
`Table 2: Randomised, placebo-controlled parallel group, forced titration and fixed-dose trials with valsartan in patients with mild to
`moderate hypertension.
`
`No. of patients
`
`25
`25
`23
`24
`25
`140
`150
`148
`150
`148
`61
`
`Dosage
`(mg o.d.)
`10
`40
`80
`160
`placebo
`20
`80
`160
`320
`placebo
`20 up to 320
`
`Duration
`(weeks)
`4
`4
`4
`4
`4
`8
`8
`8
`8
`8
`10
`
`BP reduction
`(mmHg)
`5.4§§
`6.7§§
`7.6§§
`9.4§§
`4.6§§
`6.33/5.39
`8.6/7.22
`8.96/7.34
`10.59/8.5
`1.33/2.02
`3.8§§ (160 vs. placebo)
`5.6§§ (320 vs. placebo)
`
`Response rate
`(%)§
`24
`33
`46
`54
`16
`28
`43
`44
`52
`21
`49.1
`
`Ref.
`
`[46]
`
`[47]
`
`[48]
`
`60
`placebo
`10
`72
`20 up to 160
`4
`20/15.1
`18
`placebo
`4
`3.7/5.5
`§Response rate: response rate was defined as a reduction of diastolic blood pressure by more than 10 mmHg from baseline and/or
`sitting diastolic blood pressure < 90 mmHg before morning drug intake.
`§§ Diastolic blood pressure.
`BP: Blood pressure.
`
`23.5
`-
`
`[49]
`
`Valsartan 80 mg o.d. (plus amlodipine 5 mg if
`required) exhibited a comparable blood pressure
`reduction to amlodipine 5 mg (or 10 mg amlodipine, if
`required) [54].
`
`In a similar fashion, valsartan 80 mg o.d. (plus atenolol
`50 mg o.d.) was compared with HCTZ 25 mg o.d.
`(plus atenolol 50 mg o.d.) [55] over 12 weeks. Fall in
`blood pressure as well as responder rates were
`comparable.
`
`In an 8-week placebo-controlled trial, valsartan 80 mg
`o.d. was compared with losartan 50 mg o.d. [56]. After
`4 weeks, the dose of both drugs could be doubled.
`Blood pressure reductions were similar, however, the
`responder rate of 62% under valsartan was signifi-
`cantly (p = 0.02) higher than under losartan (55%).
`Bremner et al. [57] treated 334 elderly patients (aged ‡
`65 years) with valsartan 40 mg o.d. (up to 80 mg o.d. ±
`HCTZ 12.5. mg/25 mg) or lisinopril 10 mg/20 mg o.d.
`(± HCTZ 12.5. mg/25 mg) over 1 year. Responder rates
`after 1 year were comparable with 81% under
`valsartan and 87% under lisinopril, respectively.
`Worsening of dry cough occurred significantly more
`frequently in patients under lisinopril therapy, the
`overall incidence of drug-related adverse experiences
`
`was 29.3% in valsartan-treated patients versus 35.3%
`in lisinopril-treated patients.
`
`[58] valsartan-based therapy was
`In one trial
`compared with atenolol-based treatment in patients
`with severe hypertension (diastolic blood pressure ‡
`110 mmHg and < 120 mmHg) over 6 weeks.
`Co-medication with HCTZ was required in 77.8% of
`36 atenolol-treated patients versus 67.2% of 67
`valsartan-treated patients. However, further addition
`of verapamil was required by a higher percentage of
`valsartan-treated patients. The overall responder rate
`was 85.1% under valsartan and 86.1% under atenolol
`therapy.
`
`6.3 Clinical trials investigating combination
`therapy
`In addition to the aforementioned study in patients
`with severe hypertension, the efficacy of the combina-
`tion of valsartan with HCTZ was studied by Hall et al.
