U.S. patent application number 13/274013 was filed with the patent office on 2012-10-25 for compositions and methods of treating pulmonary hypertension.
Invention is credited to Luiz Belardinelli, Hunter Campbell Gillies, Faquan Liang, John Shryock, Suya Yang.
Application Number | 20120269898 13/274013 |
Document ID | / |
Family ID | 45939010 |
Filed Date | 2012-10-25 |
United States Patent
Application |
20120269898 |
Kind Code |
A1 |
Belardinelli; Luiz ; et
al. |
October 25, 2012 |
COMPOSITIONS AND METHODS OF TREATING PULMONARY HYPERTENSION
Abstract
Provided are formulations comprising therapeutically effective
amounts of ambrisentan or a pharmaceutically acceptable salt
thereof and tadalafil or a pharmaceutically acceptable salt thereof
and methods of treating and/or preventing pulmonary hypertension by
administration of the formulations.
Inventors: |
Belardinelli; Luiz; (Palo
Alto, CA) ; Gillies; Hunter Campbell; (El Granada,
CA) ; Liang; Faquan; (San Francisco, CA) ;
Shryock; John; (East Palo Alto, CA) ; Yang; Suya;
(Palo Alto, CA) |
Family ID: |
45939010 |
Appl. No.: |
13/274013 |
Filed: |
October 14, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61393529 |
Oct 15, 2010 |
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61490454 |
May 26, 2011 |
|
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61497475 |
Jun 15, 2011 |
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Current U.S.
Class: |
424/613 ;
514/250 |
Current CPC
Class: |
A61P 7/10 20180101; A61P
9/08 20180101; A61P 9/04 20180101; A61K 31/505 20130101; A61P 9/10
20180101; A61P 11/00 20180101; A61P 11/06 20180101; A61K 31/519
20130101; A61K 31/53 20130101; A61P 13/00 20180101; A61K 31/4985
20130101; A61P 7/02 20180101; A61K 31/519 20130101; A61K 31/422
20130101; A61K 31/53 20130101; A61K 45/06 20130101; A61P 13/12
20180101; A61P 9/00 20180101; A61K 31/505 20130101; A61K 31/422
20130101; A61K 31/4985 20130101; A61P 43/00 20180101; A61K 2300/00
20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61P 9/12 20180101; A61P
7/04 20180101 |
Class at
Publication: |
424/613 ;
514/250 |
International
Class: |
A61K 31/505 20060101
A61K031/505; A61K 33/00 20060101 A61K033/00; A61P 7/02 20060101
A61P007/02; A61P 7/10 20060101 A61P007/10; A61P 11/06 20060101
A61P011/06; A61P 9/08 20060101 A61P009/08; A61P 9/10 20060101
A61P009/10; A61P 9/00 20060101 A61P009/00; A61P 13/12 20060101
A61P013/12; A61P 7/04 20060101 A61P007/04; A61K 31/557 20060101
A61K031/557; A61P 9/12 20060101 A61P009/12 |
Claims
1. A combination therapy comprising: a therapeutically effective
amount of a selective type-A endothelin receptor antagonist (ERA)
selected from the group consisting of ambrisentan, sitaxsentan and
pharmaceutically acceptable salts thereof, and a therapeutically
effective amount of a phosphodiesterase type 5 (PDE5) inhibitor
selected from the group consisting of sildenafil, tadalafil,
vardenafil and pharmaceutically acceptable salts thereof, wherein
the weight ratio of the selective type-A ERA and the PDE5 inhibitor
is in a range from about 1:1 to about 1:10.
2. The combination therapy of claim 1, wherein the selective type-A
ERA is ambrisentan or a salt thereof, and the PDE5 inhibitor is
tadalafil or a salt thereof.
3. The combination therapy of claim 2, wherein the weight ratio of
the selective type-A ERA and the PDE5 inhibitor is in a range from
about 1:2 to about 1:5.
4. The combination therapy of claim 1, wherein the selective type-A
ERA and the PDE5 inhibitor are formulated separately.
5. The combination therapy of claim 1, wherein the selective type-A
ERA and the PDE5 inhibitor are formulated in a single dosage
form.
6. The combination therapy of claim 1, which is formulated for
parenteral administration.
7. The combination therapy of claim 1, which is formulated for oral
administration.
8. The combination therapy of claim 1, wherein the combination
therapy is in tablet form or capsule form.
9. The combination therapy of claim 2, wherein the amount of
ambrisentan or a salt thereof is from about 1 mg to about 100 mg
daily.
10. The combination therapy of claim 2, wherein the amount of
ambrisentan or a salt thereof is from about 2 mg to about 20 mg
daily.
11. The combination therapy of claim 2, wherein the amount of
tadalafil or salt thereof administered is from about 5 mg to about
500 mg daily.
12. The combination therapy of claim 2, wherein the amount of
tadalafil or salt thereof administered is from about 10 mg to about
100 mg daily.
13. The combination therapy of claim 1, wherein the combination
therapy consists essentially of: a therapeutically effective amount
of a selective type-A endothelin receptor antagonist (ERA) selected
from the group consisting of ambrisentan, sitaxsentan and
pharmaceutically acceptable salts thereof, and a therapeutically
effective amount of a phosphodiesterase type 5 (PDE5) inhibitor
selected from the group consisting of sildenafil, tadalafil,
vardenafil and pharmaceutically acceptable salts thereof, wherein
the weight ratio of the selective type-A ERA and the PDE5 inhibitor
is in a range from about 1:1 to about 1:10.
14. The combination therapy of claim 1, further comprising a third
active agent comprising at least one drug selected from the group
consisting of prostanoids, PDE5 inhibitors other than tadalafil,
endothelin receptor antagonists other than ambrisentan, calcium
channel blockers, diuretics, anticoagulants, oxygen and
combinations thereof.
15. A method for treating pulmonary hypertension in a patient
comprising administering to the patient a therapeutic amount of a
selective type-A ERA selected from the group consisting of
ambrisentan, sitaxsentan and pharmaceutically acceptable salts
thereof in combination with a therapeutically effective amount of a
PDE5 inhibitor selected from the group consisting of sildenafil,
tadalafil, vardenafil and pharmaceutically acceptable salts
thereof, wherein the weight ratio of the selective type-A ERA and
the PDE5 inhibitor is in a range from about 1:1 to about 1:10.
16. The method of claim 15, wherein the selective type-A ERA is
ambrisentan or a salt thereof, and the PDE5 inhibitor is tadalafil
or a salt thereof.
17. The method of claim 15, wherein the weight ratio of the
selective type-A ERA and the PDE5 inhibitor is in a range from
about 1:2 to about 1:5.
18. The method of claim 15, wherein the selective type-A ERA and
the PDE5 inhibitor are administered in a sequential manner.
19. The method of claim 15, wherein the selective type-A ERA and
the PDE5 inhibitor are administered at the same time.
20. The method of claim 15, wherein the selective type-A ERA and
the PDE5 inhibitor are administered orally or parenterally.
21. The method of claim 16, wherein the ambrisentan or salt thereof
and the tadalafil or salt thereof are administered as a combined
dosage unit.
22. The method of claim 21, wherein the combined dosage unit is a
tablet or a capsule.
23. The method of claim 16, wherein the amount of ambrisentan or
salt thereof administered is from about 1 mg to about 100 mg
daily.
24. The method of claim 23, wherein the amount of ambrisentan or
salt thereof administered is from about 2 mg to about 20 mg
daily.
25. The method of claim 16, wherein the amount of tadalafil or salt
thereof administered is from about 5 mg to about 500 mg daily.
26. The method of claim 25, wherein the amount of tadalafil or salt
thereof administered is from about 10 mg to about 100 mg daily.
27. The method of claim 15, wherein the selective type-A ERA and
the PDE5 inhibitor are administered once daily.
28. The method of claim 15, wherein the pulmonary hypertension
comprises pulmonary arterial hypertension (PAH).
29. The method of claim 15, wherein the PAH comprises idiopathic
PAH, familial PAH or PAH associated with another disease or
condition.
30. The method of claim 15, wherein the PAH at baseline is of WHO
Class II, III or IV.
