U.S. patent application number 17/131312 was filed with the patent office on 2021-04-15 for angiotensin ii receptor antagonist for the prevention or treatment of systemic diseases in cats.
The applicant listed for this patent is Boehringer Ingelheim Vetmedica GmbH. Invention is credited to Balazs ALBRECHT, Sven ANKE, Saskia KLEY, Stefan Johannes LEHNER, Marcus STARK, Anne Michelle TRAAS, Tanja Margrit ZIMMERING.
Application Number | 20210106564 17/131312 |
Document ID | / |
Family ID | 1000005300360 |
Filed Date | 2021-04-15 |
United States Patent
Application |
20210106564 |
Kind Code |
A1 |
ALBRECHT; Balazs ; et
al. |
April 15, 2021 |
ANGIOTENSIN II RECEPTOR ANTAGONIST FOR THE PREVENTION OR TREATMENT
OF SYSTEMIC DISEASES IN CATS
Abstract
A method is described for the prophylaxis or treatment of
hypertension in a cat in need of such treatment. The method
includes administration of a therapeutically effective amount of
angiotensin II receptor 1 (AT-1) antagonist (sartan) to the cat,
where the therapeutically effective amount of the sartan is
administered in a daily dosage amount that is varied over a
treatment period, the daily dosage amount of the sartan for a first
period of time during the treatment period is 1.0 to 5.0 mg/kg of
body weight, and the daily dosage amount of the sartan is decreased
for a second period of time subsequent the first period of time
during the treatment period.
Inventors: |
ALBRECHT; Balazs;
(Sprendlingen, DE) ; ANKE; Sven; (Frankfurt am
Main, DE) ; KLEY; Saskia; (Appenheim, DE) ;
LEHNER; Stefan Johannes; (Wiesbaden, DE) ; STARK;
Marcus; (Ingelheim am Rhein, DE) ; TRAAS; Anne
Michelle; (Saint Joseph, MO) ; ZIMMERING; Tanja
Margrit; (Heidesheim am Rhein, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Boehringer Ingelheim Vetmedica GmbH |
Ingelheim am Rhein |
|
DE |
|
|
Family ID: |
1000005300360 |
Appl. No.: |
17/131312 |
Filed: |
December 22, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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16027422 |
Jul 5, 2018 |
10905676 |
|
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17131312 |
|
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62529587 |
Jul 7, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/4184 20130101;
A61K 31/4178 20130101; A61P 9/12 20180101; A61K 9/0053
20130101 |
International
Class: |
A61K 31/4178 20060101
A61K031/4178; A61K 9/00 20060101 A61K009/00; A61P 9/12 20060101
A61P009/12; A61K 31/4184 20060101 A61K031/4184 |
Claims
1. A method for the prophylaxis or treatment of hypertension in a
cat in need of such prophylaxis or treatment, the method comprising
administering a therapeutically effective amount of an angiotensin
II receptor 1 (AT-1) antagonist (sartan) to the cat, wherein the
therapeutically effective amount of the sartan is administered in a
daily dosage amount that is varied over a treatment period, the
daily dosage amount of the sartan for a first period of time during
the treatment period is 1.0 to 5.0 mg/kg of body weight, and the
daily dosage amount of the sartan is decreased for a second period
of time subsequent the first period of time during the treatment
period.
2. The method of claim 1, wherein the hypertension is associated
with chronic kidney disease or hyperthyroidism.
3. The method of claim 1, wherein the hypertension is idiopathic
hypertension.
4. The method of claim 1, wherein the daily dosage amount is varied
based upon a systolic blood pressure (SBP) value measured for the
cat.
5. The method of claim 1, wherein the daily dosage amount of the
sartan is decreased for the second period of time by an incremental
amount ranging from 0.10 to 0.50 mg/kg of body weight.
6. The method of claim 5, wherein the daily dosage amount of the
sartan is decreased when a systolic blood pressure (SBP) value
measured for the cat decreases by at least 10 mmHg, or at least 20
mmHg, or by 10 to 150 mmHg, 10 to 100 mmHg, 10 to 80 mmHg, 10 to 50
mmHg, 10 to 30 mmHg, 10 to 20 mmHg, 20 to 150 mmHg, 20 to 100 mmHg,
20 to 80 mmHg, 20 to 50 mmHg, or 20 to 30 mmHg in relation to a
baseline SBP value measured for the cat prior to the first period
of time.
7. The method of claim 1, wherein the daily dosage amount of the
sartan is decreased when a systolic blood pressure (SBP) value
measured for the cat decreases from a baseline SBP value measured
for the cat prior to the first period of time to (at or below) a
threshold value.
8. The method of claim 7, wherein the threshold value is 160 or 170
mmHg.
9. The method of claim 1, wherein the daily dosage amount of the
sartan for the second period of time is increased or decreased for
a third period of time after the second period of time and based
upon a change in SBP of the cat that is measured at an end of the
second period of time.
10. The method of claim 1, wherein the daily dosage amount of the
sartan for a first period of time during the treatment period is
2.0 to 3.0 mg/kg of body weight, and the daily dosage amount of the
sartan for the second period of time is 0.125 to 2.0 mg/kg of body
weight.
11. The method of claim 1, wherein the first period of time is at
least 14 days, or at least 28 days, or at least 120 days.
12. The method of claim 1, wherein the daily administration is an
oral administration.
13. The method of claim 1, wherein the daily administration of the
therapeutically effective amount for at least a portion of the
treatment period is provided in a single dose.
14. The method of claim 1, wherein the daily administration of the
therapeutically effective amount for at least a portion of the
treatment period is provided in a plurality of doses.
15. The method of claim 1, wherein the method excludes
administration of the therapeutically effective amount of
angiotensin II receptor 1 (AT-1) antagonist (sartan) to a cat
having an age that is less than 9 months or wherein the angiotensin
II receptor 1 (AT-1) antagonist (sartan) is administered to a cat
at least 9 months of age or wherein the angiotensin II receptor 1
(AT-1) antagonist (sartan) is administered to a cat 9 months of age
and older.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. patent application
Ser. No. 16/027,422, filed Jul. 5, 2018, which claims priority from
U.S. Provisional Patent Application Ser. No. 62/529,587, filed Jul.
7, 2017, the disclosures of which are incorporated herein by
reference in their entireties.
FIELD OF THE INVENTION
[0002] The present invention relates to the field of veterinary
medicine, especially to the prophylaxis or treatment of systemic
diseases in cats. In particular, the present invention relates to a
method of prophylaxis or treatment of systemic diseases in cats,
wherein the method comprising administration of a therapeutically
effective amount of angiotensin II receptor 1 (AT-1) antagonist
(sartan) to a cat in need of such a treatment.
BACKGROUND OF THE INVENTION
[0003] The prevalence of renal disease is high in aged cats,
whereas chronic renal failure is considered the most important one.
The prevalence of chronic kidney disease (CKD) in cats is reported
to reach up to 20% with 53% of cats were older than 7 years
(Lefebre, Toutain 2004, J. Vet. Pharm. Therap. 27, 265-281; Wolf A
M North. Am. Vet. Congress 2006). Survival in cats with mild to
moderate azotemia and extrarenal clinical signs (IRIS stage 2 &
3) ranged from 1 to 3 years. Early management and therapy is
considered to successfully influence prognosis for CKD (Wolf A M
North Am. Vet Congress 2006).
[0004] Chronic renal failure (CRF), at least in its final stage is,
regardless of the underlying causes, characterized by irreversible
structural lesions of the kidney. Thereby, progressive irreversible
lesions initially localized to one portion of the nephron (e.g.
glomeruli, peritubular capillaries, tubules or interstitial
tissue), are eventually responsible for the development of lesions
in the remaining, but initially unaffected portions of nephrons due
to their functional interdependencies. New nephrons cannot be
formed to replace others irreversibly destroyed by disease. In a
study of biopsy findings in cats with primary renal azotemia,
tubulointerstitial nephritis was observed in 70%,
glomerulonephropathy occurred in 15%, lymphoma in 11% and
amyloidosis was observed in 2% of the samples. CRF is recognized by
reduced kidney function or the presence of kidney damage (Polzin,
Osborne, Ross 2005 in: Ettinger S J, Feldman C E (eds.) Textbook of
Veterinary Internal Medicine, 6.sup.th, Vol 2. Chapter 260,
1756-1785).
[0005] Angiotensin II plays an important part in pathophysiology,
particularly as the most potent agent for increasing blood pressure
in humans. It is known that in addition to its effect of raising
blood pressure Angiotensin II also has growth-promoting effects
which contribute to left ventricular hypertrophy, vascular
thickening, atherosclerosis, renal failure and stroke. In small
animals, inhibition of the effects of Angiotensin II, via either
ACE inhibitors have been shown to exhibit renoprotectiv effects
through their simultaneous capacity to decrease blood pressure and
control proteinuria.
[0006] Current therapy aims to delay the progression of the disease
in cats by improving renal function, especially glomerular function
by maintaining glomerular perfusion. This includes dietary protein
restriction, modification of dietary lipid intake, phosphate
restriction and treatment with angiotensin-converting enzyme (ACE)
inhibitors (P. J. Barber (2004) The Kidney, in: Chandler E A,
Gaskell C J, Gaskell R M (eds.) Feline Medicine and Therapeutics,
3rd edition, Blackwell Publishing, Oxford, UK).
[0007] ACE inhibitors, especially enalapril, benazepril, imidapril
and ramipril, have been initially developed in small animal
medicine to control chronic heart failure (CHF). Based on the
pathophysiological role of the renin-angiotensin-aldosterone system
(RAAS) in progression of chronic heart failure and in progression
of renal damage, these agents have been shown to be useful in the
treatment of chronic kidney disease (CKD) in order to delay
progression of disease and reduce morbidity and suffering in small
animals, including cats. Sound evidence for this is probably the
recent approval of benazepril in Europe for the treatment of feline
CRF (Lefebre Toutain, 2004 J Vet Pharm Therap 27, 265-281).
However, the renoprotection of ACE inhibitor was likely mediated by
the effect on proteinuria rather than by blood pressure reduction.
This has been shown for ramipril, since the effect on blood
pressure was comparable to that of placebo while the proteinuria
was reduced (Remuzzi et al., 2006, J Clin Invest 116, (2)
288-296).
[0008] From a clinical point of view, ACE inhibitors are not the
preferred target to block the RAAS because of the lack of
specificity for Angiotensin I and the "angiotensin escape"
phenomenon where alternate enzymatic pathways such a cathepsin,
trypsin or the heart chymase can also convert Angiotensin I.
Moreover, during long term treatment with ACE inhibitors, ACE
activity is upregulated and Angiotensin I levels are high due the
stimulated renin secretion (Burnier & Brunner, 2000, The
Lancet, 355, 637-645).
[0009] Thus, one objective of the present invention consists in
providing a new therapeutic approach for the treatment or
prophylaxis of cats against chronic kidney disease.
[0010] A further more general aspect of the present invention
consists in providing a new therapeutic approach for the treatment
or prophylaxis of cats against systemic diseases; preferably
against systemic diseases which are related to Angiotensin II or
associated with the renin-angiotensin-aldosterone system
(RAAS).
[0011] Still a further aspect of the present invention consists in
providing a new therapeutic approach for the treatment or
prophylaxis of cats against hypertension.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] FIG. 1 is a plot of inhibition of blood pressure increase by
angiotensin II receptor 1 antagonist.
[0013] FIG. 2 is a plot of change in systolic blood pressure from
baseline values for telmisartan and placebo groups for the studies
of Examples 4 and 5.
[0014] FIG. 3 depicts an overview of the study design for Example
6.
[0015] FIG. 4 is a box plot of change in systolic blood pressure
from baseline values for telmisartan and placebo groups for the
study of Example 6.
[0016] FIG. 5 is a plot of change in systolic blood pressure from
baseline values for telmisartan and placebo groups at day 14 and
day 28 for the study of Example 6.
[0017] FIGS. 6A and 6B depict an example embodiment of a medicament
containing and administration system for a kit in parts for use
with the methods described herein, where the system includes a
plunger and a container to store medicament.
DETAILED DESCRIPTION OF THE INVENTION
[0018] Before the embodiments of the present invention it shall be
noted that as used herein and in the appended claims, the singular
forms "a", "an", and "the" include plural reference unless the
context clearly dictates otherwise. Thus, for example, reference to
"a preparation" includes a plurality of such preparations,
reference to the "carrier" is a reference to one or more carriers
and equivalents thereof known to those skilled in the art, and so
forth. Unless defined otherwise, all technical and scientific terms
used herein have the same meanings as commonly understood by one of
ordinary skill in the art to which this invention belongs. All
given ranges and values may vary by 1 to 5% unless indicated
otherwise or known otherwise by the person skilled in the art,
therefore, the term "about" was omitted from the description.
Although any methods and materials similar or equivalent to those
described herein can be used in the practice or testing of the
present invention, the preferred methods, devices, and materials
are now described. All publications mentioned herein are
incorporated herein by reference for the purpose of describing and
disclosing the substances, excipients, carriers, and methodologies
as reported in the publications which might be used in connection
with the invention. Nothing herein is to be construed as an
admission that the invention is not entitled to antedate such
disclosure by virtue of prior invention.
[0019] The solution to the above technical problem is achieved by
the description and the embodiments characterized in the
claims.
[0020] In accordance with the present invention, methods are
described herein for the prophylaxis or treatment of hypertension
(also referred to as high blood pressure) in a cat in need of such
treatment, where the methods comprise administration of a
therapeutically effective amount of angiotensin II receptor 1
(AT-1) antagonist (sartan) to the cat, the therapeutically
effective amount of the sartan being administered in a daily dosage
amount that is varied over a treatment period. For example, the
daily dosage amount of the sartan for a first period of time during
the treatment period can be 1.0 to 5.0 mg/kg of body weight, where
the daily dosage amount of the sartan is decreased for a second
period of time subsequent the first period of time during the
treatment period.
[0021] In particular, the following items are disclosed herein:
[0022] 1. An angiotensin II receptor 1 (AT-1) antagonist (sartan)
for use in a method for the prophylaxis or treatment of
hypertension in a cat in need of such prophylaxis or treatment,
wherein the method comprises administration of a therapeutically
effective amount of angiotensin II receptor 1 (AT-1) antagonist
(sartan) to the cat, wherein the therapeutically effective amount
of the sartan is administered in a daily dosage amount that is
varied over a treatment period, the daily dosage amount of the
sartan for a first period of time during the treatment period is
1.0 to 5.0 mg/kg of body weight, and the daily dosage amount of the
sartan is decreased for a second period of time subsequent the
first period of time during the treatment period.
[0023] 2. The angiotensin II receptor 1 (AT-1) antagonist (sartan)
of item 1 for use in a method for the prophylaxis or treatment of
hypertension in a cat, wherein the hypertension is associated with
chronic kidney disease or hyperthyroidism.
[0024] 3. The angiotensin II receptor 1 (AT-1) antagonist (sartan)
of item 1 for use in a method for the prophylaxis or treatment of
hypertension in a cat, wherein the hypertension is idiopathic
hypertension.
[0025] 4. The angiotensin II receptor 1 (AT-1) antagonist (sartan)
of items 1 to 3 for use in a method for the prophylaxis or
treatment of hypertension in a cat, wherein the daily dosage amount
is varied based upon a systolic blood pressure (SBP) value measured
for the cat.
[0026] 5. The angiotensin II receptor 1 (AT-1) antagonist (sartan)
of items 1 to 4 for use in a method for the prophylaxis or
treatment of hypertension in a cat, wherein the daily dosage amount
of the sartan is decreased for the second period of time by an
incremental amount ranging from 0.10 to 0.50 mg/kg of body
weight.
[0027] 6. The angiotensin II receptor 1 (AT-1) antagonist (sartan)
of items 1 to 5 for use in a method for the prophylaxis or
treatment of hypertension in a cat, wherein the daily dosage amount
of the sartan is decreased when a systolic blood pressure (SBP)
value measured for the cat decreases by at least 10 mmHg in
relation to a baseline SBP value measured for the cat prior to the
first period of time.
[0028] 7. The angiotensin II receptor 1 (AT-1) antagonist (sartan)
of items 1 to 6 for use in a method for the prophylaxis or
treatment of hypertension in a cat, wherein the daily dosage amount
of the sartan is decreased when the SBP value measured for the cat
decreases by at least 20 mmHg in relation to the baseline SBP value
measured for the cat determined prior to the first period of
time.