`[59] in 702 patients with mild to moderate essential
`hypertension. Patients received once daily valsartan
`80 mg, valsartan 160 mg, valsartan 80 mg plus HCTZ
`12.5 mg, or valsartan 80 mg plus HCTZ 25 mg over 8
`weeks. The responder rates were as follows: 36%,
`37%, 51% and 59%, respectively. Combination therapy
`
`© Ashley Publications Ltd. All rights reserved.
`
`Exp. Opin. Pharmacother. (2000) 1(2)
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1011, p. 007
`
`

`

`344 Valsartan: a novel angiotensin Type 1 receptor antagonist
`
`Table 3a: Randomised, parallel group trials comparing valsartan with angiotensin converting enzyme-inhibitors in patients with
`mild to moderate hypertension.
`
`Drug
`
`No. of
`patients
`
`Dosage
`
`Duration
`(weeks)
`
`Response rate§
`
`Valsartan vs.
`comparator
`
`Ref.
`
`BP
`reduction
`(mmHg)
`12.3/9.5
`13.1/9.5
`19.7/15.5
`
`20.4/13.7
`
`NS
`
`NS
`
`[51]
`
`[52]
`
`NS
`
`[53]
`
`Valsartan
`Enalapril
`Valsartan
`
`Enalapril
`
`137
`69
`94
`
`95
`
`80 mg o.d.
`20 mg o.d.
`80 mg o.d. ± HCTZ
`
`20 mg o.d. ± HCTZ
`
`8
`8
`12
`
`12
`
`80 mg/160 mg o.d.
`80 mg o.d./80 mg b.i.d.
`10 mg/20 mg o.d.
`
`54%
`58%
`60.6% (monotherapy);
`68.1% + HCTZ
`52.6% (monotherapy);
`66.3% + HCTZ
`Placebo
`142
`8
`5.7/4.5
`20%
`Valsartan
`177
`12
`11/9
`44.1%
`Valsartan
`187
`12
`8.3/9
`48.7%
`Lisinopril
`187
`12
`12/10.2
`57.2%
`Placebo
`183
`12
`2/3.5
`21.3%
`§Response rate: response rate was defined as a reduction of diastolic blood pressure by more than 10 mmHg and/or sitting diastolic
`blood pressure < 90 mmHg before morning drug intake.
`§§Diastolic blood pressure.
`BP: Blood pressure; HCTZ: Hydrochlorothiazide.
`
`with valsartan 80 mg o.d. and 12.5 mg HCTZ seems to
`be more effective than treatment with valsartan 160
`mg o.d.
`
`and from 127 ± 25 to 117 ± 27 g/m2 under atenolol
`therapy. Comparable results were recently reported
`for losartan [62] and irbesartan [63].
`
`In the trial by Benz et al. [60] 871 patients were
`randomised to receive either monotherapy with
`valsartan 80/160 mg, HCTZ 12.5/25 mg or combina-
`tion treatment with valsartan 80 mg plus HCTZ
`12.5/25 mg or valsartan 160 mg plus HCTZ 12.5/25
`mg, respectively, or placebo over 8 weeks. Again,
`combination therapy was statistically significantly
`more effective in comparison to monotherapy. In
`addition, the combination therapy proved to offer a
`beneficial influence on serum electrolyte balance, i.e.,
`the incidence of HCTZ-induced hypokalaemia was
`markedly reduced by concomitant valsartan.
`
`6.4 Clinical trials in patients with essential
`hypertension and end-organ disease
`In a randomised trial the effect of valsartan 80 mg o.d.
`(160 mg o.d. ± 25 mg HCTZ) was compared with
`atenolol 50 mg o.d. (100 mg o.d. ± 25 mg HCTZ) in
`hypertensive patients with echocardiographically
`proven left ventricular hypertrophy [61]. Blood
`pressure was controlled to a comparable degree after
`8 months of treatment with both drugs, 9 patients in
`the valsartan group and 8 patients in the atenolol
`group required additional medication with HCTZ. Left
`ventricular mass index decreased from 127 ± 23 to 106
`± 25 g/m2 under valsartan (p < 0.0001 vs. baseline)
`
`Nine hypertensive patients with stable renal disease
`(SRD) received either valsartan 80 mg o.d. or placebo
`over 6 months [64]. Proteinuria decreased by 26 ± 18%
`under valsartan whereas an increase by 30 ± 43%
`occurred under placebo. Fractional clearance of high
`molecular weight dextranes decreased significantly,
`glomerular filtration rate and effective renal blood
`flow remained stable.