31. A method for inhibiting endothelin-induced vasoconstriction in
a patient comprising administering to the patient a therapeutic
amount of ambrisentan or a salt thereof in combination with
tadalafil or a salt thereof, wherein the weight ratio of the amount
of the ambrisentan or salt thereof and the amount of the tadalafil
or salt thereof is in a range from about 1:1 to about 1:10.
32. A method for treating a disease in a patient comprising
administering to the patient a therapeutic amount of ambrisentan or
a salt thereof in combination with tadalafil or a salt thereof,
wherein the disease is selected from the group consisting of
hypertension, pulmonary hypertension, myocardial infarction, angina
pectoris, acute kidney failure, renal insufficiency, cerebral
vasospasms, cerebral ischemia, subarachnoid hemorrhages, asthma,
atherosclerosis, intravascular coagulation, restenosis after
angioplasty, hypertension caused by ischemia or intoxication,
kidney failure caused by ischemia or intoxication, Raynaud's
syndrome and asthmatic airway condition, and wherein the weight
ratio of the amount of the ambrisentan or salt thereof and the
amount of the tadalafil or salt thereof is in a range from about
1:1 to about 1:10.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit and priority to U.S.
Provisional Application No. 61/393,529 filed Oct. 15, 2010, U.S.
Provisional Application No. 61/490,454 filed May 26, 2011, and U.S.
Provisional Application No. 61/497,475 filed Jun. 15, 2011. The
entire disclosure of the applications identified in this paragraph
is incorporated herein by reference.
FIELD
[0002] The present disclosure relates to methods of treating and/or
preventing pulmonary hypertension by administration of
therapeutically effective amounts of a selective type-A endothelin
receptor antagonist and a phosphodiesterase type 5 inhibitor. This
disclosure also relates to pharmaceutical formulations that are
suitable for such administration.
BACKGROUND
[0003] Pulmonary hypertension (PH) has been previously classified
as primary (idiopathic) or secondary. Recently, the World Health
Organization (WHO) has classified pulmonary hypertension into five
groups:
[0004] Group 1: pulmonary arterial hypertension (PAH);
[0005] Group 2: PH with left heart disease;
[0006] Group 3: PH with lung disease and/or hypoxemia;
[0007] Group 4: PH due to chronic thrombotic and/or embolic
disease; and
[0008] Group 5: miscellaneous conditions (e.g., sarcoidosis,
histiocytosis X, lymphangiomatosis and compression of pulmonary
vessels).
See, for example, Rubin (2004) Chest 126:7-10.
[0009] Pulmonary arterial hypertension (PAH) is a particular type
of PH and is a serious, progressive and life-threatening disease of
the pulmonary vasculature, characterized by profound
vasoconstriction and an abnormal proliferation of smooth muscle
cells in the walls of the pulmonary arteries. Severe constriction
of the blood vessels in the lungs leads to very high pulmonary
arterial pressures. These high pressures make it difficult for the
heart to pump blood through the lungs to be oxygenated. Patients
with PAH suffer from extreme shortness of breath as the heart
struggles to pump against these high pressures. Patients with PAH
typically develop significant increases in pulmonary vascular
resistance (PVR) and sustained elevations in pulmonary artery
pressure (PAP), which ultimately lead to right ventricular failure
and death. Patients diagnosed with PAH have a poor prognosis and
equally compromised quality of life, with a mean life expectancy of
2 to 5 years from the time of diagnosis if untreated.
[0010] Endothelin-1 (ET-1) is the primary member of a family of
potent vasoconstrictor peptides, which are known to play an
essential role in mammalian cardiovascular physiology. ET-1 is
synthesized de novo and released from endothelial cells in response
to a variety of factors, including angiotensin II, catecholamines,
cytokines, hypoxia and shear stress. Two receptor subtypes,
endothelin receptor type A (ET.sub.A) and endothelin receptor type
B (ET.sub.B), mediate the effects of ET-1. In humans, the ET.sub.A
receptor is preferentially expressed in vascular smooth muscle
cells and is primarily responsible for the vasoconstrictive effects
of ET-1. In contrast, ET.sub.B receptors are found mainly in the
vascular endothelium, and their activation results in
vasodilatation via production of nitric oxide and prostacyclin. The
ET.sub.B receptor is also involved in regulation of circulating
concentrations of ET-1, through effects on endothelin converting
enzyme (ECE-1) expression, and the synthesis and reuptake of ET-1
by endothelial cells.
[0011] Ambrisentan is a non-sulfonamide, propanoic acid-class
endothelin receptor antagonist (ERA) with high affinity (.about.12
pM) for the ET.sub.A receptor. Ambrisentan is approved for sale by
the U.S. Food and Drug Administration (FDA) for once-daily
treatment of PAH and is marketed under the trade name
Letairis.RTM.. Other selective type-A receptor antagonists include
sitaxentan, atrasentan, and BQ-123.
[0012] Additional drugs such as phosphodiesterase type 5 inhibitors
(PDE5 inhibitor) are also approved for use in treating PAH. PDE5
inhibitors are drugs used to block the degradative action of
phosphodiesterase type 5 on cyclic GMP in the arterial wall smooth
muscle within the lungs and in the smooth muscle cells lining the
blood vessels supplying the corpus cavernosum of the penis.
[0013] Tadalafil is a PDE5 inhibitor, currently marketed under the
name Adcirca.RTM. for the treatment of pulmonary arterial
hypertension. The approved dose for pulmonary arterial hypertension
is 40 mg (two 20-mg tablets) once daily. Adverse effects of
tadalafil include hypotension, vision loss, hearing loss and
priapism. Thus, methods of increasing the anti-PH efficacy of
selective type-A ERA and PDE5 inhibitors, as well as reducing the
potential adverse effects, are highly desirable. Other PDE5
inhibitors on the market or during development include avanafil,
lodenafil, mirodenafil, sildenafil citrate, vardenafil and
udenafil.
[0014] U.S. Patent Publication No. 2008/0139593 describes a method
for treating pulmonary hypertension, comprising administration of a
therapeutically effective amount of ambrisentan to a patient,
wherein, at baseline, time from the first diagnosis of the
condition in the subject is not greater than about two years. Also
described is ambrisentan in combination with one or more suitable
drugs selected from prostanoids, PDE5 inhibitors such as
sildenafil, tadalafil, and vardenafil, ERAs, calcium channel
blockers, arylalkylamines, dihydropyridine derivatives, piperazine
derivatives and other suitable compounds for use in combination
therapy.
[0015] It has now been discovered that the combination of a
selective type-A ERA and a PDE5 inhibitor has beneficial co-action
resulting in potent relaxation of pulmonary contractions. For
example, the co-action of ambrisentan and tadalafil provides
enhanced efficacy in reducing endothelin-induced contraction of rat
pulmonary arteries and aortas.
SUMMARY OF THE DISCLOSURE
[0016] This disclosure describes the administration of a selective
type-A endothelin receptor antagonist (selective type-A ERA) in
combination with a phosphodiesterase type 5 inhibitor (PDE5
inhibitor) which co-acts in relaxating pulmonary contractions
and/or inhibiting hypoxia-induced pulmonary arterial pressure
(PAP). The ability to relax pulmonary contraction or inhibit PAP is
useful for treating and preventing pulmonary hypertension in
patients, as well as a variety of other conditions, which are
described herein. This combination therapy leads to enhanced
therapeutic effects when the selective type-A ERA is administered
in a therapeutically effective dose and the PDE5 inhibitor is
administered in a therapeutically effective dose. Either one or
both of the selective type-A ERA and the PDE5 inhibitor may be
administered in an amount less than their respective standard
therapeutic doses due to their co-action.
[0017] Certain ratios of the two agents even increase effectiveness
of the co-action so that it is substantially greater than the sum
of effectiveness of mono-administration of each agent (i.e.,
administration of a single agent). In one aspect, the ratio of the
amount of the selective type-A ERA and the amount of the PDE5
inhibitor, in order to get such enhanced effectiveness, can be from
about 2:1 to about 1:3. Alternatively, the ratio of the amount of
the selective type-A ERA and the amount of the PDE5 inhibitor can
range from 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8,
1:9 or 1:10 to about 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11,
1:12, 1:15 or 1:20. In another aspect, such combinations can
achieve an effectiveness that is at least about 5%, or
alternatively 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%,
60%, 65%, 70%, 80%, 90% or 100% greater than the sum of
effectiveness of mono-administration of each agent.