[0029] 8. The angiotensin II receptor 1 (AT-1) antagonist (sartan)
of items 1 to 7 for use in a method for the prophylaxis or
treatment of hypertension in a cat, wherein the daily dosage amount
of the sartan is decreased when the SBP value measured for the cat
decreases by 10 to 150 mmHg, 10 to 100 mmHg, 10 to 80 mmHg, 10 to
50 mmHg, 10 to 30 mmHg, 10 to 20 mmHg, 20 to 150 mmHg, 20 to 100
mmHg, 20 to 80 mmHg, 20 to 50 mmHg, or 20 to 30 mmHg in relation to
the baseline SBP value measured for the cat determined prior to the
first period of time.
[0030] 9. The angiotensin II receptor 1 (AT-1) antagonist (sartan)
of items 1 to 8 for use in a method for the prophylaxis or
treatment of hypertension in a cat, wherein the daily dosage amount
of the sartan is decreased when a systolic blood pressure (SBP)
value measured for the cat decreases from a baseline SBP value
measured for the cat prior to the first period of time to a value
that is no greater than a threshold value.
[0031] 10. The angiotensin II receptor 1 (AT-1) antagonist (sartan)
of items 1 to 8 for use in a method for the prophylaxis or
treatment of hypertension in a cat, wherein the daily dosage amount
of the sartan is decreased when a systolic blood pressure (SBP)
value measured for the cat decreases from a baseline SBP value
measured for the cat prior to the first period of time to (at or
below) a threshold value.
[0032] 11. The angiotensin II receptor 1 (AT-1) antagonist (sartan)
of item 9 or 10 for use in a method for the prophylaxis or
treatment of hypertension in a cat, wherein the threshold value is
no greater than 160 or 170 mmHg.
[0033] 12. The angiotensin II receptor 1 (AT-1) antagonist (sartan)
of item 9 or 10 for use in a method for the prophylaxis or
treatment of hypertension in a cat, wherein the threshold value is
160 or 170 mmHg.
[0034] 13. The angiotensin II receptor 1 (AT-1) antagonist (sartan)
of items 1 to 12 for use in a method for the prophylaxis or
treatment of hypertension in a cat, wherein the daily dosage amount
of the sartan for the second period of time is increased or
decreased for a third period of time after the second period of
time and based upon a change in SBP of the cat that is measured at
an end of the second period of time.
[0035] 14. The angiotensin II receptor 1 (AT-1) antagonist (sartan)
of items 1 to 13 for use in a method for the prophylaxis or
treatment of hypertension in a cat, wherein the daily dosage amount
of the sartan for a first period of time during the treatment
period is 2.0 to 3.0 mg/kg of body weight, and the daily dosage
amount of the sartan for the second period of time is 0.125 to 2.0
mg/kg of body weight.
[0036] 15. The angiotensin II receptor 1 (AT-1) antagonist (sartan)
of items 1 to 14 for use in a method for the prophylaxis or
treatment of hypertension in a cat, wherein the first period of
time is at least 14 days, or at least 28 days, or at least 120
days.
[0037] 16. The angiotensin II receptor 1 (AT-1) antagonist (sartan)
of items 1 to 15 for use in a method for the prophylaxis or
treatment of hypertension in a cat, wherein the daily
administration is an oral administration.
[0038] 17. The angiotensin II receptor 1 (AT-1) antagonist (sartan)
of items 1 to 16 for use in a method for the prophylaxis or
treatment of hypertension in a cat, wherein the daily
administration of the therapeutically effective amount for at least
a portion of the treatment period is provided in a single dose.
[0039] 18. The angiotensin II receptor 1 (AT-1) antagonist (sartan)
of items 1 to 16 for use in a method for the prophylaxis or
treatment of hypertension in a cat, wherein the daily
administration of the therapeutically effective amount for at least
a portion of the treatment period is provided in a plurality of
doses.
[0040] 19. The angiotensin II receptor 1 (AT-1) antagonist (sartan)
of items 1 to 18 for use in a method for the prophylaxis or
treatment of hypertension in a cat, wherein the method excludes
administration of the therapeutically effective amount of
angiotensin II receptor 1 (AT-1) antagonist (sartan) to a cat
having an age that is less than 9 months.
[0041] 20. The angiotensin II receptor 1 (AT-1) antagonist (sartan)
of items 1 to 18 for use in a method for the prophylaxis or
treatment of hypertension in a cat, wherein the angiotensin II
receptor 1 (AT-1) antagonist (sartan) is administered to a cat at
least 9 months of age or a cat 9 months of age and older.
[0042] 21. A method for the prophylaxis or treatment of
hypertension in a cat in need of such treatment, wherein the method
comprises administration of a therapeutically effective amount of
angiotensin II receptor 1 (AT-1) antagonist (sartan) to the cat,
wherein the therapeutically effective amount of the sartan is
administered in a daily dosage amount that is varied over a
treatment period, the daily dosage amount of the sartan for a first
period of time during the treatment period is 1.0 to 5.0 mg/kg of
body weight, and the daily dosage amount of the sartan is decreased
for a second period of time subsequent the first period of time
during the treatment period.
[0043] 22. The method of item 21, wherein the hypertension is
associated with chronic kidney disease or hyperthyroidism.
[0044] 23. The method of item 21, wherein the hypertension is
idiopathic hypertension.
[0045] 24. The method of any of items 21 to 23, wherein the daily
dosage amount is varied based upon a systolic blood pressure (SBP)
value measured for the cat.
[0046] 25. The method of any of items 21 to 24, wherein the daily
dosage amount of the sartan is decreased for the second period of
time by an incremental amount ranging from 0.10 to 0.50 mg/kg of
body weight.
[0047] 26. The method of any of items 21 to 25, wherein the daily
dosage amount of the sartan is decreased when a systolic blood
pressure (SBP) value measured for the cat decreases by at least 10
mmHg in relation to a baseline SBP value measured for the cat prior
to the first period of time.
[0048] 27. The method of item 26, wherein the daily dosage amount
of the sartan is decreased when the SBP value measured for the cat
decreases by at least 20 mmHg in relation to the baseline SBP value
measured for the cat determined prior to the first period of
time.
[0049] 28. The method of any of items 21 to 25, wherein the daily
dosage amount of the sartan is decreased when a systolic blood
pressure (SBP) value measured for the cat decreases from a baseline
SBP value measured for the cat prior to the first period of time to
a value that is no greater than a threshold value.
[0050] 29. The method of item 28, wherein the threshold value is no
greater than 160 or 170 mmHg.
[0051] 30. The method of any of items 21 to 29, wherein the daily
dosage amount of the sartan for the second period of time is
increased or decreased for a third period of time after the second
period of time and based upon a change in SBP of the cat that is
measured at an end of the second period of time.
[0052] 31. The method of any of items 31 to 30, wherein the daily
dosage amount of the sartan for a first period of time during the
treatment period is 2.0 to 3.0 mg/kg of body weight, and the daily
dosage amount of the sartan for the second period of time is 0.125
to 2.0 mg/kg of body weight.
[0053] 32. The method of any of items 21 to 31, wherein the first
period of time is at least 14 days, or at least 28 days, or at
least 120 days.
[0054] 33. The method of any of items 21 to 32, wherein the daily
administration is an oral administration.
[0055] 34. The method of any of items 21 to 33, wherein the daily
administration of the therapeutically effective amount for at least
a portion of the treatment period is provided in a single dose.
[0056] 35. The method of any of items 21 to 33, wherein the daily
administration of the therapeutically effective amount for at least
a portion of the treatment period is provided in a plurality of
doses.
[0057] 36. The method of any of items 21 to 35, wherein the method
excludes administration of the therapeutically effective amount of
angiotensin II receptor 1 (AT-1) antagonist (sartan) to a cat
having an age that is less than 9 months.
[0058] 37. A kit in parts comprising:
[0059] a container containing a pharmaceutical composition in a
liquid formulation comprising an angiotensin II receptor 1 (AT-1)
antagonist (sartan) and one or more pharmaceutically acceptable
diluents and/or carriers, the amount of sartan being within the
liquid formulation in an amount that is therapeutically effective
for the prophylaxis or treatment of hypertension in a cat in need
of such treatment; and
[0060] a syringe comprising a barrel optionally having volumetric
graduation marks optionally imprinted thereon in 0.25 mL increments
or less or in 0.10 mL increments or less.
[0061] 38. The kit in parts of item 37, further comprising an
adaptor that connects with an open end of the container, the
adaptor including an opening extending through the adaptor, wherein
the adaptor opening is smaller in dimension than the container open
end.
[0062] 39. The kit in parts of item 37 or item 38, wherein the
syringe barrel includes an open end having a geometry that
corresponds with a geometry of the adaptor opening to facilitate a
frictional fit between the barrel open end and the adaptor when the
barrel open end is inserted into the adaptor opening.
[0063] 40. The method of any of items 21 to 35 or the kit in parts
of any one of items 37 to 39, wherein the cat is at least 9 months
of age or is a cat 9 months of age and older.
[0064] The use of angiotensin II receptor 1 antagonists (sartans)
in cats for an indication is known. Blockage of angiotensin II
receptor 1 is a treatment concept which differs from blockage of
angiotensin converting enzyme as known from the ACE-inhibitors.
Receptor blockage is more specific and complete and further
downstream in the physiologic cascade of the RAAS system. The
present invention is based on certain unexpected findings, namely,
that a dosage of sartan for prophylaxis or treatment of
hypertension in a cat can be down titrated or decreased over a
treatment period, particularly when the response in the cat is
determined to be positive from such treatment (e.g., a systolic
blood pressure of the cat is reduced as a result of such treatment
and is further maintained at or below a certain level even with a
reduction in dosage amount of the sartan being administered).
[0065] In studies, it has been found that cats tolerate a
pharmacodynamically effective dose of sartans. For example, in an
open-label study in nondiabetic, hypertensive human patients with
proteinuric nephropathies the effects on renal outcome of low (80
mg once daily) and high dose (80 mg twice daily) telmisartan were
compared. The results reinforced the concept that more effective
RAAS inhibition achieved by a high dose of 160 mg daily. This dose
corresponds to a plasma level of about 2800.+-.2400 ng/ml
(Cmax.+-.SD), which exceeds the no-effect doses in toxicities
studies in animals such as dogs and rats. (Investigator brochure
1994, data on file) The resulting dose of about 2 to 3 mg/kg body
weight and day was thus expected to be toxic in cats.
Pilot-toxicity studies have surprisingly shown that such a dose (up
to 3 mg/kg) is well tolerable in cats. As used herein, the term
"mg/kg" refers to dosage amount in mg per kg bodyweight of the
cat.
[0066] Moreover, it was found that sartans effectively block the
angiotensin II receptor 1 also in cats. This finding was
unexpected, as the absolute bioavailability in cats is very low and
the mean residence time and plasma half life are rather short in
cats as compared to human beings. The oral bioavailability was
calculated to 33.6% as compared to human beings. The mean tmax oral
was 0.44 hours and the Cmax oral was 138.1 ng/ml. The mean t112
oral was 2.17 hours. The mean AUC.fwdarw..about.oral was calculated
to 150 (ng.times.h/ml), and the mean V/f oral was 20.4 l/kg. The
mean AUC.fwdarw..about.intravenous was calculated to 385
(ng.times.h/ml). The mean t112 intravenous was 2.25 hours and the
mean V/f oral was 8.8 l/kg. From this information, which was newly
generated, it can be concluded that sartans, preferably
telmisartan, can be used to treat cats with systemic diseases, such
as chronic kidney disease, such as for example chronic renal
failure, including chronic renal insufficiency.
TABLE-US-00001 TABLE 1 Abbreviations Abbreviation Pharmacokinetic
parameters AUC area under the plasma concentration time curve C max
maximum measured plasma concentration V/f Volume of distribution
(V) whereas f is the absolute bioavailability MRT mean residence
time t 1/2 terminal half-live t max time to reach Cmax
[0067] Thus, in an embodiment, the present invention relates to a
method for the prophylaxis or treatment of a systemic disease in
cats, wherein the method comprises administration of a
therapeutically effective amount of angiotensin II receptor 1
(AT-1) antagonist (sartan) to that cat in need of such a
treatment.
[0068] The term "systemic disease", as used herein, means but is
not limited to cardiovascular such as dilated cardiomyopathy (DCM),
mitral valve insufficiency (MI), hypertrophic cardiomyopathy (HCM);
and other acquired or hereditary heart diseases, e.g.
cardiopulmonary diseases, systemic hypertension for example
hypertension associated with renal diseases, chronic renal failure
and other vascular diseases, or metabolic disorders such as
diabetes mellitus. Thus, according to another aspect, the present
invention relates to a method for the prophylaxis or treatment of a
systemic disease in cats by the administration of therapeutically
effective amount of said angiotensin II receptor 1 (AT-1)
antagonist (sartan) to that cat, wherein the systemic disease is
selected from the group of cardiovascular diseases, such as dilated
cardiomyopathy (DCM), mitral valve insufficiency (MI), hypertrophic
cardiomyopathy (HCM) and other acquired or hereditary heart
diseases, hypertension (including systemic hypertension), metabolic
disorders like diabetes mellitus.
[0069] The term "systemic hypertension", as used herein, means but
is not limited to, forms of hypertension associated with renal
diseases, chronic renal failure and other vascular diseases. For
example, systemic hypertension can include hypertension of an
unknown cause, hypertension associated with chronic kidney disease,
hypertension associated with hyperthyroidism, controlled
hypertension and idiopathic hypertension. In particular, systemic
hypertension (also referred to herein as hypertension) is defined
as a persistent elevation of the systemic blood pressure (e.g.,
having a Systolic Blood Pressure or SBP of 160 mmHg or greater).
There are two subclassifications of hypertension: primary (or
idiopathic) hypertension in which no underlying disease can be
identified, and secondary hypertension occurring as a complication
of a systemic disease. In recent years, idiopathic hypertension has
been increasingly recognized in small animal medicine. The most
common causes for secondary hypertension in cats are chronic kidney
disease (CKD) and hyperthyroidism. Other diseases such as
hyperaldosteronism or pheochromocytoma are very rare causes for
secondary hypertension in cats and usually result in severe and
often therapy resistant hypertension.
[0070] The pathogenesis of idiopathic hypertension in feline
patients is not fully understood. However, activation of
renin-angiotensin-aldosteron system (RAAS) is thought to be present
in affected cats. Chronic kidney disease related HT is believed to
be induced by the activation of RAAS and eventually aldosterone
production. Effects are mainly mediated through the angiotensin-II
receptor type 1 (AT-1). Chronic RAAS activation leads to persistent
hypertension via systemic vasoconstriction, intravascular fluid
expansion and sympathetic activation. The underlying mechanism of
hypertension secondary to feline hyperthyroidism remains
undetermined, although dysfunction of RAAS is suspected. In some
cats, hyptertnsion is present at the time of diagnosis of
hyperthyroidism, while in others hypertension develops after
euthyroid state has been restored.
[0071] Regardless of the cause, hypertension can result in local or
systemic disease via destructive effects to vascular beds of
various organs. Clinically, hypertension related damage is
frequently recognized in the eyes, brain, kidney, heart and the
vessels. According to the ACVIM consensus panel on hypertension in
dogs and cats (Brown et al. Guidelines for the identification,
evaluation, and management of systemic hypertension in dogs and
cats. ACVIM Consensus Statement. J Vet Intern Med 2007; 21:
542-558), injury to these organs resulting from persistent
elevation of systolic blood pressure (SBP) is collectively termed
target organ damage (TOD), where TOD refers to a continuum of
reversible to irreversible injury and relatively mild to
potentially life-threatening consequences. Hypertension in cats
possesses a significant risk for further organ damage. Activation
and/or dysfunction of RAAS appears to play a crucial role in the
development of feline hypertension of various causes. Consequently,
RAAS inhibition seems a reasonable therapeutic target for
hypertensive cats with either idiopathic hypertension, or secondary
hypertension due to CKD or hyperthyroidism.