`
`Faulhaber et al. [65] administered either valsartan 80
`mg o.d. (n = 30) or placebo (n = 26) to hypertensive
`patients with SRD on top of their antihypertensive
`medication over 6 months. Blood pressure was
`reduced by 14.3 mmHg systolic and 7.8 mmHg
`diastolic, however, changes in renal function parame-
`ters were not observed.
`
`A comparable patient population was studied by
`Perico et al. [66], before and after 13 weeks treatment
`with valsartan 40/80 mg o.d. or lisinopril 5/10 mg o.d.
`Both drugs provided comparable blood pressure
`control and no significant differences were observed
`for renal function parameters.
`
`Muirhead et al. [67] compared the effects of captopril
`25 mg t.i.d. with valsartan 80/160 mg o.d. in 122
`normotensive or treated hypertensive patients with
`diabetes Type 2 and SRD. No significant differences
`
`© Ashley Publications Ltd. All rights reserved.
`
`Exp. Opin. Pharmacother. (2000) 1(2)
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1011, p. 008
`
`

`

`Table 3b: Randomised, parallel group trials comparing valsartan with other antihypertensive drugs in patients with mild to moderate
`hypertension.
`
`Thürmann 345
`
`Drug
`
`No. of
`patients
`
`Dosage
`
`Duration
`(weeks)
`
`Response rate§
`
`V vs.
`comparator
`
`Ref.
`
`BP
`reduction
`(mmHg)
`Valsartan
`84
`12
`16.5/13.5
`66.7% (monotherapy)
`Amlodipine
`84
`12
`19.3/14.8
`60.2% (monotherapy)
`Valsartan
`82
`12
`18.2/15.2
`73.8% (monotherapy)
`HCTZ
`85
`12
`21.6/15.1
`61.7% (monotherapy)
`Valsartan
`551
`8
`10.5
`61.6%
`Losartan
`545
`8
`9.7
`54.5%
`Placebo
`273
`8
`5
`29.3%
`§Response rate: response rate was defined as a reduction of diastolic blood pressure by more than 10 mmHg and/or sitting diastolic
`blood pressure < 90 mmHg before morning drug intake.
`§§Diastolic blood pressure.
`BP: Blood pressure; HCTZ: Hydrochlorothiazide.
`
`80 mg ± amlo. 5 mg
`5 mg ± amlo. 5 mg
`80 mg ± atenolol 50 mg
`25 mg ± atenolol 50 mg
`80 mg/160 mg o.d.
`50 mg/100 mg o.d.
`
`NS
`
`NS
`
`[54]
`
`[55]
`
`[56]
`p < 0.05
`in favour of valsartan
`
`occurred between captopril and valsartan with regard
`to microalbuminuria, HbA1c and blood pressure
`control.
`
`The combination of benazepril and valsartan in 109
`treated hypertensive patients with SRD given over 5
`weeks appeared to be safe and was effective with
`regard to further blood pressure decrease and
`proteinuria [68]. However,
`the incidence of
`hyperkalaemia was slightly higher in the combination
`group versus monotherapy.
`
`7. Clinical trials with valsartan in heart
`failure
`
`The haemodynamic and hormonal effects of valsartan
`in patients with chronic heart failure were studied in
`patients with and without ACE inhibitor therapy
`[69,70].
`
`In 103 patients on stable therapy with digitalis and
`diuretics, valsartan in the dose range 40 - 160 mg
`produced significant decreases of pulmonary
`capillary wedge pressure in comparison to pla