[0018] Non-limiting examples of selective type-A ERA include
ambrisentan and sitaxentan and pharmaceutically acceptable salts
thereof. In one aspect, the selective type-A ERA is ambrisentan.
Examples of PDE5 inhibitors include, without limitation, tadalafil,
avanafil, lodenafil, mirodenafil, sildenafil citrate, vardenafil
and udenafil and pharmaceutically acceptable salts thereof. In one
aspect, the PDE5 inhibitor is tadalafil.
[0019] Accordingly, in one aspect, this disclosure is directed to a
method for treatment and/or prevention of pulmonary hypertension in
a patient in need thereof. The method comprises administration of a
therapeutic amount of ambrisentan or a salt thereof in combination
with tadalafil or a salt thereof, wherein the ratio of the amount
of ambrisentan or a salt thereof and the amount of tadalafil or a
salt thereof is in a range from about 1:1 to about 1:10, or
alternatively from about 1:2 to about 1:5, or alternatively about
1:3.
[0020] Another aspect of this disclosure provides a method for
treating or preventing pulmonary hypertension in a patient in need
thereof comprising administering to the patient therapeutic amounts
of ambrisentan or a salt thereof in combination with tadalafil or a
salt thereof, wherein the effectiveness of administration of the
ambrisentan and the tadalafil is at least about 25%, or
alternatively 40% or 50%, greater than the sum of effectiveness of
mono-administrations of the ambrisentan and the tadalafil.
[0021] Further provided, in one aspect, is a method for treating or
preventing pulmonary hypertension in a patient in need thereof
comprising administering to the patient, once daily, therapeutic
amounts of ambrisentan or a salt thereof in combination with
tadalafil or a salt thereof, wherein the ratio of the amount of
ambrisentan or a salt thereof and the amount of tadalafil or a salt
thereof is about 1:3.
[0022] In any of the embodiments described herein, the pulmonary
hypertension comprises pulmonary arterial hypertension (PAH),
including but not limited to idiopathic PAH, familial PAH or PAH
associated with another disease or condition. In one aspect, the
PAH at baseline is of WHO Class I, II, III or IV.
[0023] In another aspect, provided is a method for inhibiting
endothelin-induced vasoconstriction in a patient in need thereof
comprising administering to the patient therapeutic amounts of
ambrisentan or a salt thereof in combination with tadalafil or a
salt thereof, wherein (a) the ratio of the amount of ambrisentan or
a salt thereof and the amount of tadalafil or a salt thereof is in
a range from about 1:1 to about 1:10 and/or (b) the effectiveness
of administration of the ambrisentan and the tadalafil is at least
about 25% greater than the sum of effectiveness of
mono-administrations of the ambrisentan and the tadalafil.
[0024] Also provided, in one aspect, is a method for treating or
preventing a disease in a patient in need thereof comprising
administering to the patient therapeutic amounts of ambrisentan or
a salt thereof in combination with tadalafil or a salt thereof,
wherein the disease is selected from the group consisting of
hypertension, pulmonary hypertension, myocardial infarction, angina
pectoris, acute kidney failure, renal insufficiency, cerebral
vasospasms, cerebral ischemia, subarachnoid hemorrhages, asthma,
atherosclerosis, intravascular coagulation, restenosis after
angioplasty, hypertension caused by ischemia or intoxication,
kidney failure caused by ischemia or intoxication, Raynaud's
syndrome and asthmatic airway condition, and wherein (a) the ratio
of the amount of ambrisentan or a salt thereof and the amount of
tadalafil or a salt thereof is in a range from about 1:1 to about
1:10 and/or (b) the effectiveness of administration of the
ambrisentan and the tadalafil is at least about 25% greater than
the sum of effectiveness of mono-administrations of the ambrisentan
and the tadalafil.
[0025] Still further provided is a method for reducing undesirable
side effects of ambrisentan or a salt thereof comprising
administering to the patient a therapeutic amount of tadalafil or a
salt thereof, wherein (a) the ratio of the amount of ambrisentan or
a salt thereof and the amount of tadalafil or a salt thereof is in
a range from about 1:1 to about 1:10 and/or (b) the effectiveness
of administration of the ambrisentan and the tadalafil is at least
about 25% greater than the sum of effectiveness of
mono-administrations of the ambrisentan and the tadalafil.
[0026] A method for reducing a therapeutically effective dose of
ambrisentan or a salt thereof is also provided, the method
comprising administering to the patient a therapeutic amount of
tadalafil or a salt thereof, wherein (a) the ratio of the amount of
ambrisentan or a salt thereof and the amount of tadalafil or a salt
thereof is in a range from about 1:1 to about 1:10 and/or (b) the
effectiveness of administration of the ambrisentan and the
tadalafil is at least about 25% greater than the sum of
effectiveness of mono-administrations of the ambrisentan and the
tadalafil.
[0027] Yet in one aspect, this disclosure provides a method for
reducing undesirable side effects of tadalafil or a salt thereof
comprising administering to the patient a therapeutic amount of
ambrisentan or a salt thereof, wherein (a) the ratio of the amount
of ambrisentan or a salt thereof and the amount of tadalafil or a
salt thereof is in a range from about 1:1 to about 1:10 and/or (b)
the effectiveness of administration of the ambrisentan and the
tadalafil is at least about 25% greater than the sum of
effectiveness of mono-administrations of the ambrisentan and the
tadalafil.
[0028] In another aspect, provided is a method for reducing a
therapeutically effective dose of tadalafil or a salt thereof
comprising administering to the patient a therapeutic amount of
ambrisentan or a salt thereof, wherein (a) the ratio of the amount
of ambrisentan or a salt thereof and the amount of tadalafil or a
salt thereof is in a range from about 1:1 to about 1:10 and/or (b)
the effectiveness of administration of the ambrisentan and the
tadalafil is at least about 25% greater than the sum of
effectiveness of mono-administrations of the ambrisentan and the
tadalafil.
[0029] Pharmaceutical formulations are also provided. One aspect
provides a pharmaceutical formulation comprising therapeutic
amounts of tadalafil or a salt thereof and ambrisentan or a salt
thereof, and a pharmaceutically acceptable carrier, wherein (a) the
ratio of the amount of ambrisentan or a salt thereof and the amount
of tadalafil or a salt thereof is in a range from about 1:1 to
about 1:10 and/or (b) the effectiveness of combination of the
ambrisentan and the tadalafil is at least about 25% greater than
the sum of effectiveness of mono-administrations of the ambrisentan
and the tadalafil.
[0030] In one aspect, this disclosure provides a method for
treating pulmonary hypertension in a patient comprising
administering a therapeutically effective amount of a combination
therapy comprising of a selective type-A endothelin receptor
antagonist, in combination with a PDE5 inhibitor and metabolites
thereof, co-acting to provide therapeutic benefit to patients with
pulmonary hypertension in absence of a substantial deleterious side
effect in a therapeutically effective ratio in a range from about
1:1 to about 1:10.
[0031] In another aspect, this invention discloses a method for
treating pulmonary hypertension in a patient comprising
administering a therapeutically effective amount of a combination
therapy comprising of a selective type-A endothelin receptor
antagonist, a PDE5 inhibitor, and a third active agent effective
for the treatment of pulmonary hypertension or a related condition,
and metabolites thereof, co-acting to provide therapeutic benefit
to patients with pulmonary hypertension in absence of a substantial
deleterious side effect in a therapeutically effective molar ratio
in a range from about 1:1 to about 1:10.
[0032] In one aspect, this disclosure provides a pharmaceutical
formulation of a combination therapy comprising therapeutic amounts
of a selective type-A endothelin receptor antagonist and a PDE5
inhibitor co-acting to provide therapeutic benefit to patients with
pulmonary hypertension in absence of a substantial deleterious side
effect in a therapeutically effective ratio in a range from about
1:1 to about 1:10.
[0033] In one aspect, this disclosure provides a pharmaceutical
formulation comprising therapeutic amounts of tadalafil or a salt
thereof and ambrisentan or a salt thereof, and a pharmaceutically
acceptable carrier, wherein the ratio of the amount of ambrisentan
or a salt thereof and the amount of tadalafil or a salt thereof is
about 1:3.