[0072] Thus, in another embodiment, the present invention relates
to a method for the prophylaxis or treatment of systemic
hypertension (also referred to herein as hypertension) in cats,
where the method comprises administration of a therapeutically
effective amount of angiotensin II receptor 1 (AT-1) antagonist
(sartan) to a cat in need of such a treatment, where the
hypertension is associated with one or more other systemic diseases
including (without limitation) CKD, hyperthyroidism, controlled
hypertension and idiopathic hypertension. In a further embodiment,
the therapeutically effective amount of the sartan is administered
to a cat in a daily dosage amount that is varied over a treatment
period. The variation of the treatment period can be a daily dosage
amount of the sartan for a first period of time during the
treatment period that is 1.0 to 5.0 mg/kg of body weight, and the
daily dosage amount of the sartan is decreased for a second period
of time subsequent the first period of time during the treatment
period. The daily dosage amount of the sartan can be decreased for
the second period of time by an incremental amount ranging from
0.10 to 0.50 mg/kg of body weight. In an embodiment, the daily
dosage amount of the sartan can be decreased for the second period
of time by an incremental amount ranging from 0.10 to 0.50 mg/kg of
the cat's body weight. The daily dosage amount of the sartan can be
decreased based upon a certain criteria for the cat, such as a
measured systolic blood pressure (SBP) of the cat. For example, the
daily dosage amount of the sartan can be decreased when a SBP value
measured for the cat decreases by at least 10 mmHg in relation to a
baseline SBP value measured for the cat prior to the first period
of time. In another embodiment, the daily dosage amount of the
sartan can be decreased when a SBP value measured for the cat is no
greater than a predetermined or threshold value (e.g., 120 mmHg).
As described herein, a daily dosage amount of sartan can be further
decreased in any suitable amounts for any number of consecutive
dosage periods and based upon a positive response by the cat to
such decreased dosage.
[0073] In humans, angiotensin II receptor 1 (AT1 receptor
antagonists (sartans) are known to significantly reduce proteinuria
in both diabetic and non-diabetic patients, even in those with mild
to moderate chronic renal failure (CRF). Moreover, there is
published evidence for the efficacious use of AT1 receptor
antagonists for treatment of nephropathies in type II diabetes
Cupisti A, et al., 2003, Biomed Pharmacother; 57 (3-4): 169-172;
Rysava R, et al., 2005, Press Monit; (10(4): 207-213; WO92/10182).
In cats tubulointerstitial nephritis is reported to be the major
causative (>70%) finding for CRF whereas in human beings and
dogs glomerulonephropathy is more prominent compared to cats.
Glomerular lesions are more often seen in dogs and humans and
consequently the clinical finding of moderate to marked
proteinuria, resulting from loss of glomerular permselectivity, is
more common in dogs and humans. Tubulointerstitial nephritis as
seen in cats showed less proteinuria. Proteinuria is recognized as
an important predictor of disease progression in humans and dogs
with spontaneous kidney disease and reduction of proteinuria is
associated with improved outcome in clinical trials to show the
renoprotective effects of blocking the RAAS by either ACE or ARBs
in human suffering from nephropathy (Karalliede & Viberti, J
Human Hypertension 2006). Due to the fact that there is less
proteinuria in cats because of the tubulointerstitial origin of
CRF, the reduction of proteinuria as renoprotective effect in
delaying progression of CRF might be expected to be less important
in this species. However, in a clinical field trial an independent
and significant correlation between proteinuria (determined as UPC)
and survival in cats suffering from CRF have been reported.
Surprisingly, even in azotemic cats with only minor proteinuria
(acc. to IRIS, UPC<0.25) this correlation was evident (Syme,
Elliot 2006, J Vet Intern Med, 20, 528-535).
[0074] Thus, according to a preferred embodiment the systemic
disease is chronic kidney disease, preferably chronic renal
failure, e.g. as defined as stage II to IV in Table 2.
[0075] The diagnosis of reduced kidney function such as chronic
renal failure is based upon exclusion of pre- and postrenal causes
and standard blood markers, e.g. urea and creatinine in plasma or
serum. Abnormal concentrations of these parameters are described as
azotemia. Standard urine markers of reduced kidney function include
urine specific gravity, proteinuria and others (Polzin D J, Osborne
C A, Ross S, 2005: Chronic Kidney Disease, In: Ettinger S J,
Feldman E C (ed.) Textbook of Veterinary Internal Medicine 6.sup.th
edition, W.B. Saunders Company, Philadelphia, USA). The
international renal interest society (IRIS) has proposed a staging
system based on azotemia to define CRF patients (Polzin D J 2006:
Treating feline kidney disease: an evidence-based approach,
Proceedings of The North American Veterinary Conference). The main
category for staging being plasma creatinine [mg/dl], which is
completed by two subcategories independent from stage, urine
protein:creatinine ratio (UPC) and blood pressure [mmHg]. With the
applied system, feline patients are staged along a continuum of
progressive kidney disease.
TABLE-US-00002 TABLE 2 Stages of feline chronic kidney disease
Subcategory Sub- systolic category blood pressure Plasma UPC (mmHg,
creatinine (independent independent Stage (mg/dl) Comments from
stage) from stage) I <1.6 Non-azotemic: some <0.2 = Non-
<150 = minimal other renal abnor- proteinuric risk of end-organ
mality is present 0.2-0.4 = damage II 1.6-2.8 Mildly azotemic:
Borderline 150-159 = low usually mild clinical proteinuric risk of
end-organ signs >0.4 = damage III 2.9-5.0 Moderately azotemic:
Proteinuric 160-179 = mod- many extra-renal erate risk of end-
clinical signs organ damage IV >5.0 Severly azotemic:
.gtoreq.180 = high risk invasive life support of end-organ methods
required damage
[0076] As described herein, a method for the prophylaxis or
treatment of chronic renal failure in cats comprises administration
of a therapeutically effective amount of angiotensin II receptor 1
(AT-1) antagonist (sartan) to that cat in need of such a treatment
and wherein said chronic renal failure is characterized by any one
of the clinical manifestations as listed in table 2, or any
combination thereof. For example, the present invention relates to
a method for the prophylaxis or treatment of cats having an plasma
creatine of .gtoreq.1.6 (mg/dl of blood), and/or having a
proteinuric of .gtoreq.0.2 (subcategory UPC), wherein the method
comprises administration of a therapeutically effective amount of
angiotensin II receptor 1 (AT-1) antagonist (sartan) to that cat in
need of such a treatment.
[0077] A comprehensive list of angiotensin II receptor antagonists
can be found on pages 2 to 22 of WO 92/10182 and pages 7 to 18 of
WO 95/26188, which all are incorporated herein by reference.
Angiotensin II receptor antagonists are described inter alia in
EP-A-253310, EP-A-323841, EP-A-324377, EP-A-420237, EP-A-443983,
EP-A-459136, EP-A-475206, EP-A-502314, EP-A-504888, EP-A-514198, WO
91/14679, WO 93/20816, WO 02/092081, U.S. Pat. Nos. 4,355,040,
4,880,804 and 6,028,091. Forms which are frequently mentioned are
sartans, such as candesartan, eprosartan, irbesartan, losartan,
olmesartan, tasosartan, telmisartan or valsartan. Those which are
particularly preferred according to the present invention are
irbesartan, losartan und telmisartan. All of these sartans, or
pharmaceutical salts or polymorphs thereof are well known to a
person skilled in the art, and its use is within the meaning of the
present invention.
[0078] Thus the present invention relates to a method for the
prophylaxis or treatment of cats suffering from a systemic disease,
preferably from chronic kidney disease, e.g. chronic renal failure,
wherein the method comprising administration of a therapeutically
effective amount of angiotensin II receptor 1 (AT-1) antagonist
(sartan) to that cat in need of such a treatment and wherein the
angiotensin II receptor 1 (AT-1) antagonist (sartan) is selected
from the group consisting of: candesartan, eprosartan, irbesartan,
losartan, olmesartan, tasosartan, telmisartan or valsartan,
preferably of irbesartan, losartan und telmisartan.
[0079] Telmisartan is an angiotensin II receptor antagonist
developed for the treatment of hypertension and other medical
indications as disclosed in EP-A-502314. Its chemical name is
4'-[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-ylme-
thyl]-biphenyl-2-carboxylic acid having the following
structure:
##STR00001##
[0080] Telmisartan is already sold on the market under the trade
name Micardis.RTM. (Boehringer Ingelheim, Germany) for
treatment/prophylaxis of humans. Telmisartan is also licensed in
the EU under the trade name Semintra.RTM. for the reduction of
proteinuria associated with CKD in cats. It exists in two
polymorphic forms as disclosed in WO 00/43370, U.S. Pat. Nos.
6,358,986 and 6,410,742. Sodium salts of telmisartan and its
solvate, hydrate, and hemihydrate are disclosed in WO
03/037876.
[0081] Thus, according to a further embodiment, the present
invention relates to a method for the prophylaxis or treatment of a
systemic disease in cats, such as chronic kidney disease, e.g.
chronic renal failure, wherein the method comprising administration
of a therapeutically effective amount of telmisartan or
pharmaceutically acceptable salt thereof, preferably of a
telmisartan as mentioned above.
[0082] As already mentioned herein, it has been surprisingly found
that use of telmisartan effectively inhibits the angiotensin II
receptor pressure response in cats. Moreover, it has been found
that doses of less than 0.05 mg telmisartan per kg body weight of
cat led to an inhibition of the blood pressure response of about
75% in the majority of the tested cats. Moreover, a study in
laboratory cats was established to investigate the Angiotensin II
induced increase in diastolic blood pressure prior to and after
administration of telmisartan. This test was established to
estimate the potency as well as the duration of action of sartans,
in particular of telmisartan in cats. Approximately 24 hours after
the last oral dosing, diastolic blood pressure responses to
increasing intravenous doses of Angiotensin II were significantly
reduced when the target dose of telmisartan was compared with
Placebo. Thus it could be concluded that administration of the
target dose, despite the short elimination half-life and
bioavailability, in the cat given once daily is capable to exhibit
the intended pharmacodynamic action and duration.
[0083] Thus, according to another aspect, the present invention
relates to a method for the prophylaxis or treatment of a systemic
disease in cats, preferably of chronic kidney disease, e.g. chronic
renal failure, wherein the method comprising administration of a
therapeutically effective amount of angiotensin II receptor 1
(AT-1) antagonist (sartan), preferably telmisartan or
pharmaceutically acceptable salt thereof, to that cat in need of
such a treatment, wherein the therapeutically effective amount of
such angiotensin II receptor 1 (AT-1) antagonist is about 0.01 to
about 10 mg/kg of body weight. Preferably, said therapeutically
effective amount of such angiotensin II receptor 1 (AT-1)
antagonist is about 0.05 to about 8 mg/kg of body weight, even more
preferably about 0.1 to about 5 mg/kg of body weight, even more
preferably about 0.2 to about 4 mg/kg of body weight, even more
preferably about 0.3 to about 3 mg/kg of body weight, even more
preferably about 0.4 to about 2.5 mg/kg of body weight, even more
preferably about 0.5 to about 2 mg/kg of body weight, most
preferred about 0.75 to about 1.5 mg/kg of body weight. Thus, said
therapeutically effective amount of such angiotensin II receptor 1
(AT-1) antagonist is for example 0.01, 0.02, 0.03, . . . 0.08,
0.09, 0.1, etc.; 0.11, 0.12, 0.125, 0.13, . . . 0.18, 0.19, 0.2,
etc.; 0.21, 0.22, 0.23, . . . 0.28, 0.29, 0.3 etc. . . . ; 0.81,
0.82, 0.83, . . . 0.88, 0.89, 0.9 etc.; 0.91, 0.92, 0.93, . . .
0.98, 0.99, 1.0 etc.; 1.01, 1.02, 1.03, . . . 1.08, 1.09, 1.1 etc.;
. . . 1.2, 1.3, . . . 1.8, 1.9, 2.0 etc.; 2.1, 2.2, 2.3, . . . 2.8,
2.9, 3.0 etc.; . . . ; 8.1, 8.2, 8.3, . . . 8.8, 8.9, 9.0 etc.;
9.1, 9.2, 9.3, . . . 9.8, 9.9, 10 mg/kg of body weight. Angiotensin
II receptor 1 (AT-1) antagonist, preferably telmisartan may be
administered once, twice or thrice a day in a daily dosage as
mentioned above.
[0084] In cases when angiotensin II receptor 1 (AT-1) antagonist is
administered by parenteral route, said angiotensin II receptor 1
(AT-1) antagonist, preferably telmisartan is administered in a
dosage of about 0.01 to about 4 mg/kg of body weight. Preferably,
said therapeutically effective amount of such angiotensin II
receptor 1 (AT-1) antagonist is about 0.05 to about 3 mg/kg of body
weight, even more preferably about 0.1 to about 2.5 mg/kg of body
weight, even more preferably about 0.15 to about 2.0 mg/kg of body
weight, even more preferably about 0.2 to about 1.5 mg/kg of body
weight, most preferred about 0.25 to about 1.25 mg/kg of body
weight. Thus, said therapeutically effective amount of such
angiotensin II receptor 1 (AT-1) antagonist is for example 0.01,
0.02, 0.03, . . . 0.08, 0.09, 0.1, etc.; 0.11, 0.12, 0.13, . . .
0.18, 0.19, 0.2, etc.; 0.21, 0.22, 0.23, . . . 0.28, 0.29, 0.3 etc.
. . . ; 0.81, 0.82, 0.83, . . . 0.88, 0.89, 0.9 etc.; 0.91, 0.92,
0.93, . . . 0.98, 0.99, 1.0 etc.; 1.01, 1.02, 1.03, . . . 1.08,
1.09, 1.1 etc.; . . . 1.1, 1.2, 1.3, . . . 1.8, 1.9, 2.0 etc.; 2.1,
2.2, 2.3, . . . 2.8, 2.9, 3.0 etc.; 3.1, 3.2, 3.3, . . . 3.8, 3.9,
4 mg/kg of body weight. Angiotensin II receptor 1 (AT-1)
antagonist, preferably telmisartan may be administered once twice
or trice a day in a daily dosage as mentioned above.
[0085] In cases when angiotensin II receptor 1 (AT-1) antagonist,
preferably telmisartan is administered by oral, rectal, nasal or
inhalative route a dosage of about 0.03 to about 10 mg/kg of body
weight is preferred. Preferably, said therapeutically effective
amount of such angiotensin II receptor 1 (AT-1) antagonist is about
0.10 to about 8 mg/kg of body weight, even more preferably about
0.20 to about 7.5 mg/kg of body weight, even more preferably about
0.25 to about 7.0 mg/kg of body weight, even more preferably about
0.25 to about 6.0 mg/kg of body weight, most preferred about 0.25
to about 5 mg/kg of body weight. Thus, said therapeutically
effective amount of such angiotensin II receptor 1 (AT-1)
antagonist is for example 0.03, 0.04, 0.05, . . . 0.08, 0.09, 0.1,
etc.; 0.11, 0.12, 0.13, . . . 0.18, 0.19, 0.2, etc.; 0.21, 0.22,
0.23, . . . 0.28, 0.29, 0.3 etc. . . . ; 0.81, 0.82, 0.83, . . .
0.88, 0.89, 0.9 etc.; 0.91, 0.92, 0.93, . . . 0.98, 0.99, 1.0 etc.;
1.01, 1.02, 1.03, . . . 1.08, 1.09, 1.1 etc.; . . . 1.1, 1.2, 1.3,
. . . 1.8, 1.9, 2.0 etc.; 2.1, 2.2, 2.3, . . . 2.8, 2.9, 3.0 etc.;
. . . ; 8.1, 8.2, 8.3, . . . 8.8, 8.9, 9.0 etc.; 9.1, 9.2, 9.3, . .
. 9.8, 9.9, 10 mg/kg of body weight. Telmisartan may be
administered once twice or trice a day in a daily dosage as
mentioned above.