[0034] In another aspect, this disclosure provides a pharmaceutical
formulation of a combination therapy comprising a selective type-A
endothelin receptor antagonist, a PDE5 inhibitor, and a third
active agent effective for the treatment of pulmonary hypertension
or a related condition, and metabolites thereof, co-acting to
provide therapeutic benefit to patients with pulmonary hypertension
in absence of a substantial deleterious side effect in a
therapeutically effective molar ratio in a range from about 1:1 to
about 1:10.
BRIEF DESCRIPTION OF THE DRAWINGS
[0035] As used throughout the Figures, the term "AMB" refers to
ambrisentan, "TAD" refers to tadalafil, "BOS" refers to bosentan,
and "MAC" refers to macitentan.
[0036] FIG. 1 shows that ambrisentan (10 nM) and tadalafil (30 nM),
in combination, relaxed endothelin-induced contraction of rat
pulmonary arteries and aortas significantly more effectively than
mono-administration of either drug. Data are expressed as
mean.+-.SEM, n=3. *p<0.01 vs. mono-therapy of 10 nM Ambrisentan
or 30 nM tadalafil.
[0037] FIG. 2 shows that the combination of ambrisentan and
tadalafil exhibited more than additive effects than mono-therapy of
either drug, and thus, beneficial co-action exists between
ambrisentan and tadalafil. Such co-action, however, was not
observed between non-selective ERA, such as bosentan and
macitentan, when administered with tadalafil. *p<0.01 vs.
Ambrisentan (AMB) or Tadalafil (TAD). #p<0.05 vs.
mono-administrations of Bosentan (BOS), Macitentan (MAC) and TAD or
combination of ABM with TAD. ---: represents the predicted additive
effect of AMB with TAD.
[0038] FIG. 3 shows the effects of TAD with AMB or BOS to attenuate
ET-1-induced contraction of rat aortic rings. Data are expressed as
mean.+-.SEM. *p<0.01 vs. 10 nM AMB or 30 nM TAD. #p<0.05 vs.
100 nM BOS or 30 nM TAD. ---: represents the additive effect of AMB
with TAD. The data show that the effect of the combination of AMB
and TAD is greater than the additive effects of each drug
(indicated by the dotted line), whereas the combinatory effect of
BOS and TAD is not.
[0039] FIG. 4 are contraction graphs showing the effects of TAD in
combination with AMB or BOS on ET-1-induced contraction of rat
aortic rings (top: no treatment; middle: AMB+TAD; bottom: BOS+TAD).
It is shown that the combination of AMB and TAD (middle) relaxed
contraction more significantly than the combination of BOS and TAD
(bottom).
[0040] FIG. 5 shows that endothelium involved in co-action or
additive effect of ET Receptor antagonists with TAD.
[0041] FIG. 6 shows that in the presence of BQ-788, a selective
type-B endothelin receptor antagonist, the combination effect of
AMB with TAD was significantly reduced. This indicates that ET
type-B receptor is involved in co-action effect of AMB with
TAD.
[0042] FIG. 7 illustrates the ET-1 and PDE5 signaling in
endothelial cells and smooth muscle cells.
[0043] FIG. 8 illustrates the mechanism underlying the co-action
between a selective type-A ERA and a PDE5 inhibitor that target
vasorelaxation from two different pathways.
[0044] FIG. 9 illustrates the lack of beneficial co-action between
a non-selective ERA or a selective type-B ERA and a PDE5 inhibitor
that target the same pathway.
[0045] FIG. 10 demonstrates the co-action between TAD with AMB in
an in vivo pulmonary arterial hypertension (PAH) animal model.
DETAILED DESCRIPTION OF THE DISCLOSURE
1. Definitions and General Parameters
[0046] As used in the present specification, the following words
and phrases are generally intended to have the meanings as set
forth below, except to the extent that the context in which they
are used indicates otherwise.
[0047] It is to be noted that as used herein and in the claims, the
singular forms "a," "an" and "the" include plural referents unless
the context clearly dictates otherwise. Thus, for example,
reference to "a pharmaceutically acceptable carrier" in a
composition includes two or more pharmaceutically acceptable
carriers, and so forth.
[0048] "Comprising" is intended to mean that the compositions and
methods include the recited elements, but do not exclude others.
"Consisting essentially of" when used to define compositions and
methods, shall mean excluding other elements of any essential
significance to the combination for the intended use. Thus, a
composition consisting essentially of the elements as defined
herein would not exclude trace contaminants from the isolation and
purification method and pharmaceutically acceptable carriers, such
as phosphate buffered saline, preservatives, and the like.
"Consisting of" shall mean excluding more than trace elements of
other ingredients and substantial method steps for administering
the compositions of this disclosure. Embodiments defined by each of
these transition terms are within the scope of this disclosure.
[0049] An "endothelin receptor antagonist (ERA)" is an agent that
blocks endothelin receptors. There are at least two major known
endothelin receptors, ET.sub.A and ET.sub.B, both of which are G
protein-coupled receptors whose activation result in elevation of
intracellular-free calcium. Three main kinds of ERAs exist:
selective type-A receptor antagonists, e.g., sitaxentan,
ambrisentan, atrasentan, BQ-123, which affect endothelin A
receptors; dual antagonists, e.g., bosentan, macitentan,
tezosentan, which affect both endothelin A and B receptors; and
selective type-B receptor antagonists, e.g., BQ-788, which affect
endothelin B receptors.
[0050] A "selective type-A endothelin receptor antagonist" or
"selective type-A ERA" selectively targets the type-A endothelin
receptor.
[0051] "Ambrisentan" or "AMB" is described in U.S. Pat. Nos.
5,703,017; 5,932,730 and 7,109,205. It refers to the chemical
compound,
(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic
acid and has the following chemical formula:
##STR00001##
Ambrisentan is approved for sale by the U.S. Food and Drug
Administration (FDA) for once-daily treatment of PAH and is
marketed under the trade name Letairis.RTM.. In Europe, Ambrisentan
is approved under the trade name Volibris.RTM..
[0052] "Ambrisentan" as used herein is intended to include the
metabolites of ambrisentan described in U.S. Patent Publication No.
2010/0204163. The ambrisentan metabolites include the compounds
having the following chemical formula:
##STR00002##
wherein R.sup.1 is --OH or --OCH.sub.3; R.sup.2 is --H, lower alkyl
or glycosidyl; and R.sup.3 and R.sup.4 are independently
--CH.sub.3, --C(O)H or --CH.sub.2OR.sup.6, wherein R.sup.6 is --H
or a hydrocarbyl group having 1 to 20 carbon atoms.
[0053] "Sitaxentan" refers to the chemical compound
N-(4-chloro-3-methyl-1,2-oxazol-5-yl)-2-[2-(6-methyl-2H-1,3-benzodioxol-5-
-yl)acetyl]thiophene-3-sulfonamide, and its pharmaceutically
acceptable salts. Sitaxentan is described in Barst R J et al.,
(2004) American Journal of Respiratory Critical Care Medicine 169
(4): 441-7. Sitaxentan has the following chemical formula:
##STR00003##
Sitaxentan was marketed as Thelin.RTM. for the treatment of PAH in
2008 but was later removed from the market in 2010.
[0054] A "phosphodiesterase type 5 inhibitor" or "PDE5 inhibitor"
refers to an agent that blocks the degradative action of
phosphodiesterase type 5 on cyclic GMP in the arterial wall smooth
muscle within the lungs and in the smooth muscle cells lining the
blood vessels supplying the corpus cavernosum of the penis. PDE5
inhibitors are used for the treatment of pulmonary hypertension and
in the treatment of erectile dysfunction. Examples of PDE5
inhibitors include, without limitation, tadalafil, avanafil,
lodenafil, mirodenafil, sildenafil citrate, vardenafil and udenafil
and pharmaceutically acceptable salts thereof. In one aspect, the
PDE5 inhibitor is tadalafil.
[0055] "Tadalafil" or "TAD" is described in U.S. Pat. Nos.
5,859,006 and 6,821,975. It refers to the chemical compound,
(6R-trans)-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-pyr-
azino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione and has the following
chemical formula:
##STR00004##
Tadalafil is currently marketed in pill form for treating erectile
dysfunction (ED) under the trade name Cialis.RTM. and under the
trade name Adcirca.RTM. for the treatment of PAH.