[0086] According to another aspect of the invention, the present
invention relates to a method for the prophylaxis or treatment of a
systemic disease in cats, such as chronic kidney disease, e.g.
chronic renal failure, wherein the method comprising administration
of a therapeutically effective amount of angiotensin II receptor 1
(AT-1) antagonist (sartan), preferably telmisartan or
pharmaceutically acceptable salt thereof, to that cat in need of
such a treatment, wherein the therapeutically effective amount of
such angiotensin II receptor 1 (AT-1) antagonist is administered in
a therapeutically effective amount that result in an cumulative
intravenous concentration of at least 0.025 mg/kg of body weight
(bw) Preferably, said angiotensin II receptor 1 (AT-1) antagonist
(sartan), preferably telmisartan is administered to an cumulative
intravenous concentration of at least 0.05 mg/kg of bw, more
preferably of 0.1 mg/kg of bw, even more preferably 0.15 mg/kg of
bw even more preferably 0.2 mg/kg of bw, even more preferably 0.25
mg/kg of bw, even more preferably 0.40 mg/kg of bw, even more
preferably 0.5 mg/kg of bw, even more preferably 0.75 mg/kg of bw,
even more preferably 1 mg/kg of bw. Upper limits of cumulative
intravenous concentration of about 1 mg/kg of bw are well
tolerable, however, cumulative intravenous concentrations of up to
5, 4, 3 and 2 mg/kg of bw are also within the meaning of the
present invention as well as any further higher non-toxic
cumulative intravenous concentration of said angiotensin II
receptor 1 (AT-1) antagonist (sartan). A person skilled in the art,
in view of the teaching given herein, is entitled to estimate that
upper non-toxic cumulative intravenous concentration by standard
techniques.
[0087] Optionally, the angiotensin II receptor 1 (AT-1) antagonist
(sartan), preferably telmisartan can be administered in combination
with other drugs. Such other drugs are, for example Ca-channel
blockers (e.g. Amlodipine), beta-blockers (e.g. Atenolol,
Carvediol), cardiotonic-Ca-sensitising agents (e.g. Pimobendan,
Levosimendan), selective If-current inhibitors (i.e. Cilobradine,
Ivabradine), ACE inhibitors (e.g. ramipril, benazepril, enalapril);
anti-obesity drugs (such as Amphetamine derivatives, Sibutramine,
Orlistat, Rimonabat) and the like. Thus, according to another
aspect, the present invention relates to a method for the
prophylaxis or treatment of a systemic disease in cats, preferably
of chronic kidney disease, e.g. chronic renal failure, wherein the
method comprising administration of a therapeutically effective
amount of angiotensin II receptor 1 (AT-1) antagonist (sartan),
preferably telmisartan or pharmaceutically acceptable salt thereof,
together with another active substance, to that cat in need of such
a treatment, wherein said further active substance is a Ca-channel
blocker (e.g. Amlodipine), beta-blocker (e.g. Atenolol, Carvediol),
cardiotonic-Ca-sensitising agent (e.g. Pimobendan, Levosimendan),
selective If-current inhibitor (i.e. Cilobradine, Ivabradine), ACE
inhibitor (e.g. ramipril, benazepril, enalapril); an anti-obesity
drug (such as Amphetamine derivatives, Sibutramine, Orlistat,
Rimonabat) and the like.
[0088] Telmisartan and the other active compounds can be orally
administered in a wide variety of different dosage forms, i.e.,
they may be formulated with various pharmaceutically acceptable
inert carriers in the form of tablets, capsules, lozenges, troches,
hard candies, powders, sprays, aqueous suspensions, elixirs,
syrups, and the like. Such carriers include solid diluents or
fillers, sterile aqueous media and various non-toxic organic
solvents. Moreover, such oral pharmaceutical formulations can be
suitably sweetened and/or flavored by means of various agents of
the type commonly employed for such purposes. In general, the
compounds of this invention are present in such oral dosage forms
at concentration levels ranging from about 0.5% to about 90% by
weight of the total composition, in amounts which are sufficient to
provide the desired unit dosages. Other suitable dosage forms for
the compounds of this invention include controlled release
formulations and devices well known to those who practice in the
art.
[0089] For purposes of oral administration, tablets containing
various excipients such as sodium citrate, calcium carbonate and
calcium phosphate may be employed along with various disintegrants
such as starch and preferably potato or tapioca starch, alginic
acid and certain complex silicate, together with binding agents
such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
Additionally, lubricating agents such as magnesium stearate, sodium
lauryl sulfate and talc or compositions of a similar type may also
be employed as fillers in soft and hard-filled gelatin capsules;
included lactose or milk sugar as well as high molecular weight
polyethylene glycols. When aqueous suspensions and/or elixirs are
desired for oral administration, the essential active ingredient
therein may be combined with various sweetening or flavoring
agents, coloring matter or dyes and, if so desired, emulsifying
agents and/or water, ethanol, propylene glycol, glycerin and
various like combinations thereof.
[0090] For purposes of parenteral administration, solutions of the
compounds in sesame or peanut oil or in aqueous propylene glycol
may be employed, as well as sterile aqueous solutions of the
corresponding pharmaceutically acceptable salts. Such aqueous
solutions should be suitably buffered if necessary, and the liquid
diluent rendered isotonic with sufficient saline or glucose. These
particular aqueous solutions are especially suitable for
intravenous, intramuscular and subcutaneous injection purposes. In
this connection, the sterile aqueous media employed are readily
obtained by standard techniques well known to those skilled in the
art. For instance, distilled water is ordinarily used as the liquid
diluent and the final preparation is passed through a suitable
bacterial filter such as a sintered glass filter or a diatomaceous
earth or unglazed porcelain filter. Preferred filters of this type
include the Berkefeld, the Chamberland and the Asbestos Disk-Metal
Seitz filter, wherein the fluid is sucked into a sterile container
with the aid of a suction pump. The necessary steps should be taken
throughout the preparation of these inject-able solutions to insure
that the final products are obtained in a sterile condition.
[0091] For purposes of transdermal administration, the dosage form
of the particular compound or compounds may include, by way of
example, solutions, lotions, ointments, creams, gels,
suppositories, rate-limiting sustained release formulations and
devices therefore. Such dosage forms comprise the particular
compound or compounds and may include ethanol, water, penetration
enhancer and inert carriers such as gel-producing materials,
mineral oil, emulsifying agents, benzyl alcohol and the like.
[0092] These preformulated combinations of active substances are
generally incorporated with one or more formulation adjuvants such
as mannitol, sorbitol, xylitol, saccharose, calcium carbonate,
calcium phosphate, lactose, croscarmellose sodium salt (cellulose
carboxymethylether sodium salt, cross-linked), crospovidone, sodium
starch glycolate, hydroxypropylcellulose (low-substituted), maize
starch, polyvinylpyrrolidone, copolymers of vinylpyrrolidone with
other vinyl derivatives (copovidone), hydroxypropylcellulose,
hydroxypropylmethylcellulose, microcrystalline cellulose or starch,
magnesium stearate, sodium stearylfumarate, talc,
hydroxypropylmethylcellulose, carboxymethylcellulose, cellulose
acetate phthalate, polyvinyl acetate, water, water/ethanol,
water/glycerol, water/sorbitol, water/polyethyleneglycol,
propyleneglycol, cetylstearyl alcohol, carboxy-methylcellulose or
fatty substances such as hard fat or suitable mixtures thereof,
into conventional galenic preparations such as plain or coated
tablets, capsules, powders, suspensions or suppositories.
[0093] Tablets may be obtained for example by mixing the active
substance or substances with one or more excipients and
subsequently compressing them. The tablets may also consist of
several layers. Examples of excipients are: [0094] inert diluents
such as mannitol, sorbitol, xylitol, saccharose, calcium carbonate,
calcium phosphate and lactose; [0095] disintegrants such as
croscarmellose sodium salt (cellulose carboxymethylether sodium
salt, cross-linked), crospovidone, sodium starch glycolate,
hydroxypropylcellulose (low-substituted) and maize starch; [0096]
binders such as polyvinylpyrrolidone, copolymers of
vinylpyrrolidone with other vinyl derivatives (copovidone),
hydroxypropylcellulose, hydroxypropylmethylcellulose,
microcrystalline cellulose or starch; [0097] lubricants such as
magnesium stearate, sodium stearyl fumarate and talc; [0098] agents
for achieving delayed release such as hydroxypropylmethylcellulose,
carboxymethylcellulose, cellulose acetate phthalate and polyvinyl
acetate; and [0099] pharmaceutically permitted colourings such as
coloured iron oxides.
[0100] Furthermore, if telmisartan is used in combination with
another drug used for the prophylaxis or treatment of a systemic
disease, preferably of chronic kidney disease, e.g. chronic renal
failure in cats, the pharmaceutical composition according to the
invention may be a kit of parts which comprises: [0101] a first
containment containing a pharmaceutical composition comprising a
therapeutically effective amount of telmisartan or a
physiologically acceptable salt thereof and one or more
pharmaceutically acceptable diluents and/or carriers; and [0102] a
second containment containing another drug used for the prophylaxis
or treatment of a systemic disease, preferably chronic renal
failure, or a physiologically acceptable salt thereof and one or
more pharmaceutically acceptable diluents and/or carriers.
[0103] A preferred kit of parts comprises one or more Ca-channel
blockers (e.g. Amlodipine), beta-blockers (e.g. Atenolol,
Carvediol), cardiotonic-Ca-sensitising agents (e.g. Pimobendan,
Levosimendan), selective If-current inhibitors (i.e. Cilobradine,
Ivabradine), ACE inhibitors (e.g. ramipril, benazepril, enalapril);
anti-obesity drugs (such as Amphetamine derivatives, Sibutramine,
Orlistat, Rimonabat) and the like, in the second containment.
[0104] According to a further aspect, the present invention also
relates to the use of an angiotensin II receptor 1 (AT-1)
antagonist (sartan), preferably of telmisartan for the manufacture
of a pharmaceutical composition comprising a therapeutically
effective amount of said angiotensin II receptor 1 (AT-1)
antagonist for the treatment of a systemic disease in cats.
[0105] Preferably the systemic disease is selected from the group
of cardiovascular diseases, such as dilated cardiomyopathy (DCM),
mitral valve insufficiency (MI), hypertrophic cardiomyopathy (HCM)
and other acquired or hereditary heart diseases, systemic
hypertension, for example hypertension associated with renal
diseases, chronic kidney disease (CKD) and other vascular diseases,
metabolic disorders like diabetes mellitus. For example, the
systemic disease is systemic hypertension associated with one or
more of CKD, hyperthyroidism, controlled hypertension and
idiopathic hypertension.
[0106] Preferred sartans are those mentioned in an exemplarily
manner supra. Most preferred is the use of telmisartan or any
pharmaceutically acceptable salt thereof, such as Micardis.RTM. or
Semintra.RTM.. The preferred doses which can be used according to
the invention are those mentioned supra. Preferred administration
routes are orally, bucally, parenterally, nasally, rectally or
topically, whereas the oral administration being most preferred.
Parenteral administration may include subcutaneous, intravenous,
intramuscular and intrasternal injections and infusion
techniques.
[0107] In another embodiment of the invention, administration of a
dosage of a sartan (e.g., telmisartan) is regulated during
treatment of a cat and based upon a condition associated with the
cat. The dosage regulation can be modified after certain treatment
periods and in dependence upon a measured change (e.g.,
improvement) in a physical condition of a cat. For example, in
treatment of a cat for hypertension (e.g., hypertension associated
with one or more of CKD, hyperthyroidism, controlled hypertension
and idiopathic hypertension), a sartan can be administered to the
cat at an initial dosage amount (e.g., any of the suitable dosage
amounts as previously described herein) and then modified after a
certain time period, where the modification in dosage amount can be
based upon the measured systolic blood pressure (SBP) of the cat.
The SBP of the cat can be measured in any suitable manner (e.g.,
utilizing a blood pressure cuff wrapped around the tail or a limb
of the cat). In example embodiments (e.g., such as certain examples
described herein), an initial daily dosage amount can be
administered to a cat for a certain time period, where the SBP of
the cat is determined after such time period. In the event the
determined SBP of the cat is not greater than a threshold value,
the daily dosage amount can be reduced or titrated down to a
smaller amount. Further reductions or down titrations of the daily
dosage amount can be implemented in the dosage regimen in the event
the SBP of the cat remains below the threshold value and/or drops
even further below the threshold value. Alternatively, in other
embodiments, the daily dosage amount can also be increased or
titrated up in the event the SBP determined for a cat is at a value
that exceeds the threshold value by a predetermined amount. The
dosages can be administered in any suitable manner such as those
previously described herein (e.g., orally, parenterally, etc.) and
can further be in any suitable form (e.g., solid or liquid) and
combined with any other suitable active ingredient or any other
excipient or other substance as previously noted herein.
[0108] According to a further aspect of the present invention the
present invention relates to an angiotensin II receptor 1 (AT-1)
antagonist (sartan), preferably telmisartan or a pharmaceutically
acceptable salt thereof, for the use in a method of treating
hypertension in a cat, wherein the therapeutically effective amount
of the sartan is administered in a daily dosage amount that is
varied over a treatment period, the daily dosage amount of the
sartan for a first period of time during the treatment period is
1.0 to 5.0 mg/kg of body weight, and the daily dosage amount of the
sartan is decreased for a second period of time subsequent the
first period of time during the treatment period. In a specific
embodiment said hypertension is hypertension which is associated
with chronic kidney disease or hyperthyroidism or said hypertension
is idiopathic hypertension.
[0109] In example embodiment, an initial dosage amount of a sartan
can be administered to a cat for treatment of hypertension in an
amount of from about 0.10 to about 8.0 mg/kg, such as about 0.10 to
about 5.0 mg/kg, about 0.75 to about 5.0 mg/kg, or about 1.0 to 3.0
mg/kg (e.g., about 1.5 mg/kg or about 2.0 mg/kg), where such dosage
amount can be administered once per day, twice per day or three
times (thrice) per day. For example, a daily dosage amount of the
sartan to be administered to the cat can be from about 0.10 to
about 8.0 mg/kg, such as from about 1.0 to about 4.0 mg/kg, from
about 2.0 to about 3.0 mg/kg, etc. A decrease or down titration in
daily dosage (as well as an increase or up titration in daily
dosage) between a first predetermined or prescribed time period and
a second (subsequent) prescribed time period can be in any suitable
amount, e.g., a change in daily dosage or incremental change (i.e.,
an incremental increase or decrease or, in other words, an increase
or decrease by a predetermined or stepped amount) in a range of
about 0.05 to about 1.0 mg/kg, or about 0.1 to about 0.5 mg/kg,
etc. For example, changes in daily dosage titration between a first
prescribed time period and a second (subsequent) prescribed time
period can be modified or adjusted by a delta or incremental
(decreased or increased) change of about 1.0 mg/kg, about 0.9
mg/kg, about 0.8 mg/kg, about 0.75 mg/kg, about 0.5 mg/kg, about
0.4 mg/kg, about 0.3 mg/kg, about 0.25 mg/kg, about 0.2 mg/kg,
about 0.125 mg/kg, about 0.1 mg/kg, by 0.05 mg/kg or in any other
suitable incremental amount (i.e., any other set decreased or set
increased amount).
[0110] The daily dosage amount of a sartan administered to a cat
can be adjusted over any selected number of time intervals. For
example, the initial time period (e.g., a time period including day
one of treatment) for the initial daily dosage amount of the sartan
administered to a cat for treatment of hypertension can be from
about 1 day to about 30 days or more, such as from about 5 days to
about 28 days, from about 7 days to about 14 days, etc. At the end
of the initial time period, an adjustment that is made in the daily
dosage amount can be implemented for a second or subsequent time
period that can be from about 1 day to about 30 days or more, such
as from about 5 days to about 28 days, from about 7 days to about
14 days, etc. Any further number of subsequent time periods of
adjustment in daily dosage can be further implemented as desired
and based upon efficacy of treatment. In some embodiments, the
total treatment period at which a cat can be treated with varying
daily dosage amounts (e.g., over certain periods of time) can be at
least about 120 days (e.g., a treatment period can last for at
least 3 months, at least 4 months, at least 5 months, at least 6
months, etc.).
[0111] The methods for treatment or prophylaxis of hypertension in
cats by administration of a sartan (including modification of
dosage of the sartan during a treatment period) have been
determined to be effective for cats varying in ages. However, no
study has been conducted to determine the effectiveness of such
methods for a cat having an age of less than 9 months. Accordingly,
the treatment methods described herein are preferably for cats
having an age of at least 9 months (i.e., an age of 9 months and
older). Further, the treatment methods described herein exclude
cats having an age of less than 9 months.