[0056] "Avanafil" refers to the chemical compound
4-[(3-Chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-1-pyrrolidinyl]--
N-(2-pyrimidinylmethyl)-5-pyrimidinecarboxamide, and its
pharmaceutically acceptable salts. Avanafil is described in Limin
M. et al., (2010) Expert Opin Investig Drugs, 19(11):1427-37.
Avanafil has the following chemical formula:
##STR00005##
Avanafil is being developed for erectile dysfunction. Avanafil
currently has no trademarked term associated with it but it is
being developed by Vivus Inc.
[0057] "Lodenafil" refers to the chemical compound,
bis-(2-{4-[4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,-
3-d]pyrimidin-5-yl)-benzenesulfonyl]piperazin-1-yl}-ethyl)carbonate
and has the following chemical formula:
##STR00006##
More information about lodenafil is available at Toque H A et al.,
(2008) European Journal of Pharmacology, 591(1-3):189-95. Lodenafil
is manufactured by Cristalia Produtos Quimicose Farmac uticos in
Brazil and sold there under the brand-name Helleva.RTM.. It has
undergone Phase III clinical trials, but is not yet approved for
use in the United States by the U.S. FDA.
[0058] "Mirodenafil" refers to the chemical compound,
5-Ethyl-3,5-dihydro-2-[5-([4-(2-hydroxyethyl)-1-piperazinyl]sulfonyl)-2-p-
ropoxyphenyl]-7-propyl-4H-pyrrolo[3,2-d]pyrimidin-4-one and has the
following chemical formula:
##STR00007##
More information about mirodenafil can be found at Paick J S et
al., (2008) The Journal of Sexual Medicine, 5 (11): 2672-80.
Mirodenafil is not currently approved for use in the United States
but clinical trials are being conducted.
[0059] "Sildenafil citrate," marketed under the name Viagra.RTM.,
is described in U.S. Pat. No. 5,250,534. It refers to
1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyri-
midin-5-yl)phenylsulfonyl]-4-methylpiperazine and has the following
chemical formula:
##STR00008##
Sildenafil citrate, sold as Viagra.RTM., Revatio.RTM. and under
various other trade names, is indicated to treat erectile
dysfunction and PAH.
[0060] "Vardenafil" refers to the chemical compound,
4-[2-Ethoxy-5-(4-ethylpiperazin-1-yl)sulfonyl-phenyl]-9-methyl-7-propyl-3-
,5,6,8-tetrazabicyclo[4.3.0]nona-3,7,9-trien-2-one and has the
following chemical formula:
##STR00009##
Vardenafil is described in U.S. Pat. Nos. 6,362,178 and 7,696,206.
Vardenafil is marketed under the trade name Levitra.RTM. for
treating erectile dysfunction.
[0061] "Udenafil" refers to the chemical compound,
3-(1-methyl-7-oxo-3-propyl-4,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)--
N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide
and has the following chemical formula:
##STR00010##
More information about udenafil can be found at Kouvelas D. et al.,
(2009) Curr Pharm Des, 15(30):3464-75. Udenafil is marketed under
the trade name Zydena.RTM. but not approved for use in the United
States.
[0062] Each of the compounds described above, as used throughout,
is intended to include a free acid, free base, or a
pharmaceutically acceptable salt thereof.
[0063] As used herein, the term "salt" refers to a pharmaceutically
acceptable salt of a compound that is derived from a variety of
physiologically acceptable organic and inorganic counter ions. Such
counter ions are well known in the art and include, by way of
example only, sodium, potassium, calcium, magnesium, aluminum,
lithium and ammonium, for example tetraalkylammonium, and the like
when the molecule contains an acidic functionality; and when the
molecule contains a basic functionality, salts of organic or
inorganic acids, such as hydrochloride, sulfate, phosphate,
diphosphate, nitrate hydrobromide, tartrate, mesylate, acetate,
malate, maleate, besylate, fumarate, tartrate, succinate, citrate,
lactate, pamoate, salicylate, stearate, methanesulfonate,
p-toluenesulfonate, and oxalate, and the like. Suitable
pharmaceutically acceptable salts also include those listed in
Remington's Pharmaceutical Sciences, 17th Edition, pg. 1418 (1985)
and P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of
Pharmaceutical Salts Properties, Selection, and Use; 2002. Examples
of acid addition salts include those formed from acids such as
hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids,
and with organic acids, such as alginic, ascorbic, anthranilic,
benzoic, camphorsulfuric, citric, embonic (pamoic), ethanesulfonic,
formic, fumaric, furoic, galacturonic, gentisic, gluconic,
glucuronic, glutamic, glycolic, isonicotinic, isothionic, lactic,
malic, mandelic, methanesulfonic, mucic, pantothenic, phenylacetic,
propionic, saccharic, salicylic, stearic, succinic, sulfinilic,
trifluoroacetic and arylsulfonic for example benzenesulfonic and
p-toluenesulfonic acids. Examples of base addition salts formed
with alkali metals and alkaline earth metals and organic bases
include chloroprocaine, choline, N,N-dibenzylethylenediamine,
diethanolamine, ethylenediamine, lysine, meglumaine
(N-methylglucamine), and procaine, as well as internally formed
salts. Salts having a non-physiologically acceptable anion or
cation are within the scope of the disclosure as useful
intermediates for the preparation of physiologically acceptable
salts and/or for use in non-therapeutic, for example, in vitro,
situations.
[0064] The disclosure specifically contemplates using salts of both
ambrisentan and tadalafil and further contemplates mixtures of
salts of tadalafil and/or ambrisentan.
[0065] In certain embodiments, the ambrisentan and/or tadalafil as
used herein has not been sufficiently ionized and may be in the
form a co-crystal. In one embodiment, the present disclosure
provides a co-crystal composition comprising a co-crystal of
ambrisentan and/or tadalafil, wherein said co-crystal comprises
ambrisentan and/or tadalafil and a co-crystal former. The term
"co-crystal" refers a crystalline material which comprises
ambrisentan and/or tadalafil and one or more co-crystal formers,
such as a pharmaceutically acceptable salt. In certain embodiments,
the co-crystal can have an improved property as compared to the
free form (i.e., the free molecule, zwitter ion, hydrate, solvate,
etc.) or a salt (which includes salt hydrates and solvates). In
further embodiments, the improved property is selected from the
group consisting of: increased solubility, increased dissolution,
increased bioavailability, increased dose response, decreased
hygroscopicity, a crystalline form of a normally amorphous
compound, a crystalline form of a difficult to salt or unsaltable
compound, decreased form diversity, more desired morphology, and
the like. Methods for making and characterizing co-crystals are
well known to those of skill in the art.
[0066] The phrase "combination therapy", in defining use of a
selective type-A endothelin receptor antagonist and a PDE5
inhibitor, is intended to embrace administration of each agent in a
sequential manner in a regimen that will provide beneficial effects
of the drug combination, and is intended as well to embrace
co-administration of these agents in a substantially simultaneous
manner, such as by oral ingestion of a single capsule having a
fixed ratio of these active agents or ingestion of multiple,
separate capsules for each agent. "Combination therapy" will also
include simultaneous or sequential administration by intravenous,
intramuscular or other parenteral routes into the body, including
direct absorption through mucous membrane tissues, as found in the
sinus passages. Sequential administration also includes drug
combination where the individual elements may be administered at
different times and/or by different routes but which act in
combination to provide a beneficial effect, such as enhanced
effectiveness.
[0067] In a particular embodiment, a combination therapy consists
essentially of two active agents, namely, a selective type-A
endothelin receptor antagonist and a PDE5 inhibitor.
[0068] In another embodiment, a combination therapy is a three-way
combination comprising a selective type-A endothelin receptor
antagonist, a PDE5 inhibitor and a third active agent effective for
the treatment of the pulmonary hypertension condition or a
condition related thereto. Illustratively and without limitation,
the combination can include a third active agent selected from the
group consisting of prostanoids, phosphodiesterase inhibitors other
than tadalafil, endothelin receptor antagonists other than
ambrisentan, calcium channel blockers, diuretics, anticoagulants,
oxygen and combinations thereof.