[0112] As noted herein, for the treatment or prophylaxis of
hypertension for a cat by administration of a sartan to the cat,
the SBP of the cat can be used as the criteria for determining
whether an adjustment in the daily dosage to the cat can be
implemented. In example embodiments, it may be desirable to adjust
the daily dosage of the sartan administered to the cat when the SBP
of the cat drops below (for down titration or decreased dosage) a
first threshold value or rises above (for up titration or increased
dosage) a second threshold value. For example, in a scenario in
which, after the initial treatment period, the SBP of the cat
decreases below or is no greater than a first threshold value, the
daily dosage amount for administration to the cat can be reduced by
any amount (e.g., any of the dosage incremental values as noted
herein). An example threshold SBP value can be set, e.g., within a
range from about 120 mmHg to about 170 mmHg. For example, a
threshold SBP value can be set at no greater than about 170 mmHg,
no greater than about 165 mmHg, no greater than about 160 mmHg, no
greater than about 155 mmHg, no greater than about 150 mmHg, no
greater than about 145 mmHg, no greater than about 140 mmHg, no
greater than about 135 mmHg, no greater than about 130 mmHg, no
greater than about 125 mmHg, no greater than about 120 mmHg or any
values there between.
[0113] Alternatively, or in combination with establishing a
threshold SBP value, a change in SBP value or delta SBP value
(where the change or delta is the difference between two SBP
values) for the cat can also trigger a modification in the daily
dosage amount administered to the cat. For example, a change in SBP
value that will trigger a change in dosage amount administered to
the cat can be from about 10 mmHg to about 150 mmHg, about 10 mmHg
to about 100 mmHg, about 10 mmHg to about 80 mmHg, about 10 mmHg to
about 50 mmHg, about 10 mmHg to about 30 mmHg, about 10 mmHg to
about 20 mmHg, about 20 mmHg to about 150 mmHg, about 20 mmHg to
about 100 mmHg, about 20 mmHg to about 80 mmHg, about 20 mmHg to
about 50 mmHg, about 20 mmHg to about 30 mmHg, or about 5 mmHg to
about 30 mmHg, such as from about 10 mmHg to about 25 mmHg, with
further examples being a change in SBP value of at least about 5
mmHg, at least about 10 mmHg, at least about 15 mmHg, at least
about 20 mmHg, at least about 25 mmHg, or at least about 30
mmHg.
[0114] In preferred embodiments, the methods of regulation (change
in dosage amount) are implemented by administration of the sartan
to a cat as a liquid formulation (e.g., any suitable liquid
formulation of the types previously described herein). In such
embodiments, a suitable dispenser can be provided to facilitate
administration at varying dosage amounts. However, the methods of
regulation can also be implemented by administration of the sartan
as a solid formulation (e.g., as a tablet).
[0115] For liquid formulations, a kit of parts can be provided
which includes a containment containing a liquid formulation of a
pharmaceutical composition comprising a therapeutically effective
amount of telmisartan or a physiologically acceptable salt thereof
and one or more pharmaceutically acceptable diluents and/or
carriers, and a suitable dispenser for dispensing dosages to a cat
in varying amounts in accordance with a dosage regimen as described
herein. In other words, a suitable dispenser is provided to
facilitate a change in dosage amount (e.g., a decrease/down
titration or an increase/up titration in dosage) based upon a
change in physical condition (e.g., change in SBP) of the cat
during the course of treatment.
[0116] A suitable dispenser for the liquid formulation comprises a
syringe including printed indicia or graduation marks on the barrel
of the syringe defining any suitable number of volumetric
increments for the liquid formulation to be drawn within the
syringe barrel for administration to the cat. In an example
embodiment, the syringe has a size ranging from 1.0 mL to 6.0 mL or
greater (e.g., from 2.0 mL to 5.0 mL) and further includes
graduation marks in 0.05 mL increments, in 0.1 mL increments, in
0.25 mL increments, in 0.50 mL increments, and/or in any other
suitable graduations or increments. By providing a liquid
formulation having a suitable concentration of the sartan within
solution, such volumetric increments of the syringe are suitable
for enabling administration of the sartan to a cat in the varying
dosage amounts (e.g., from 0.1 to 8.0 mg/kg) based upon the weight
of the cat.
[0117] Some non-limiting examples of down titration dosage schemes
(which are also described in greater detail in Examples 4-6 below)
are as follows.
[0118] A. A sartan (e.g., telmisartan) is administered in liquid
form (e.g., using a 10 mg/mL telmisartan solution, and a 2 mL
dosing syringe demarcated in 0.10 mL or smaller increments) to a
cat for the treatment or prophylaxis of hypertension at a daily
dosage amount of 3.0 mg/kg (e.g., in two doses per day, each dosage
amount being 1.5 mg/kg) for an initial period of 14 days. The daily
dosage amount is modified based upon SBP measurements of the cat,
e.g., at periodic veterinary visits (e.g., every 2-4 weeks). The
cat can have hypertension associated with chronic kidney disease
(CKD), hypertension associated with hyperthyroidism, controlled
hypertension and/or idiopathic hypertension. Initially (e.g., at or
before a first veterinary visit at Day 0), a baseline SBP of the
cat is measured. After the initial 14 day period of treatment
(e.g., at a second veterinary visit, such as at Day 14 of the
treatment period), the daily dosage amount is decreased or down
titrated to 2.0 mg/kg (e.g., in one dose per day). The daily dosage
can be further decreased depending upon the SBP value measured for
the cat (e.g., at a third visit, such as at Day 28 of the treatment
period). For example, a decrease in SBP from the baseline SBP value
(obtained for the cat prior to the initial period of administration
of the sartan) of at least 20 mmHg can result in a decrease in
daily dosage. Alternatively (or in combination with a measured
decrease in SBP from baseline SBP), a decrease in SBP to a value no
greater than a threshold value (where the threshold value is, e.g.,
120 mmHg) can result in a decrease in daily dosage. The daily
dosage can be decreased by about 1.0 mg/kg or less (e.g., about 0.5
mg/kg, about 0.4 mg/kg, about 0.3 mg/kg, about 0.25 mg/kg, about
0.2 mg/kg, about 0.15 mg/kg, about 0.125 mg/kg, about 0.1 mg/kg or
about 0.05 mg/kg). Periodically, the dosage can be further
decreased in the same or different incremental amounts (e.g., at
the second visit, third visit, etc. of the treatment period) based
upon the cat either maintaining the SBP value at no greater than
the threshold value and/or maintaining a decrease in SBP of at
least about 20 mmHg over a sufficient time period (e.g., 14 days or
less). In this example, the initial daily dosage is 3.0 mg/kg, and
such daily dosage can be decreased or titrated down (based upon
sufficient decrease in SBP) to a daily dosage value ranging from
0.125 mg/kg to 2.0 mg/kg. For example, the daily dosage can be
titrated down from 3.0 mg/kg.fwdarw.2.0 mg/kg.fwdarw.1.0
mg/kg.fwdarw.0.5 mg/kg, etc., where such down titration is
implemented when the SBP value of the cat after a certain time
period (e.g., 14 days or less) is maintained at no greater than a
threshold value (e.g., no greater than 120 mmHg) and/or is
maintained at a value lower than at least about 20 mmHg from the
baseline SBP value for the cat. In a specific example embodiment,
the daily dosage amount for the cat can be set at 2.0 mg/kg (e.g.,
single daily dosage) when the SBP for the cat is maintained within
120-180 mmHg, and is further down titrated (e.g., to 1.5
mg/kg.fwdarw.1.0 mg/kg.fwdarw.0.5 mg/kg) when the SBP for the cat
is maintained at no greater than 120 mmHg. The treatment period for
the cat can be, e.g., 26 weeks (i.e., 6 months) with visits every
2-4 weeks to determine whether an adjustment is to be made in daily
dosage of the sartan based upon the SBP value measured for the cat
(e.g., where the daily dosage can be down titrated based upon the
SBP value for the cat being maintained at no greater than 120
mmHg).
[0119] B. A sartan (e.g., telmisartan) is administered in liquid
form (e.g., using a 4 mg/mL telmisartan solution, and a 5 mL dosing
syringe demarcated in 0.25 mL or smaller increments) to a cat for
the treatment or prophylaxis of hypertension at a daily dosage
amount of 2.0 mg/kg (e.g., in one dose per day) for an initial
period of 28 days. The daily dosage amount is modified based upon
SBP measurements of the cat, e.g., at periodic veterinary visits
(e.g., every 2-4 weeks). The cat can have hypertension associated
with chronic kidney disease (CKD), hypertension associated with
hyperthyroidism, controlled hypertension and/or idiopathic
hypertension. After the initial period, the daily dosage is
decreased or down titrated if the cat has a SBP no greater than 160
mmHg. The down titration of the daily dosage can be in increments
of 1.0 mg/kg or less (e.g., about 0.5 mg/kg, about 0.4 mg/kg, about
0.3 mg/kg, about 0.25 mg/kg, about 0.2 mg/kg, about 0.15 mg/kg,
about 0.125 mg/kg, about 0.1 mg/kg or about 0.05 mg/kg). For
example, the initial daily dosage of 2.0 mg/kg can be decreased or
down titrated to 1.5 mg/kg if the SBP of the cat is no greater than
160 mmHg. Further subsequent decreases or down titrations in daily
dosage (e.g., 1.5 mg/kg.fwdarw.1.0 mg/kg.fwdarw.0.5 mg/kg) can also
be implemented in the treatment regimen when the SBP of the cat is
maintained at no greater than 160 mmHg for a sufficient time period
(e.g., from 2-4 weeks) between visits (e.g., between a current
visit and the previous visit) and at the current daily dosage. In
this example, the initial daily dosage is 2.0 mg/kg, and such daily
dosage can be decreased or titrated down (based upon sufficient
decrease in SBP) to a daily dosage value ranging from 0.125 mg/kg
to 2.0 mg/kg (e.g., from 0.5 mg/kg to 2.0 mg/kg) when the SBP value
for the cat is no greater than a threshold value (e.g., SBP no
greater than 160 mmHg).
[0120] In certain scenarios, the dosage can be increased or up
titrated after having been decreased or down titrated in a previous
portion of the treatment period if the SBP of the cat has increased
to an undesirable value or by an undesirable amount. For example,
consider a scenario in which the daily dosage amount of a sartan to
a cat was decreased from 3.0 mg/kg daily to 1 mg/kg daily (due to a
decrease in SBP to no greater than 120 mmHg and/or a decrease from
baseline SBP of at least 20 mmHg). In a subsequent time period
(e.g., within 14 days of the down titration in dosage), if the SBP
of the cat has increased significantly (e.g., the current SBP is
120 mmHg or greater or the current SBP is no longer at least 20
mmHg less than the baseline SBP), the daily dosage of sartan for
the cat can be increased or up titrated to a greater value (e.g.,
the original amount, or to 3.0 mg/kg or to 2.0 mg/kg). During the
next period at which the SBP of the cat is measured, an optional
further adjustment (decrease or increase) in daily dosage can be
implemented depending upon the response of the cat to the change in
dosage (based upon the currently measured SBP vs. the previously
measured SBP and/or the baseline SBP).
[0121] As previously noted, a kit of parts can be provided which
includes a containment system for a liquid formulation of a
pharmaceutical composition comprising a therapeutically effective
amount of sartan (e.g., telmisartan or a physiologically acceptable
salt thereof) and one or more pharmaceutically acceptable diluents
and/or carriers, and a suitable dispenser for dispensing dosages to
a cat in varying amounts in accordance with a dosage regimen (e.g.,
down titrating, up titrating, etc.) as described by the embodiments
herein. An example embodiment of a kit of parts is depicted in
FIGS. 6A and 6B. Referring to FIG. 6A, the kit of parts includes a
syringe comprising a barrel 10 and a plunger 20 configured to fit
and frictionally move or slide in a telescoping manner within the
barrel 10 (to facilitate aspiration of the plunger to draw fluid
into the barrel and forcing fluid flow from the barrel via the
plunger), a vial or container 40, and a plug-in adaptor 30
configured to facilitate withdrawal of fluid into the barrel 10
from the open end of the container 40 during use. The syringe and
container components can be constructed of any suitable materials
acceptable to ensure effective operation of the components to
deliver the desired dosage amount of the sartan to a cat being
treated. For example, the barrel 10 can be constructed of
polypropylene material, the plunger 20 can be constructed of a high
density polyethylene material, the plug-in adaptor 30 can be
constructed of a low density polyethylene material, and the
container 40 can be constructed of a high density polyethylene
material. In addition, the syringe and container components can
have any suitable dimensions and geometric configurations that
facilitate suitable interactivity with each other and suitable
operational performance during administration of the sartan
solution to a cat being treated. In an example embodiment, the
container 40 has a volumetric capacity of at least about 45 mL and
contains a 10 mg/mL telmisartan solution. The container 40 further
includes a cap (not shown) to close the open end of the container
during periods of non-use.
[0122] The syringe and container components can further have any
dimensions (length, width, inner diameter, outer diameter, etc.)
suitable for their intended purposes. As an example, the barrel 10
can have a length dimension of 87 mm-89 mm, an outer diameter of
8.0 mm-8.6 mm and an inner diameter of 6.6 mm-6.8 mm, where such
dimensions enable the barrel to hold at least 2.0 mL of solution.
The plunger 20 and other container components can also have
suitable dimensions that facilitate suitable engagement and/or
interaction with the syringe barrel.
[0123] The syringe barrel 10 includes an open end 15 through which
the solution is aspirated (via the plunger 20) from the container
40. The barrel open end 15 has a frustoconical shape that
corresponds in geometrical shape and dimension(s) with a
corresponding central opening 35 of the adaptor 30, where the
adaptor central opening 35 extends through the adaptor (e.g., along
a central axis of the adaptor). In particular, the interior wall
surfaces defining the adaptor central opening 35 correspond in
dimension(s) and shape such that, when the barrel open end 15 is
inserted within the adaptor central opening 35, the barrel open end
frictionally and snugly fits within the adaptor central opening.
The frictional engagement between the barrel open end 15 and the
interior wall surfaces of the adaptor central opening 35 can
further provide a fluid tight seal between the engaging surface
portions between barrel 10 and adaptor 30 such that fluid is only
transferred from the container 40, through the adaptor central
opening 35, and into the barrel 10 via its open end 15. Referring
to FIG. 6B, the barrel 10 further includes demarcations on its
exterior surface that facilitate aspiration of a precise amount of
the sartan solution from the container 40 into the barrel in 0.1 mL
increments. In particular, the demarcations are in 0.1 mL
increments from 0 to 2.0 mL. Such incremental demarcations,
combined with the amount of sartan in solution within the container
40, facilitate administration of dosages of sartan to a cat in any
suitable amounts as described herein (including down titrating and
up titrating in any suitable amounts as described herein).
[0124] The plug-in adaptor 30 also has a suitable external diameter
or transverse cross-section that corresponds with the opening in
the container 40 so as to provide a snug, friction and fluid tight
fit with the container. The adaptor central opening 35 is smaller
in cross-sectional dimension or diameter than the cross-sectional
dimension or diameter of the container open end. Thus, when the
adaptor 30 is inserted in a plug fit arrangement and secured into
the opening of the container 40 (with the adaptor opening 35 facing
upward or away from the container opening), the adaptor 30 reduces
the dimension(s) of the opening or fluid passage from the container
40 that facilitates withdrawal of sartan solution from the
container.
[0125] The corresponding geometries and dimensions of the barrel
open end 15 and adaptor central opening 35 further serve as a "key"
that ensures that only the syringe barrel 10 (with demarcations as
set forth in FIG. 6B) can be effectively used with the adaptor 30.
In other words, any other syringe barrel having a different shaped
and/or different dimensioned open end will not fit securely within
the adaptor central opening 35 to facilitate adequate aspiration of
fluid from the container 40. At the same time, the syringe barrel
10 is only suitable for use with the adaptor 30 provided with the
kit in parts. This therefore ensures that the barrel 10 (with its
demarcations) cannot be exchanged with another kit in parts that
may include a different adaptor and/or container that includes a
different type of medicament (e.g., a kit in parts that includes a
container having a different medicament or a sartan solution having
a different mg/mL amount of sartan within the solution).
EXAMPLES
[0126] The following examples serve to further illustrate the
present invention; but the same should not be construed as a
limitation of the scope of the invention disclosed herein.
Example 1
[0127] The aim of this exploratory study was to investigate the
pharmacokinetic behaviour in plasma and the absolute
bioavailability of telmisartan in male and female cats following a
single oral or intravenous administration.
[0128] Four clinically healthy male and female domestic short hair
cats (HsdCpb: CADS) with a body weight range of 2.6-4.2 kg were
used in this study. The animals were randomly allocated to 2
groups, 2 animals per group. The study was designed as a 2.times.2
cross-over trial (i.e. two periods, days 1 and 15) in which the
test article telmisartan was given by single oral or intravenous
administration at a dose of 1 mg/kg body weight.
[0129] Blood samples were drawn at 0 h (i.e. prior to treatment), 5
(after i. v. injection only), 15, 30 and 60 min as well as 2, 4, 8,
24, 72 and 96 h after each treatment. Clinical observations were
also conducted at these time points. Plasma samples were sent to
the analytical laboratory and analysed there using a validated
method. The plasma levels measured in each animal were subjected to
various pharmacokinetic calculations.
[0130] The results of this study may be summarised as follows:
[0131] No specific clinical signs were noted during the entire
course of the study.
[0132] Pharmacokinetic analyses for telmisartan revealed the
following results:
TABLE-US-00003 TABLE 3 Route of Administration Parameter oral i.v.
t max [hour] mean 0.438 -- C max [ng/ml] mean 138.10 -- AUC 0
.fwdarw. .infin. mean 150.426 384.751 [ng h/ml] AUC 0 .fwdarw.
.infin. mean 138.598 375.945 [ng h/ml] t 1/2 [hour] mean 2.169
2.252 Cl/f or Cl [ml/min kg] mean 171.588 45.535 V/f or V [l/kg]
mean 20.453 8.856 MRT [hour] mean 1.969 0.789
[0133] The points estimate for the absolute bioavailability were
0.316 for AUC 0.fwdarw.t and 0.336 for AUC 0.fwdarw.00 with
respective 95% confidence intervals of 0.086-1.165 and
0.0.90-1.245. Individual data showed that the bioavailability was
clearly lower in animal no. 101 (i.e. 0.116 for AUC
0.fwdarw..infin.) in comparison with the other animals (i.e.
0.387-0.582).
[0134] The test article telmisartan was well tolerated after a
single oral or intravenous administration to cats at a dose of 1
mg/kg body weight.
[0135] Mean plasma concentrations increased until 15-30 min after
oral administration of telmisartan and declined rapidly afterwards.
No quantifiable plasma concentrations could be found at 24 h after
both routes, orally and intravenously.
[0136] The absolute bioavailability after oral administration was
found to be 33%.
Example 2
[0137] The aim of this study was to investigate the effects of an
escalating intravenous dose of telmisartan on the blood pressure
response of anaesthetised cats after administration of angiotensin
II. The originally intended endpoint of the study was to find a
dose of telmisartan which inhibits .gtoreq.90% of the angiotensin
blood pressure response.
[0138] Four clinically healthy adult male and female domestic short
hair cats (HsdCpb: CADS) with a body weight range of 2.5-3.5 kg
were used in this study. The animals were anaesthetised with sodium
pentobarbital and anaesthesia was sustained by continuous infusion
of diluted anaesthetic. A catheter was inserted into a carotid
artery and connected to a pressure transducer for registration of
the arterial pressure. Another catheter was placed into the femoral
vein for administration of angiotensin II (A2) or the test article
telmisartan. The systolic and diastolic blood pressure [mmHg] in
the carotid artery were recorded and analysed at discrete intervals
as described below.
[0139] At first, the diastolic blood pressure was registered 6
times every 5 minutes. The mean of these 6 measurements were set as
the baseline blood pressure. Then two bolus injections of A2 were
administered at a dose of 0.1 .mu.g/kg in an interval of 10 min.
The maximum increase in diastolic blood pressure obtained from the
second A2-bolus relative to the baseline blood pressure was taken
as the control angiotensin II-blood pressure response (i.e.
reference value).
[0140] Five minutes after the reference value was obtained, the
first injection of telmisartan was administered. Thirty minutes
later the diastolic blood pressure was recorded, immediately
followed by bolus injection of A2 at a dose of 0.1 .mu.g/kg and the
maximum increase in diastolic blood pressure was obtained. This
procedure was to be repeated accordingly until the intended
endpoint of the experiment (i.e. an A2-pressure response
.ltoreq.10% of the control A2-pressure response corresponding to
.gtoreq.90% inhibition) was reached. During the course of the
experiment it had been shown that the dose of telmisartan had to be
increased at single time points in order to increase the effect. In
addition, the endpoint of a 90% inhibition could not be reached in
3 of 4 animals even after several consecutive steps as described
above so that the experiment was terminated in these individual
animals before. At the end of the experiment, the anaesthetised
animals were euthanized with an overdose of sodium
pentobarbital.
[0141] The results of this study may be summarised as follows (see
FIG. 1):
[0142] The mean baseline diastolic blood pressure of the individual
animals ranged from 82-99 mmHg and the control angiotensin II-blood
pressure response was between 34 and 63 mmHg.
[0143] After treatment with telmisartan, the response pattern was
similar in 3 animals (i.e. animal nos. 102, 151, 152). In these
animals the maximal inhibition of the blood pressure increase
relative to the control angiotensin II-blood pressure response was
roughly 80-95% in contrast to 50% inhibition in animal no. 101.
[0144] However, the final cumulative dose of the test article was
only 0.1 mg/kg in this animal whereas this dose ranged between 0.34
and 0.4 mg/kg in the other animals.
[0145] In animal no. 101 the maximum effect of 50% inhibition was
reached at a cumulative dose of 0.05 mg/kg. In animal nos. 102 and
152 a 73% inhibition was already reached after the 1st dose of 0.04
and 0.02 mg/kg, respectively. In animal no. 151 the same inhibition
of 73% was reached at a cumulative dose of 0.04 mg/kg. In all 4
animals, further escalation of the dose did not produce markedly
higher effects which were appropriately related to the increase of
the dose.
[0146] In conclusion, escalating intravenous doses of the test
article telmisartan led to an inhibition of the diastolic blood
pressure increase in anaesthetised cats after administration of
angiotensin II.
[0147] An inhibition of 73% was found at the cumulative dose of
0.04 mg/kg telmisartan in 3 of 4 animals. In one animal, a maximum
inhibition of 50% was observed at a cumulative dose of 0.05 mg/kg.
In all 4 animals, further dose escalations did not produce an
appropriate dose response relationship.
Example 3
[0148] The aim of this blinded controlled, randomised exploratory
study was to investigate the safety of telmisartan in male and
female cats after repeated oral administration over four weeks.
[0149] Twelve clinically healthy approximately 1 year old male and
female, domestic short hair cats (HsdCpb: CADS) with a body weight
range of 2. 5-5. 1 kg were used in this study. The animals were
allocated to 3 groups, 4 animals per group. All animals were
treated with the test article telmisartan or control article (i.e.
placebo) once daily on days 0 to 27. The test/control article was
administered orally at three different does levels of 0.0 (placebo;
group I), 1 (group II) and 3 (group III) mg telmisartan/kg body
weight. The bottles with the test/control article looked identical
with the exception of the animal no. in order to achieve
blinding.
[0150] Blood samples for haematology and clinical chemistry were
collected from the animals on days-1 (i.e. prior to the first
treatment) and again on days 3, 7, 14, 28. Body weights were
measured weekly and electrocardiography recording were made on
days-1, 14, 21 and 28. A detailed physical examination including
determination of rectal temperature and respiratory rate was
carried out on days -1, 7, 14, 22 and 28. Systolic blood pressure
(once daily) and heart rate (twice daily) were determined five days
per week beginning prior to treatment until necropsy. The
palatability of the administered article was assessed at various
time points throughout treatment using a scoring system. On day 28
of the study, all animals were subjected to necropsy and stomach
and kidneys were examined histopathologically. Relevant parameters
were analysed using appropriate statistical procedures.
[0151] The results of this study can be summarised as follows:
[0152] No clinical findings clearly attributable to the treatment
with the test article were observed during the entire study
period.
[0153] Although no significant differences were found the results
of the assessment of the palatability might indicate a slightly
impaired palatability of the test article formulation. However, the
palatability was predominantly good or acceptable in the animals of
both treated groups II and III.
[0154] Physical and ECG examinations did not reveal
treatment-related findings at all time points of investigation.
[0155] No significant differences were found in the body weights,
rectal temperature, respiratory and heart rates during the course
of the study.
[0156] The systolic blood pressure was significantly lower in the
treated groups II and III compared to the control group I on single
occasions after initiation of treatment. In addition, differences
of borderline significance were found including the time before
treatment. Changes from baseline did not reveal significant
differences between treated groups and controls. However, the
course of the mean values over time might suggest a tendency of a
slight reduction of the systolic blood pressure in groups II and
III compared to group I from day 20 onwards.
[0157] No treatment-related differences were found between treated
groups and the concurrent controls in the haematological and
clinical chemistry parameters including the differential leukocyte
count on each day of examination during the study. Urinalysis did
also not provide evidence of a treatment effect.
[0158] No animal showed any specific finding during necropsy.
[0159] Histopathology revealed a few findings in stomach and
kidneys but there were no histopathological findings considered to
be associated with the treatment.
[0160] Due to the exploratory nature of this study the number of
animals per treatment group was rather low. Taking this fact into
consideration the results of the present study may permit the
following conclusions:
[0161] A slightly impaired palatability of the test article
formulation containing telmisartan might be identified.
[0162] The course of the mean values over time might suggest a
tendency of a slight reduction of the systolic blood pressure in
the animals treated with telmisartan towards the end of the study
period.
[0163] The test article telmisartan was well tolerated after
repeated oral administration over 4 weeks to cats at doses of 1 and
3 mg/kg body weight.
Example 4
[0164] A U.S. study was conducted to evaluate the safety and
effectiveness of telmisartan in cats with systemic hypertension,
where the primary variable for statistical analysis was mean
Systolic Blood Pressure (mSBP) reduction from baseline (Day 0) to
Visit 2 (Day 14.+-.2) and Visit 3 (Day 28.+-.2). The change in mSBP
from baseline to Visit 3 was deemed clinically significant if a
reduction in mSBP was at least 20 mmHg.
[0165] Domestic cats, one year of age or older, that met the
enrollment criteria defined in the protocol were randomly assigned
to treatment with telmisartan oral solution (Investigational
Veterinary Product, IVP) or placebo (Investigational Control
Product, ICP) in a 2:1 randomization scheme. Of a total of 9,157
cases screened (representing 7,605 individual cats), 290 cases met
the criteria for enrollment. The most common reason for screen
failure (90% of cases) was that the cat did not have hypertension.
Two of the 290 cases enrolled were excluded from the safety and
efficacy populations as they were immediately removed from the
study and did not receive any IVP or ICP. Of the remaining 288 cats
used for the safety summary, 192 received IVP and 96 received ICP
from a total of 33 sites within the United States (US) and Canada.
From this population, an additional 67 cats were excluded, leaving
a total of 221 cats from 20 sites to be included in the efficacy
analysis, representing 142 IVP-treated and 79 ICP-treated cats.
Overall, both treatment groups were evenly distributed with regard
to demographics and baseline characteristics including age, body
weight, mSBP, retinal/fundic changes, and laboratory values. The
median age of cats enrolled in this study was 14.2 years.
[0166] Cats were classified as belonging to one or more of three
subpopulations of hypertension: CKD and/or hyperthyroidism and
idiopathic hypertension. A specific breakdown of the cats in the
study classified in the subpopulations is set forth in Table 4:
TABLE-US-00004 TABLE 4 Number of cats in each subpopulation
Subpopulation Placebo Telmisartan Total (N) CKD 42 82 124 (56.1%)
Idiopathic 27 39 66 (29.9%) CKD and Hyperthyroid 9 16 25 (11.3%)
Hyperthyroid 1 5 6 (2.7%) Total Across Subpopulations 79 142
221
[0167] A cat could have been enrolled into the CKD and hyperthyroid
populations if it had both diseases. The majority of the cats in
the safety and efficacy populations (.about.68%) were enrolled into
the CKD subpopulation. The idiopathic hypertension subpopulation
represented approximately 29% of the enrolled cats, followed by the
hyperthyroid subpopulation at approximately 14%. The percentages do
not total 100% because a majority of the hyperthyroid subpopulation
cats were also represented in the CKD subpopulation. When this
group is separated into an additional subpopulation (CKD and
hyperthyroid), it represents approximately 11% of the safety and
the efficacy populations.
[0168] The two treatment groups (IVP and ICP) were similarly
balanced with regard to the baseline mSBP (determined at Visit 1).
The minimum and maximum mSBP were identical for both treatment
groups. Overall, the two treatment groups were comparable in the
pretreatment mSBP values, as set forth in Table 5:
TABLE-US-00005 TABLE 5 Mean SBP values at baseline Baseline mSBP
for cats Placebo Telmisartan in efficacy analysis (mmHg) (mmHg)
Mean 175 177 Median 175 176 Minimum 160 160 Maximum 200 200
[0169] Upon enrollment into the study, cats were orally
administered telmisartan by their owners, where the owners were
given the option of dosing the treatments around or on the food or
via syringe. A dosing syringe was provided with demarcations in 0.1
mL increments as well as a dose and volume to be given, rounded to
the nearest 0.1 mL (where the calculation was based on kg of body
weight for each cat at Visit 1, and the dose was recalculated at
each subsequent visit using the current body weight).
[0170] The cats were started on a 1.5 mg/kg twice daily (BID) dose
(i.e., 3 mg/kg daily dosage) of either IVP or ICP for reduction of
mSBP. Following Visit 2 (approximately Day 14), the dose was
decreased to the 2 mg/kg once daily (SID) maintenance dose. The
reduction and maintenance dosage regimen for the cats in the study
is set forth in Table 6:
TABLE-US-00006 TABLE 6 Treatment Groups -Treatment- Minimum Time
Dose of active Treatment number of Period ingredient Dosage type
cats Phase (days) (rate) (volume) Telmisartan .gtoreq.160 Reduction
Days 1- 1.5 mg/kg BID 0.375 mL/kg BID Oral Solution 14 (.+-.2)
(IVP) Maintenance Days 15- 2 mg/kg SID 0.5 mL/kg SID 28 (.+-.2)
Negative .gtoreq.80 Reduction Days 1- 0 mg/kg BID 0.375 mL/kg BID
Control 14 (.+-.2) (ICP) Maintenance Days 15- 0 mg/kg SID 0.5 mL/kg
SID 28 (.+-.2)
[0171] The maintenance dose for a cat in the study could be further
down-titrated if the mSBP of the cat remained below 120 mmHg from
Visit 2 (at about day 14) and onward. For cats having such reduced
mSBP, the dose was reduced by decreasing the current dosage by 50%
(e.g., dosage reduced from 2 mg/kg SID to 1 mg/kg SID, and then
from 1 mg/kg SID to 0.5 mg/kg SID). The down titration dosage
regimen for cats maintaining a mSBP below 120 mmHg is set forth in
Table 7:
TABLE-US-00007 TABLE 7 Maintenance dosing -Treatment- mSBP Dosage
of active observed ingredient Product dose Treatment type (mmHg)
(rate) (volume) Telmisartan Oral >180 Rescue Rescue Solution
(IVP) 180-120 Maintenance: Maintenance: 2 mg/kg SID 0.5 mL/kg SID
<120 Down Titration: Down Titration: 1 mg/kg SID** 0.25 mL/kg
SID** Negative Control >180 Rescue Rescue (ICP) 180-120 0 mg/kg
0.5 mL/kg SID <120 0 mg/kg 0.25 mL/kg SID** **After a cat
received 1 mg/kg SID dosing, additional dose reduction was allowed
to a minimum of 0.5 mg/kg SID or 0.125 mL/kg SID if mSBP was
<120 mmHg.
[0172] Only 14 cats in the safety population had doses
down-titrated during the study, whereas the majority of cats were
maintained on the 2 mg/kg SID maintenance dose following Visit
2.
[0173] Baseline physical examination parameters, including mSBP and
retinal photographs, were obtained and compared to Visit 2 and
Visit 3 (approximately Day 28) to assess possible
hypertension-related Target Organ Damage (TOD). Baseline blood and
urine values were obtained and compared to Visit 3 to determine the
clinical significance of changes in laboratory values. At Visit 2
and at Unscheduled Visits, blood and urine samples were collected
at the discretion of the Investigator. Changes in all parameters
were summarized by treatment group as well as by subpopulation, if
appropriate.
[0174] The primary variable for statistical analysis was mSBP
reduction from baseline observed at Visit 2. In addition, the
arithmetic mean reduction at Visit 3 in the telmisartan group must
have been .gtoreq.20 mmHg to demonstrate clinical relevance.