[0069] The phrase "therapeutically-effective" is intended to
qualify the amount of each agent for use in the combination therapy
which will achieve the goal of improvement in pulmonary functions,
while avoiding or reducing an adverse side effect typically
associated with each agent. The therapeutically effective amount
will vary depending upon the specific activity of the therapeutic
agent being used, the severity of the patient's disease state, and
the age, physical condition, existence of other disease states, and
nutritional status of the patient. Additionally, other medication
the patient may be receiving will effect the determination of the
therapeutically effective amount of the therapeutic agent to
administer.
[0070] "Co-action" means that the therapeutic effect of a PDE5
inhibitor such as tadalafil when administered in combination with a
selective type-A endothelin receptor antagonist such as ambrisentan
(or vice-versa) is greater than the sum of the therapeutic effects
of the agents when administered separately. The term "therapeutic
amount" used herein includes a less than standard therapeutic
amount of one or both drugs, meaning that the amount required for
the desired effect is lower than when the drug is used separately.
A therapeutic amount also includes when one drug is given at a
standard therapeutic dose and another drug is administered in a
less than standard therapeutic dose. For example, ambrisentan could
be given in a therapeutic dose and tadalafil could be given in a
less than standard therapeutic dose to provide an enhanced result.
In some embodiments, both drugs can be administered in a standard
therapeutic dose for much greater efficacies.
[0071] The term "treatment" or "treating" means any treatment of a
disease or condition in a subject, such as a mammal, including: 1)
preventing or protecting against the disease or condition, that is,
causing the clinical symptoms not to develop; 2) inhibiting the
disease or condition, that is, arresting or suppressing the
development of clinical symptoms; and/or 3) relieving the disease
or condition that is, causing the regression of clinical
symptoms.
[0072] As used herein, the term "preventing" refers to the
prophylactic treatment of a patient in need thereof. The
prophylactic treatment can be accomplished by providing an
appropriate dose of a therapeutic agent to a subject at risk of
suffering from an ailment, thereby substantially averting onset of
the ailment.
[0073] It will be understood by those skilled in the art that in
human medicine, it is not always possible to distinguish between
"preventing" and "suppressing" since the ultimate inductive event
or events may be unknown, latent, or the patient is not ascertained
until well after the occurrence of the event or events. Therefore,
as used herein the term "prophylaxis" is intended as an element of
"treatment" to encompass both "preventing" and "suppressing" as
defined herein. The term "protection," as used herein, is meant to
include "prophylaxis."
[0074] The term "susceptible" refers to a patient who has had at
least one occurrence of the indicated condition.
[0075] The term "patient" typically refers to a "mammal" which
includes, without limitation, human, monkeys, rabbits, mice,
domestic animals, such as dogs and cats, farm animals, such as
cows, horses, or pigs, and laboratory animals.
[0076] As used herein, "pharmaceutically acceptable carrier"
includes any and all solvents, dispersion media, coatings,
antibacterial and antifungal agents, isotonic and absorption
delaying agents and the like. The use of such media and agents for
pharmaceutically active substances is well known in the art. Except
insofar as any conventional media or agent is incompatible with the
active ingredient, its use in the therapeutic compositions is
contemplated. Supplementary active ingredients can also be
incorporated into the compositions.
[0077] "Intravenous administration" is the administration of
substances directly into a vein, or "intravenously". Compared with
other routes of administration, the intravenous (N) route is the
fastest way to deliver fluids and medications throughout the body.
An infusion pump can allow precise control over the flow rate and
total amount delivered, but in cases where a change in the flow
rate would not have serious consequences, or if pumps are not
available, the drip is often left to flow simply by placing the bag
above the level of the patient and using the clamp to regulate the
rate. Alternatively, a rapid infuser can be used if the patient
requires a high flow rate and the IV access device is of a large
enough diameter to accommodate it. This is either an inflatable
cuff placed around the fluid bag to force the fluid into the
patient or a similar electrical device that may also heat the fluid
being infused. When a patient requires medications only at certain
times, intermittent infusion is used, which does not require
additional fluid. It can use the same techniques as an intravenous
drip (pump or gravity drip), but after the complete dose of
medication has been given, the tubing is disconnected from the N
access device. Some medications are also given by IV push or bolus,
meaning that a syringe is connected to the IV access device and the
medication is injected directly (slowly, if it might irritate the
vein or cause a too-rapid effect). Once a medicine has been
injected into the fluid stream of the IV tubing there must be some
means of ensuring that it gets from the tubing to the patient.
Usually this is accomplished by allowing the fluid stream to flow
normally and thereby carry the medicine into the bloodstream;
however, a second fluid injection is sometimes used, a "flush",
following the injection to push the medicine into the bloodstream
more quickly.
[0078] "Oral administration" is a route of administration where a
substance is taken through the mouth, and includes buccal,
sublabial and sublingual administration, as well as enteral
administration and that through the respiratory tract, unless made
through, e.g., tubing so the medication is not in direct contact
with any of the oral mucosa. Typical form for the oral
administration of therapeutic agents includes the use of tablets or
capsules.
2. Methods
[0079] Generally, the present disclosure relates to methods of
treating or preventing pulmonary hypertension. The method comprises
administration of therapeutic amounts of a selective type-A
endothelin receptor antagonist (selective type-A ERA) and a
phosphodiesterase type 5 inhibitor (PDE5 inhibitor). In a
particular aspect, the method comprises administration of a
therapeutic amount of tadalafil or a salt thereof and a therapeutic
amount of ambrisentan or a salt thereof. In one embodiment, either
one or both of ambrisentan or tadalafil are administered in an
effective amount. The two agents may be administered separately or
together in separate or a combined dosage unit. If administered
separately, the ambrisentan may be administered before or after
administration of the tadalafil.
[0080] As further discussed in the Examples, presented herewith is
evidence of co-action of the combination of ambrisentan (AMB) and
tadalafil (TAD) to relax endothelin-induced contractions and to
inhibit hypoxia-induced pulmonary arterial pressure (PAP) in a
pulmonary arterial hypertension (PAH) animal model. Such enhanced
efficacy of the co-action is apparent as the combined effect is
greater than the additive effects of mono-administration of each
drug. In one aspect, such enhanced efficacy amounts to at least
about 5% enhanced effectiveness over the additive effectiveness of
mono-administration of each drug. Alternatively, such enhancement
is at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%,
60%, 65%, 70%, 80%, 90% or 100%. In other words, the combinations
can achieve an effectiveness that is at least about 5%, or
alternatively 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%,
60%, 65%, 70%, 80%, 90% or 100% greater than the sum of
effectiveness of mono-administrations of either agent.
[0081] As demonstrated in the Examples, such an enhanced effect
does not exist between TAD and a non-selective ERA such as bosentan
(BOS) or macitentan (MAC). These results, therefore, suggest that
type-B endothelin receptor in endothelium contributes to the
enhanced effect of ambrisentan and tadalafil on vasorelaxation. As
illustrated in FIGS. 8 and 9, the enhanced effect is due to
ambrisentan and tadalafil co-acting in the endothelin receptor
type-A and PDE5 pathways, respectively. Accordingly, similar
enhanced effects are found between any selective type-A ERA and any
PDE5 inhibitor. Additionally, a combination of a selective type-A
ERA and a PDE5 inhibitor also results in enhanced effects in
treating other diseases and conditions associated with the activity
of endothelin receptor type-A.
[0082] As suggested by the above mechanism, the enhanced effect of
the co-action of a selective type-A ERA and a PDE5 inhibitor
depends on the amounts of each individual agent and/or ratios of
such amounts. In one aspect, the ratio of the amount of the
selective type-A ERA and the amount of the PDE5 inhibitor, in order
to achieve such enhanced effects, can be from about 2:1, or
alternatively 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8,
1:9 or 1:10 to about 1:3, or alternatively about 1:4, 1:5, 1:6,
1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:15 or 1:20.
[0083] In one aspect, the ratio of amounts is a ratio of molar
amounts of each agent. In another aspect, the ratio of amounts is a
weight ratio of each agent.
[0084] In some embodiments, the ratio of the amount of the
selective type-A ERA and the amount of the PDE5 inhibitor, in order
to achieve enhanced effects, is around 1:3, which, for instance,
can be from about 1:1.5 to about 1:5, or alternatively from about
1:2 to about 1:4. In one aspect, the selective type-A ERA is
ambrisentan or a salt thereof. In one aspect, the PDE5 inhibitor is
tadalafil or a salt thereof. In another aspect, the ratio is a
weight ratio of each agent. In one aspect, the amount of
ambrisentan or a salt thereof is from about 5 mg to about 10 mg
daily for a human subject. In another aspect, the amount of
tadalafil or a salt thereof is from about 15 mg to about 30 mg
daily for a human subject.
[0085] In some embodiments, the ratio of the amount of the
selective type-A ERA and the amount of the PDE5 inhibitor, in order
to achieve enhanced effects, is around 1:1, which, for instance,
can be from about 2:1 to about 1:2, or alternatively from about 1:1
to about 1:2. In one aspect, the selective type-A ERA is
ambrisentan or a salt thereof. In one aspect, the PDE5 inhibitor is
tadalafil or a salt thereof. In another aspect, the ratio is a
weight ratio of each agent. In one aspect, the amount of
ambrisentan or a salt thereof is from about 5 mg to about 10 mg
daily for a human subject. In another aspect, the amount of
tadalafil or a salt thereof is from about 5 mg to about 10 mg daily
for a human subject.
[0086] In some embodiments, the ratio of the amount of the
selective type-A ERA and the amount of the PDE5 inhibitor, in order
to achieve enhanced effects, is around 1:10, which, for instance,
can be from about 1:5 to about 1:15, or alternatively from about
1:8 to about 1:12. In one aspect, the selective type-A ERA is
ambrisentan or a salt thereof. In one aspect, the PDE5 inhibitor is
tadalafil or a salt thereof. In another aspect, the ratio is a
weight ratio of each agent. In one aspect, the amount of
ambrisentan or a salt thereof is from about 2 mg to about 5 mg
daily for a human subject. In another aspect, the amount of
tadalafil or a salt thereof is from about 20 mg to about 40 mg
daily for a human subject.
[0087] In some embodiments, the ratio of the amount of the
selective type-A ERA and the amount of the PDE5 inhibitor, in order
to achieve enhanced effects, is around 1:4, which, for instance,
can be from about 1:2 to about 1:7, or alternatively from about 1:3
to about 1:5. In one aspect, the selective type-A ERA is
ambrisentan or a salt thereof. In one aspect, the PDE5 inhibitor is
tadalafil or a salt thereof. In another aspect, the ratio is a
weight ratio of each agent. In one aspect, the amount of
ambrisentan or a salt thereof is from about 5 mg to about 10 mg
daily for a human subject. In another aspect, the amount of
tadalafil or a salt thereof is from about 30 mg to about 40 mg
daily for a human subject.
[0088] In some embodiments, the ratio of the amount of the
selective type-A ERA and the amount of the PDE5 inhibitor, in order
to achieve enhanced effects, is around 1:8, which, for instance,
can be from about 1:5 to about 1:10, or alternatively from about
1:7 to about 1:9. In one aspect, the selective type-A ERA is
ambrisentan or a salt thereof. In one aspect, the PDE5 inhibitor is
tadalafil or a salt thereof. In another aspect, the ratio is a
weight ratio of each agent. In one aspect, the amount of
ambrisentan or a salt thereof is from about 2 mg to about 5 mg
daily for a human subject. In another aspect, the amount of
tadalafil or a salt thereof is from about 30 mg to about 40 mg
daily for a human subject.
[0089] Non-limiting examples of selective type-A ERA include
ambrisentan and sitaxentan and salts thereof. In one aspect, the
selective type-A ERA is ambrisentan. Examples of PDE5 inhibitors
include, without limitation, tadalafil, avanafil, lodenafil,
mirodenafil, sildenafil citrate, vardenafil and udenafil and salts
thereof. In one aspect, the PDE5 inhibitor is tadalafil.
[0090] Non-limiting examples of disease or condition associated
with the activity of endothelin receptor type-A include
hypertension, pulmonary hypertension, myocardial infarction, angina
pectoris, acute kidney failure, renal insufficiency, cerebral
vasospasms, cerebral ischemia, subarachnoid hemorrhages, asthma,
atherosclerosis, intravascular coagulation, restenosis after
angioplasty, hypertension caused by ischemia or intoxication,
kidney failure caused by ischemia or intoxication, Raynaud's
syndrome and asthmatic airway condition.
2.1 Pulmonary Hypertension (PH)
[0091] The pulmonary hypertension condition treated by the method
of the disclosure, can comprise any one or more of the conditions
recognized according to the World Health Organization (WHO) or
Venice (2003) classification (see, for example, Rubin (2004) Chest
126:7-10) or the most recent Dana Point classification (Simonneau
(2009) JACC 54; 54:S43-S54):
[0092] Group 1: Pulmonary arterial hypertension (PAH) [0093] 1.1
idiopathic PAH [0094] 1.2 familial PAH [0095] 1.3 PAH associated
with: [0096] 1.3.1 collagen vascular disease [0097] 1.3.2
congenital systemic-to-pulmonary shunts (including Eisenmenger's
syndrome) [0098] 1.3.3 portal hypertension [0099] 1.3.4 HIV
infection [0100] 1.3.5 drugs and toxins [0101] 1.3.6 other (thyroid
disorders, glycogen storage disease, Gaucher disease, hereditary
hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative
disorders, splenectomy) [0102] 1.4 PAH associated with significant
venous or capillary involvement [0103] 1.4.1 pulmonary
veno-occlusive disease (PVOD) [0104] 1.4.2 pulmonary capillary
hemangiomatosis (PCH) [0105] 1.5 persistent pulmonary hypertension
of the newborn
[0106] Group 2: Pulmonary hypertension with left heart disease
[0107] 2.1 left-sided atrial or ventricular heart disease [0108]
2.2 left-sided valvular heart disease
[0109] Group 3: Pulmonary hypertension associated with lung
diseases and/or hypoxemia [0110] 3.1 chronic obstructive pulmonary
disease (COPD) [0111] 3.2 interstitial lung disease [0112] 3.3
sleep-disordered breathing [0113] 3.4 alveolar hypoventilation
disorders [0114] 3.5 chronic exposure to high altitude [0115] 3.6
developmental abnormalities
[0116] Group 4: Pulmonary hypertension due to chronic thrombotic
and/or embolic disease [0117] 4.1 thromboembolic obstruction of
proximal pulmonary arteries [0118] 4.2 thromboembolic obstruction
of distal pulmonary arteries [0119] 4.3 non-thrombotic pulmonary
embolism (tumor, parasites, foreign material)
[0120] Group 5: Miscellaneous (sarcoidosis, histiocytosis X,
lymphangiomatosis, compression of pulmonary vessels (adenopathy,
tumor, fibrosing mediastinitis))
[0121] In one aspect, the pulmonary hypertension condition
comprises PAH (WHO Group 1), for example idiopathic PAH, familial
PAH or PAH associated with another disease or condition.
[0122] Pulmonary hypertension at baseline can be mild, moderate or
severe, as measured for example by WHO functional class, which is a
measure of disease severity in patients with pulmonary
hypertension. The WHO functional classification is an adaptation of
the New York Heart Association (NYHA) system and is routinely used
to qualitatively assess activity tolerance, for example in
monitoring disease progression and response to treatment (Rubin
(2004) Chest 126:7-10). Four functional classes are recognized in
the WHO system:
[0123] Class I: pulmonary hypertension without resulting limitation
of physical activity; ordinary physical activity does not cause
undue dyspnea or fatigue, chest pain or near syncope;
[0124] Class II: pulmonary hypertension resulting in slight
limitation of physical activity; patient comfortable at rest;
ordinary physical activity causes undue dyspnea or fatigue, chest
pain or near syncope;
[0125] Class III: pulmonary hypertension resulting in marked
limitation of physical activity; patient comfortable at rest; less
than ordinary activity causes undue dyspnea or fatigue, chest pain
or near syncope;
[0126] Class IV: pulmonary hypertension resulting in inability to
carry out any physical activity without symptoms; patient manifests
signs of right-heart failure; dyspnea and/or fatigue may be present
even at rest; discomfort is increased by any physical activity.
[0127] In one aspect, the subject at baseline exhibits pulmonary
hypertension (e.g., PAH) of at least WHO Class I, for example WHO
Class I, II or Class III.