Telmisartan was successful in fulfilling both primary criteria for
efficacy in cats as described below.
[0175] The change in mSBP from baseline (Visit 1) to Visit 2 was
calculated for each cat, and the mean change from baseline for each
treatment group was determined as set forth in Table 8:
TABLE-US-00008 TABLE 8 Change in mSBP LSM mSBP change from p-value
baseline Lower Upper com- Treatment to Visit 2 95% CI 95% CI
parison to Group N (.DELTA.mmHg)* (.DELTA.mmHg)** (.DELTA.mmHg)**
placebo Placebo 79.sup. -7.5 -13.6 1.5 . Telmisartan 141.sup.+
-23.3 -28.2 -18.3 0.0005 .sup.+One cat had a valid Visit 3 but not
a valid Visit 2 and thus was removed from the Visit 2 means
calculation. *LSM: Least Squares Means **CI = Confidence
Interval
[0176] There was a statistically significant difference (p=0.0005)
between the telmisartan and placebo groups. The telmisartan group
had a mean decrease of mSBP of 23.3 mmHg, while the placebo group
had a mean decrease in mSBP of 7.5 mmHg. A placebo effect was seen
in the study; however, it was not considered to be a clinically
relevant decrease in mSBP. Therefore, telmisartan was successful in
statistically significantly reducing mSBP when compared to placebo.
Further, a clinically relevant reduction in mSBP was predefined to
be .gtoreq.20 mmHg in the telmisartan group at Visit 3 (at about
Day 28), where the means of the treatment group at baseline (Visit
1) minus the means of the treatment group at Visit 3 were
calculated. A resultant arithmetic mean decrease of 23.9 mmHg for
the IVP group was determined. These results of the efficacy
analysis of this study confirm telmisartan is effective for the
reduction and control of hypertension in cats.
[0177] With regard to the efficacy of the down titration (decrease
in daily dosage) for cats maintaining a mSBP of lower than 120
mmHg, the data in Table 9 shows the down titration of telmisartan
to certain cats in the study:
TABLE-US-00009 TABLE 9 Cases down-titrated at each visit by new
dose and treatment group Visit IVP Cases ICP Cases Total 1
mg/kg/day Visit 2 n = 11 358-406, 329-535, 329- n = 3 330-408, 14
454, 323-533, 323-416, 325-528, 322-631, 322-460, 308- 318-512 754,
303-423, 265-836, 263-567 Unscheduled n = 0 None* n = 1 325-430 1
Visit 3 n = 8 330-509, 330-404, 325- n = 0 None 8 560, 318-597,
317-405, 308-591, 308-474, 298-556 0.5 mg/kg/day Visit 2 n = 0 None
n = 0 None 0 Unscheduled n = 1 323-416 n = 0 None 1 Visit 3 n = 2
329-454, 358-406 n = 0 None 2 *Case 305-402 is not included in this
table because the dose was titrated at an Unscheduled Visit while
the cat was in acute renal failure and the Owner was instructed to
stop all medications
[0178] At Visit 2, 14 cats (11 telmisartan and three placebo) were
assigned a lower dose (1.0 mg/kg SID) due to having a mSBP <120
mmHg. Ten of the 11 telmisartan cats were enrolled in an
extended-use study at Visit 3 (see Example 5). Three of the 10
telmisartan cats (329-454, 323-416, and 358-406) continued to have
a mSBP <120 mmHg following Visit 2 and were further decreased in
dose to 0.5 mg/kg SID. The remaining 7 of the 10 telmisartan cats
remained on the 1.0 mg/kg dose through the end of the study. The
eleventh telmisartan cat (263-567) was assigned a lower dose at
Visit 2; however, the cat was actually removed from the study at
that visit due to experiencing a serious adverse event (SAE). At
Visit 3, 8 telmisartan cats were assigned a lower dose of 1.0 mg/kg
SID and two telmisartan cats were assigned a lower dose of 0.5
mg/kg SID due to having a mSBP <120 mmHg. All 10 cats were
subsequently enrolled into the extended-use study (Example 5).
[0179] In this study, the incidence of target organ damage (TOD)
was similar in the IVP and placebo groups and was low overall. When
evaluating retinal lesions, the majority of the photos scored the
"same"; but there was a slight numerical increase in the percentage
of IVP cats (11.5%) compared to ICP cats (8.1%) scoring "better",
and roughly no difference in the percentage of cats with retinal
lesions scoring "worse" between the two treatment groups. Thus,
this study suggests that telmisartan does not cause retinal
deterioration and may promote improvement by decreasing the
deleterious effects of hypertension on the retina. This study
further confirms the safety of telmisartan in this population of
hypertensive cats. There were very few Serious Adverse Events
(SAEs) attributable to telmisartan. The most common AEs (vomiting,
diarrhea, lethargy, and weight loss) are common findings in
geriatric cat studies, especially when cats are given oral
medication. Vomiting, diarrhea, and lethargy occurred slightly more
often in the IVP group in comparison to the ICP group.
[0180] In conclusion, the data from this study demonstrates the
safety and efficacy of telmisartan oral solution to control
hypertension in cats under clinical conditions at doses of 1.5
mg/kg BID (i.e., 3.0 mg/kg/day) for two weeks followed by 2
mg/kg/day as maintenance, with the ability to titrate the dose down
(e.g., in 0.5 mg/kg/day increments) to adjust for blood pressure
response on an individual basis.
Example 5
[0181] An extensive use study was conducted to evaluate the
six-month safety of telmisartan oral solution administered orally
to cats for the control of systemic hypertension in cats. In
particular, cats receiving telmisartan and completing the study of
Example 4 were utilized for this extensive use study. The primary
variables for assessment in this extensive use study were adverse
events and change from baseline in retinal photographs. In general,
the study of this example was conducted to show additional
supportive safety data for extended treatment of cats with
telmisartan.
[0182] Domestic cats greater than one year of age that met the
enrollment criteria for the study of Example 4 were eligible for
enrollment in this extended-use study. Additionally, the cat's mean
Systolic Blood Pressure (mSBP) had to be .ltoreq.180 mmHg at Visit
3 (Day 28.+-.2) in the previous study of Example 4. A total of 107
cats met the enrollment criteria and were utilized for this study.
No placebo group was used in this study.
[0183] Cats were identified as belonging to one or more of the same
three subpopulations as in Example 4 (CKD and/or hyperthyroidism or
idiopathic hypertension), where a cat could have been enrolled into
the CKD and hyperthyroid populations if it had both diseases. The
subpopulations of the cats in this study are set forth in Table 10
below:
TABLE-US-00010 TABLE 10 Subpopulation allocation (4 populations)
Subpopulation Total N (%) CKD 63 (58.9%) Idiopathic 31 (29.0%) CKD
and Hyperthyroid 10 (9.3%) Hyperthyroid 3 (2.8%) Total Across
Subpopulations 107
[0184] As indicated in Table 10, the populations enrolled in this
extended use study, the majority were enrolled into the CKD
subpopulation (68.2%). The idiopathic subpopulation represented
29.0%, followed by the hyperthyroid subpopulation at 12.1%. The
percentages do not total 100% because a majority of the
hyperthyroid subpopulation cats were also included in the CKD
subpopulation. When the hyperthyroid subpopulation is separated
into an additional subpopulation (CKD and hyperthyroid), it
represents 9.3% of the study population.
[0185] As in Example 4, the dosing regimen for each cat in this
study was implemented using a dosing syringe demarcated in 0.1 mL
increments and based upon the weight of the cat at each visit. Upon
enrollment into this extended-use study, the majority of cats
(90.7%) were receiving a maintenance dose of 2 mg/kg once daily
(SID). The maintenance dose was down-titrated if the mSBP was below
the target range of 120-160 mmHg at any visit. In those cases, the
dose was reduced to 1 mg/kg and further reduced to 0.5 mg/kg SID if
mSBP remained below the target range. Twenty-six of the 107 cats
had doses down-titrated during this extended-use study.
[0186] In particular, cats enrolled in this extended study were
initially administered a dose of telmisartan of 2 mg/kg SID. If a
cat's mSBP dropped below the targeted range (<120 mmHg), the
dose was decreased or down titrated within the range of 0.5-2 mg/kg
SID. The dose was chosen based on the mSBP values in Table 11
below:
TABLE-US-00011 TABLE 11 Dosing Treatment Treatment SBP observed
Dose of active ingredient Dosage type (mm Hg) (rate) (volume)
Telmisartan >180 Rescue Rescue Oral Solution 180-120 2 mg/kg SID
0.5 mL/kg SID (IVP) <120 1 mg/kg SID* 0.25 mL/kg SID* *After a
cat received 1 mg/kg SID dosing, additional dose reduction was
allowed to a minimum of 0.5 mg/kg SID or 0.125 mL/kg SID if mSBP
was <120 mmHg. If at any visit the dose was the same as a dose
the animal had been on previously AND that dose was known for that
animal to have been too high or too low (causes the animal to be
outside the targeted range of 120-160 mmHg), the Investigator may
have chosen an alternate dose (within the allowed range of 0.5-2.0
mg/kg SID) in order to maintain the animal in the targeted range
(120-160 mmHg).
[0187] Thus, the daily telmisartan dose for each cat was titrated,
if necessary, at each visit according to the mSBP criteria set
forth in Table 11. If, at any visit, the dose was the same as a
dose the cat had previously received and that dose was known to be
too high or too low for the cat (i.e., it caused the mSBP of the
animal to be outside the targeted range of 120-160 mmHg), an
alternate dose (within the allowed range of 0.5-2.0 mg/kg SID) was
optionally chosen to maintain the animal in the targeted range
(120-160 mmHg). An example of how one cat in this study had its
daily dosage modified by being titrated down and up (based upon its
measured mSBP value at each visit) is depicted in Table 12
below:
TABLE-US-00012 TABLE 12 Dosing of Cat 329-454 Telmisartan daily
dose Study Visit Mean SBP (mmHg) (mg/kg) Visit 1 (Week 0) 160.0 3.0
(1.5 BID) Visit 2 (Week 2) 108.3 1.0 SID Visit 3 (Week 4) 116.0 0.5
SID Visit 4 (Week 8) 157.7 2.0 SID Visit 5 (Week 14) 100.0 1.0 SID
Visit 6 (Week 20) 125.3 2.0 SID Visit 7 (Week 26) 126.0 End of
study
[0188] Only 8 cats were removed from the study due to mSBP >180
mmHg, and were considered rescue cases. In summary, rescue cases
accounted for 7.5% (8/107) of all end of study outcomes. This
indicates that in 90.7% of cases (97/107), SBP was maintained
within the target range (120-180 mmHg). Two cats (1.9% of the
cases) were rescued due to hypotension.
[0189] Changes in mSBP and retinal photographs were assessed at
Weeks 4, 14, and 26 (Days 28.+-.2, 98.+-.7, and 182.+-.7,
respectively) to monitor blood pressure control and to determine
possible hypertension-related Target Organ Damage (TOD). Blood and
urine values were documented at Weeks 4, 14, and 26 to support
safety of telmisartan. At Weeks 8 (Day 56.+-.7), Week 20 (Day
140.+-.7), and at unscheduled visits, blood and urine samples were
collected at the discretion of the Investigator. All parameters
were evaluated by the Investigator for clinical significance. The
parameters were then compared to baseline, and changes were
summarized by treatment group as well as by subpopulation, if
appropriate.
[0190] The data for group mean for blood pressure measurements and
mean change in mSBP at Weeks 4, 8, 14, 20 and 26 are provided in
the following Tables 13 and 14, respectively:
TABLE-US-00013 TABLE 13 Group mSBP by visit Standard Minimum
Maximum Mean Median Error mSBP mSBP Visit (mmHg) (mmHg) (mmHg)
(mmHg) (mmHg) Baseline 176 175 1.1 160 200 (n = 107) Week 4 148 149
1.8 95 179 (n = 107) Week 8 148 148 2.0 105 195 (n = 102) Week 14
142 144 2.1 77 207 (n = 92) Week 20 145 148 2.0 89 184 (n = 81)
Week 26 150 147 2.2 104 207 (n = 73)
TABLE-US-00014 TABLE 14 Mean change from baseline by visit Mean
Median Minimum Maximum mSBP mSBP Standard mSBP mSBP Change Change
Error Change Change Visit (.DELTA.mmHg) (.DELTA.mmHg) (mmHg)
(.DELTA.mmHg) (.DELTA.mmHg) Week 4 -29 -26 1.9 -76 14 (n = 107)
Week 8 -28 -28 1.9 -79 7 (n = 102) Week 14 -33 -32 2.2 -115 25 (n =
92) Week 20 -30 -28 1.9 -91 16 (n = 81) Week 26 -25 -28 2.2 -69 30
(n = 73)
[0191] The mSBP measured for the cats in the study at each visit
was stable: 148 mmHg (Weeks 4 and 8), 142 mmHg (Week 14), 145 mmHg
(Week 20), and 150 mmHg (Week 26), compared to 176 mmHg at
baseline. This provides an indication that telmisartan can control
SBP in this population of cats over an extended period of time.
[0192] The majority of cats (90.7%) were enrolled into the study at
a dose of 2.0 mg/kg SID. Eight cats (7.5%) were enrolled at a dose
of 1.0 mg/kg SID, and two cats (1.9%) were enrolled at a dose of
0.5 mg/kg SID. Throughout the study period, most cats (86.7%-88.8%)
were maintained at a dose of 2.0 mg/kg. The remaining cats were
down-titrated to either 1.0 mg/kg or 0.5 mg/kg. At the end of the
study, most cats (87.7%) were receiving the 2.0 mg/kg dose. Table
15 provides the data for dose level of the cats at each visit:
TABLE-US-00015 TABLE 15 Dose level at each visit Dose Level (SID)
0.5 mg/kg 1.0 mg/kg 2.0 mg/kg Visit N % N % N % Week 4 (N = 107) 2
1.9% 8 7.5% 97 90.7% Week 8 (N = 98) 2 2.0% 9 9.2% 87 88.8% Week 14
(N = 90) 3 3.3% 9 10.0% 78 86.7% Week 20 (N = 80) 5 6.3% 4 5.0% 71
88.8% Week 26 (N = 73) 4 5.5% 5 6.8% 64 87.7%
[0193] The specific case identified cats (a total of 26 cats) that
were assigned a lower dose during the study due to having a SBP
below 120 mmHg, is set forth in Table 16 below:
TABLE-US-00016 TABLE 16 Cases down titrated at each visit by new
dose Visit Cases (N) Cases (IDs) 1 mg/kg SID Week 4 8 298-556,
308-474, 308-591, 317-405, 318-597, 325-560, 330-404, 330-509 Week
8 7 263-505, 265-836, 322-490, 323-533, 325-661, 326-583, 331-1113
Week 14 8 263-579, 264-404, 303-423, 305-409, 308-474, 308-754,
329-454, 329-535 Week 20 3 269-434, 303-441, 334-465 Unscheduled 8
301-953, 318-794, 322-631, 323-514, 329-454, 329-599, 329-737,
331-888 0.5 mg/kg SID Week 4 2 329-454, 358-406 Week 8 2 298-556,
323-514 Week 14 3 265-836, 322-631, 323-533 Week 20 2 305-409,
308-474 Unscheduled 1 263-579 <0.5 mg/kg SID = Hypotensive
Rescue.sup.+ Week 8 0 NA Week 14 0 NA Week 20 1 263-579 Unscheduled
1 323-533 .sup.+Both cats were considered rescued based on mSBP
<120 mmHg at visit following down titration to 0.5 mg/kg SID.
Neither cat had clinical signs associated with hypotension;
however, they were still removed from the study due to erroneous
termination prompt from Sponsor in EDC system.
[0194] The data in Table 16 indicates that 9 cats were assigned a
lower dose at Week 8, 11 cats at Week 14, 5 cats at Week 20, and 9
cats at an unscheduled visit. Of these cats, seven were
down-titrated twice within the study period, and two were
down-titrated three times. Two cats (263-579 and 323-533) were
removed from the study due to continued hypotension (mSBP <120
mmHg) following reduction to the lowest allowable dose.
[0195] Serious AEs (SAEs) occurred in 24 cats (22.4%) and
Non-serious AEs (NSAEs) occurred in 91 cats (85.0%) during the
study. The most commonly reported SAEs were weight loss (8.4%),
anemia and dehydration (6.5%), anorexia, vomiting (5.6%), and
lethargy, and the most common NSAEs were weight loss, vomiting,
dehydration, and diarrhea. Overall, 11 SAEs were determined to be
possibly attributable to telmisartan (10.3%). In general,
considering the geriatric age of the enrolled population (mean of
14.1 years) and the cats targeted for recruitment (hypertensive
cats with CKD and/or hyperthyroidism or idiopathic hypertension),
the overall incidence of SAEs was as expected. The most common
NSAEs (vomiting, diarrhea, and weight loss) are common findings in
geriatric cat studies and are expected in cats given oral
medication. The AE assessment also involved clinical evaluation of
developing or worsening of hypertension-related TOD. The results of
this study showed that SAEs for TOD considered possibly related to
telmisartan were substantially less prevalent than the values
proposed in literature as typical.
[0196] For the assessment of change in retinal photographs, a
majority of cats remained the same. Further, at all subsequent
visits, 6.9% to 7.4% improved when compared to baseline. This
indicates that telmisartan does not cause retinal deterioration and
may promote improvement by decreasing the deleterious effects of
hypertension on the retina.
[0197] IRIS staging and sub-staging were determined for all cats
enrolled into the CKD and CKD and hyperthyroid subpopulations and
having laboratory values at baseline. During the study period, a
majority of cats remained the same regarding IRIS staging and
proteinuria sub-staging. Furthermore, it is important to note that
83.0% to 98.1% of cats were scored as "better", and zero cats were
scored as "worse" in the blood pressure sub-staging.
[0198] The data plotted in FIG. 2 shows the SBP change from
baseline at the start of each study for each of Examples 4 and 5
(where mean baseline was about 176 mmHg and mean baseline for
placebo was about 175 mmHg). As is evident from the plotted data,
the SBP change from baseline (with a reduction in SBP) was greater
for the telmisartan group in relation to the placebo group at each
of Day 14 and Day 28. In addition, the mean change in SBP for the
telmisartan group was greater than 20 mmHg for each visit.
[0199] In conclusion, under clinical conditions, data from this
study provide substantial evidence of the safety and effectiveness
of telmisartan oral solution to control hypertension in cats at a
dose of 2 mg/kg/day with the ability to titrate the dose to adjust
for blood pressure response on an individual basis. This conclusion
is based on the assessment of change in mSBP, adverse events (AEs),
change in retinal photographs, and IRIS staging and
sub-staging.
Example 6
[0200] A European study was conducted to investigate the efficacy
and safety of telmisartan oral solution for the treatment of
systemic hypertension in cats. The first part or phase of the study
(Day 1 to Day 28) occurred over a 28-day placebo-controlled,
double-blinded treatment period (efficacy phase of the study). In a
second part or phase of the study (Day 29 to Day 120), the effect
and safety of telmisartan on mean Systolic Blood Pressure (mSBP)
control over an extended treatment period of an additional 92 days
was also evaluated (extended use phase of the study). The mSBP was
defined as the arithmetic mean of 3 blood pressure measurements at
each study visit. Baseline SBP was defined as the arithmetic mean
of the mSBP at Screening Visit Day -14 to -2 and Screening Visit
Day -1.
[0201] The target population for this study was domestic
client-owned cats with moderate to severe systemic hypertension
(cats having a mSBP of at least about 160 mmHg). A total of 285
client-owned cats from 51 study sites (24 in Germany, 9 in France,
11 in the United Kingdom, 4 in the Netherlands and 3 in
Switzerland) were randomized for treatment with either telmisartan
(189 cats, starting dose of 2.0 mg/kg once daily, which could be
reduced from Day 28 onwards during the second [extended use] phase)
or placebo (96 cats, 0.0 mg/kg once daily) in a 2:1 ratio. A
schematic overview of the study and the two phases of treatment is
depicted in FIG. 3. There was a similar pre-treatment mSBP observed
for both treatment groups (about 177-179 mmHg).
[0202] Cats diagnosed with moderate to severe systemic hypertension
in compliance with the "ACVIM consensus statement: Guidelines for
the Identification, Evaluation, and Management of Systemic
Hypertension in Dogs and Cats" (Brown et al. Guidelines for the
identification, evaluation, and management of systemic hypertension
in dogs and cats. ACVIM Consensus Statement. J Vet Intern Med 2007;
21: 542-558) at two separate Screening Visits within 14 days of the
start of treatment were eligible for the study. The etiology of the
hypertension was classified as due to chronic kidney disease (CKD),
due to hyperthyroidism, due to both CKD and hyperthyroidism or as
idiopathic hypertension. Cats were not allowed any substances which
are known to affect blood pressure from 14 days prior to the start
of treatment. Cats were excluded if their mSBP was in a malignant
range (>200 mmHg) at Screening Visits, or if they had highly
variable blood pressure measurements (differences over 3
consecutive measurements of >20%). Further exclusion criteria
included uncontrolled hyperthyroidism (Total T4>60 nmol/L),
acute or severe TOD, suspected or confirmed concomitant disease
influencing blood pressure and/or likely to interfere with the
study outcome, azotemia (due to acute or decompensated renal
disease, pre- or post-renal factors or presenting a risk of
non-completion of the study or hospitalization), or
pregnant/lactating queens and cats intended for breeding.
[0203] Oral administration of the telmisartan solution (and
placebo) was the route of delivery used in this study. During the
development of telmisartan, studies with therapeutic doses of 1.0,
1.5, 2.0 and 3.0 mg/kg per day were initially conducted. The
starting dose for the first phase of this study was set at 2.0
mg/kg per day of telmisartan orally. A 5 mL dosing syringe
(demarcated in 0.25 mL increments) was used for the first phase and
a 2 mL dosing syringe (demarcated in 0.1 mL increments, to achieve
down titrations as necessary) to perform dosing either directly
into the mouth of the cat or with a very small amount of food.
[0204] For the first (efficacy) phase of the study, all recruited
cats were examined on two visits at Day 14 and Day 28. Examinations
included measurement of mSBP, a complete physical examination,
fundoscopic examination, an assessment of quality of life, and
abbreviated clinical pathology (hematology and biochemistry). On
Day 28, unmasking was performed and only cats assigned to
telmisartan were allowed to continue forward for the second
(extended use) phase of the study. These cats were further
examined, as above, for visits at Days 56, 84 and 120. During the
second (extended) phase of the study, it was possible to decrease
or down titrate the dose for certain cats as described herein. In
particular, it was possible (in this second phase of the study) to
down titrate the dosage of telmisartan in cats with SBP measurement
<160 mmHg in 0.5 mg/kg decrements or amounts (e.g., decreasing
in a stepped manner from 2 mg/kg.fwdarw.1.5 mg/kg.fwdarw.1
mg/kg.fwdarw.0.5 mg/kg, SID) to the lowest possible dose of 0.5
mg/kg once a day upon the discretion of the Investigator.
[0205] At the outset of the study, the population of cats being
administered telmisartan or placebo consisted of 189 cats in the
telmisartan group and 96 cats in the placebo group. Certain cats
were screened from the study at the conclusion due to various
reasons (e.g., having a mSBP greater than 200, having certain
severe TODs, certain cats did not complete the study, etc.). The
safety of both phases of treatment was evaluated after the end of
the study in utilizing a screened population consisting of 174 cats
in the telmisartan group and 88 cats in the placebo group. The
results of the study confirmed superiority of telmisartan over
placebo after 14 days of treatment, and further demonstrated a
clinically relevant decrease in mSBP (equal to or greater than 20
mmHg) after 28 days of treatment.
[0206] The treatment groups were homogenous with regard to breed,
gender, age, body weight, baseline SBP, medical history and
classification of hypertension. The data in relation to the number
of cats in each hypertension classification per group (telmisartan
and placebo) is set forth in Table 17 below:
TABLE-US-00017 TABLE 17 Classification of hypertension in each
group Telmisartan Placebo Total (n = 189) (n = 96) (n = 285)
Baseline mSBP (mmHg) (.+-.SD) 179.3 (.+-.9.9) 177.4 (.+-.9.9)
Classification of hypertension [N (%)] Hypertension associated with
57 (30.2) 30 (31.3) 87 (30.5) CKD Hypertension associated with 9
(4.8) 5 (5.2) 14 (4.9) CKD and controlled hyperthyroidism
Hypertension associated with 14 (7.4) 7 (7.3) 21 (7.4) controlled
hyperthyroidism Idiopathic hypertension 109 (57.7) 54 (56.3) 163
(57.2)
[0207] A wide range of concomitant medications were administered
during the study, and there were no clinically relevant changes in
a physical or clinical pathology parameter observed in
telmisartan-treated cats following 120 days of treatment. Although
a similar appetite was observed in both treatment groups, more cats
in the placebo group had a normal appetite on Day 28 than in the
telmisartan treated group. However, the proportion of cats with
increased appetite rose in the telmisartan group and decreased in
the placebo group between day -1 and 28 (11% of the telmisartan
treated cats had an increased appetite in comparison to 5.9% of the
placebo treated cats). Overall, a total of 271 adverse events were
recorded in 149 cats across both treatment groups and both
treatment phases. During the efficacy phase, in the telmisartan
group, a total of 115 adverse events were coded for 58 cats
(29.9%), and in the placebo group, a total of 36 adverse events
were coded for 29 cats (29%). Some differences were observed
between the groups in the following categories: Renal and Urinary
disorders, Eye disorders, Systemic disorders and Respiratory Tract
disorders. The difference in the above mentioned disorders was
related to various non-frequent medical conditions, which are
typical for the included feline population except for Respiratory
Tract disorders. The difference between the two groups regarding
the Respiratory Tract disorders was due to numerous single
incidental disorders related to both upper and lower respiratory
tract. Observations considered by the Investigator to be most
likely due to the treatment were gastrointestinal signs. During the
second (extended use) phase, 62 cats (32.0%) had at least one
adverse event. The diagnosis of TOD was very low in both treatment
groups.
[0208] The data with regard to change in SBP for both the
telmisartan and placebo groups in the first (efficacy) phase of the
study (at Day 14 and Day 28) is set forth in Table 18 below (a
visual representation of this data is also plotted in FIG. 5):
TABLE-US-00018 TABLE 18 Mean SBP changes during the first
(efficacy) phase Endpoint successfully Parameter Telmisartan
Placebo Comparison achieved mSBP change n = 174 n = 88 p value of
t-test Yes (.DELTA.mmHg) on Day 14 -19.219 -9.045 <0.0001 (95%
Confidence (-22.52, -15.92) (-12.80, -5.30) Intervals) mSBP change
n = 165 n = 87 Clinical relevance Yes (.DELTA.mmHg on Day 28
-24.629 -11.44 defined as mean (95% Confidence (-28.14, -21.11)
(-14.95, -7.94) systolic blood Intervals) pressure change > 20
mmHg
[0209] The mean differences of SBP changes on Day 14 in comparison
to the baseline were -19.219 mmHg for the telmisartan group and
-9.045 mmHg for the placebo group. The two-sided unequal variances
t-test demonstrated superiority of telmisartan versus placebo by a
p-value <0.0001. The mean difference between baseline SBP and
SBP on Study Visit Day 28 was -24.629 mmHg for the telmisartan
group. This value exceeded the minimum threshold of 20 mmHg which
is required to demonstrate clinical relevance of the treatment
effect, thus demonstrating the efficacy of telmisartan in
comparison to placebo in the treatment of hypertension in cats.
[0210] The data with regard to change in SBP for the telmisartan
group in the second (extended use) phase of the study (at Day 56,
Day 84 and Day 120) is set forth in Table 19 below:
TABLE-US-00019 TABLE 19 mSBP changes during the second (extended
use) phase Parameter Telmisartan Mean Systolic Blood Pressure
change on Day 56 -26.94 compared to baseline SBP (.DELTA.mmHg): n =
152 cats (-30.79, -23.08) (95% Confidence Intervals) Mean Systolic
Blood Pressure change on Day 84 -26.50 compared to baseline SBP
(.DELTA.mmHg): n = 148 cats (-30.60, -22.40) (95% Confidence
Intervals) Mean Systolic Blood Pressure change on Day 120 -27.62
compared to baseline SBP (.DELTA.mmHg): n = 144 cats (-32.05,
-23.19) (95% Confidence Intervals)
[0211] The data presented in Table 20 shows the mean SBP reduction
over the different intervals/time periods of the study for cats in
both the telmisartan group and the placebo group divided into two
categories: baseline mSBP being between 160-179 mmHg and baseline
mSBP being between 180-200 mmHg:
TABLE-US-00020 TABLE 20 mSBP changes at SABP at baseline: between
180-200 mmHg Between 160-179 mmHg Telmisartan Placebo Telmisartan
Placebo Baseline Baseline Baseline Baseline mSABP: mSABP: mSABP:
mSABP: 171.9 170.9 mmHg 188.4 mmHg 188.5 mmHg mmHg (n = 98) (n =
56) (n = 76) (n = 32) Mean SABP reduction (.DELTA.mmHg) compared to
baseline at respective visit Visit (n = number of cats) Day 14
-16.7 -8.8 -22.3 -9.5 (n = 98) (n = 56) (n = 76) (n = 32) Day 28
-22.9 -11.9 -26.6 -10.9 (n = 94) (n = 55) (n = 71) (n = 32) Day 56
-24.7 NA -29.6 NA (n = 87) (n = 65) Day 84 -23.2 NA -30.7 NA (n =
85) (n = 63) Day 120 -23.5 NA -32.9 NA (n = 81) (n = 63)
[0212] The data in Table 21 below summarizes a comparison in number
of cats within each group in which the mSBP value was maintained
below 160 mmHg:
TABLE-US-00021 TABLE 21 Frequency of cats with mSBP <160 mmHg
Telmisartan Placebo Study Visit Day N (%) with Systolic Blood
Pressure <160 mmHg Pre-Treatment 0 (0) 0 (0) Visit Day 14 81
(46.6) 27 (30.7) Visit day 28 101 (62.0) 34 (40.0) Visit Day 56 105
(70.9) Not conducted Visit Day 84 97 (67.8) Not conducted Visit Day
120 98 (73.1) Not conducted
[0213] The number of cats at each dosage amount at each visit day
is set forth in Table 22 below:
TABLE-US-00022 TABLE 22 Overview of Telmisartan dose Mean Dose
(mg/kg) Actual (95% Confidence Dose Number of Cats Study Visit Day
intervals) (mg/kg) receiving dose Day 0 (n = 174) 2.0 2.0 174 (NA)
Visit Day 14 (n = 174) 2.0 2.0 174 (NA) Visit day 28 (n = 163) 1.95
2.0 148 (1.93-1.98) 1.5 15 Visit Day 56 (n = 148) 1.89 2.0 124
(1.84-1.93) 1.5 15 1.0 9 Visit Day 84 (n = 143) 1.84 2.0 112
(1.78-1.90) 1.5 20 1.0 7 0.5 4
[0214] The data plotted in FIGS. 4 and 5 show the SBP change from
baseline (at start of the study for each of the first and second
phases of this study). As is evident from the plotted data, the SBP
change from baseline (with a reduction in SBP) was greater for the
telmisartan group in relation to the placebo group in the first
phase (Day 14 and Day 28). In addition, the mean change in SBP for
the telmisartan group was greater than 20 mmHg for each of the
visit days.
[0215] The second (extended use) phase indicates that treatment
with telmisartan resulted in a sustained clinically relevant
reduction in mSBP of greater than 20 mmHg for the whole study
duration of 120 days. The SBP was restored to normal or levels
considered to be only mild or minimal risk (<160 mmHg) in 62.0%
of telmisartan-treated cats and it was possible to down-titrate the
dose to <2 mg/kg in 21.7% of telmisartan treated cats.
[0216] During this study, a number of other physical parameters (in
addition to measured SBP) for the cats were monitored (e.g., mean
body weight, mean heart rate, respiratory rate, and rectal
temperature). There was no clinically significant change observed
in any of these parameters following 120 days treatment with
telmisartan.
[0217] In conclusion, this study reveals that, in cats diagnosed
with systemic hypertension, treatment with 2 mg/kg telmisartan oral
solution was superior to placebo in reducing mSBP by a clinically
relevant magnitude within the 28 days efficacy phase. A further 92
days of treatment with telmisartan oral solution was safe and
maintained a clinically relevant reduction in mSBP.
* * * * *