[0128] In another aspect, the subject at baseline exhibits mean PAP
at rest of at least about 30 mmHg, for example at least about 35,
at least about 40, at least about 45 or at least about 50 mmHg.
[0129] The methods of the present disclosure, when applied to a
subject, can achieve one or more of the following objectives:
[0130] (a) adjustment of one or more hemodynamic parameters towards
a more normal level, for example lowering mean PAP or PVR, raising
cardiac output or index, or lowerin PCWP or LVEDP, versus
baseline;
[0131] (b) improvement of pulmonary function versus baseline, for
example increasing exercise capacity or activity, illustratively as
measured in a test of 6-minute walking distance (6MWD) or measure
of activity, or lowering Borg dyspnea index (BDI);
[0132] (c) improvement of one or more quality of life parameters
versus baseline, for example an increase in score on at least one
of the SF-36.RTM. health survey functional scales;
[0133] (d) general improvement versus baseline in the severity of
the condition, for example by movement to a lower WHO functional
class;
[0134] (e) improvement of clinical outcome following a period of
treatment, versus expectation in absence of treatment (e.g., in a
clinical trial setting, as measured by comparison with placebo),
including improved prognosis, extending time to or lowering
probability of clinical worsening, extending quality of life (e.g.,
delaying progression to a higher WHO functional class or slowing
decline in one or more quality of life parameters such as
SF-36.RTM. health survey parameters), and/or increasing longevity;
and/or
[0135] (f) adjustment towards a more normal level of one or more
molecular markers that can be predictive of clinical outcome (e.g.,
plasma concentrations of endothelin-1 (ET-1), cardiac troponin T
(cTnT) or B-type natriuretic peptide (BNP)).
[0136] What constitutes a therapeutically effective amount for
treating PH, or in particular, PAH, can vary depending on the
particular pulmonary hypertension condition to be treated, the
severity of the condition, body weight and other parameters of the
individual subject, and can be readily established without undue
experimentation by the physician or clinician based on the
disclosure herein.
[0137] Various clinical parameters and standards to measure the
effectiveness of a PH therapy are described below and are known in
the art as well. Accordingly, the effectiveness of a PH therapy,
such as that of any combination formulation of the present
disclosure, can be measured by these parameters or standards.
Additionally, the relative effectiveness of a therapy, such as that
of a combination of two agents, as compared to the effectiveness of
mono-administrations of each agent, can be determined with these
clinical parameters or standards, as well as in a non-clinical
setting. Examples of such non-clinical settings include, without
limitation, an in vitro assay or animal study. Non-limiting
examples of in vitro assays are provided in Examples.
A. Improvement on Clinical Parameters
[0138] In one aspect, the subject being treated experiences, during
or following the treatment period, at least one of
[0139] (a) adjustment of one or more hemodynamic parameters
indicative of the pulmonary hypertension condition towards a more
normal level versus baseline;
[0140] (b) increase in exercise capacity versus baseline;
[0141] (c) lowering of BDI versus baseline;
[0142] (d) improvement of one or more quality of life parameters
versus baseline; and/or
[0143] (e) movement to a lower WHO functional class.
[0144] Any suitable measure of exercise capacity can be used; a
particularly suitable measure is obtained in a 6-minute walk test
(6MWT), which measures how far the subject can walk in 6 minutes,
i.e., the 6-minute walk distance (6MWD).
[0145] The Borg dyspnea index (BDI) is a numerical scale for
assessing perceived dyspnea (breathing discomfort). It measures the
degree of breathlessness after completion of the 6 minute walk test
(6MWT), where a BDI of 0 indicates no breathlessness and 10
indicates maximum breathlessness.
[0146] In various aspects, an effective amount of a PH therapy
adjusts one or more hemodynamic parameters indicative of the
pulmonary hypertension condition towards a more normal level. In
one such aspect, mean PAP is lowered, for example by at least about
3 mmHg, or at least about 5 mmHg, versus baseline. In another such
aspect, PVR is lowered. In yet another such aspect, PCWP or LVEDP
is raised.
[0147] In various aspects, an effective amount of a PH therapy
improves pulmonary function versus baseline. Any measure of
pulmonary function can be used; illustratively 6MWD is increased or
BDI is lowered.
[0148] In one such aspect, 6MWD is increased from baseline by at
least about 10 m, for example at least about 20 m or at least about
30 m. In many instances, the method of the present embodiment will
be found effective to increase 6MWD by as much as 50 m or even
more.
[0149] In another such aspect, BDI, illustratively as measured
following a 6MWT, is lowered from baseline by at least about 0.5
index points. In many instances, the method of the present
embodiment will be found effective to lower BDI by as much as 1
full index point or even more.
[0150] The SF-36.RTM. health survey provides a self-reporting,
multi-item scale measuring eight health parameters: physical
functioning, role limitations due to physical health problems,
bodily pain, general health, vitality (energy and fatigue), social
functioning, role limitations due to emotional problems, and mental
health (psychological distress and psychological well-being). The
survey also provides a physical component summary and a mental
component summary.
[0151] In various aspects, an effective amount of a PH therapy can
improve quality of life of the subject, illustratively as measured
by one or more of the health parameters recorded in an SF-36.RTM.
survey. For example, an improvement versus baseline is obtained in
at least one of the SF-36 physical health related parameters
(physical health, role-physical, bodily pain and/or general health)
and/or in at least one of the SF-36 mental health related
parameters (vitality, social functioning, role-emotional and/or
mental health). Such an improvement can take the form of an
increase of at least 1, for example at least 2 or at least 3
points, on the scale for any one or more parameters.
B. Improvement of Prognosis
[0152] In another embodiment, the treatment method of the present
disclosure can improve the prognosis for a subject having a
pulmonary hypertension condition. The treatment of this embodiment
can provide (a) a reduction in probability of a clinical worsening
event during the treatment period, and/or (b) a reduction from
baseline in serum brain natriuretic peptide (BNP) or NT pro-BNP or
its N-terminal prohormone, NT-pro-BNP concentration, wherein, at
baseline, time from first diagnosis of the condition in the subject
is not greater than about 2 years.
[0153] Time from first diagnosis, in various aspects, can be, for
example, not greater than about 1.5 years, not greater than about 1
year, not greater than about 0.75 year or not greater than about
0.5 year. In one aspect, administration of ambrisentan can begin
substantially immediately, for example, within about one month or
within about one week, upon diagnosis.
[0154] In this embodiment, the treatment period is long enough for
the stated effect to be produced. Typically, the longer the
treatment continues the greater and more lasting will be the
benefits. Illustratively, the treatment period can be at least
about one month, for example at least about 3 months, at least
about 6 months or at least about 1 year. In some cases,
administration can continue for substantially the remainder of the
life of the subject.
[0155] Clinical worsening event (CWEs) include death, lung
transplantation, hospitalization for the pulmonary hypertension
condition, atrial septostomy, initiation of additional pulmonary
hypertension therapy or an aggregate thereof. Therefore, the
treatments of the present disclosure can be effective to provide a
reduction of at least about 25%, for example at least about 50%, at
least about 75% or at least about 80%, in probability of death,
lung transplantation, hospitalization for pulmonary arterial
hypertension, atrial septostomy and/or initiation of additional
pulmonary hypertension therapy during the treatment period.
[0156] Time to clinical worsening of the pulmonary hypertension
condition is defined as the time from initiation of an ambrisentan
treatment regime to the first occurrence of a CWE.
[0157] In another particular aspect, the method is effective to
provide a reduction from baseline of at least about 15%, for
example at least about 25%, at least about 50% or at least about
75%, in BNP or NT-pro-BNP concentration.
[0158] The pulmonary hypertension condition according to this
embodiment can comprise any one or more of the conditions in the
WHO, Venice (2003) or Dana Point (2009) classifications described
above. In one aspect, the condition comprises PAH (WHO Group 1),
for example idiopathic PAH, familial PAH or PAH associated with
another disease.
[0159] In various aspects of this embodiment, the subject at
baseline exhibits PH (e.g., PAH) of WHO Class I-IV, for example
Class I, Class II, Class III or Class IV as described above.
[0160] In a more particular embodiment, the subject at baseline has
a resting PAP of at least about 25 mmHg, for example at least about
30 mmHg, at least about 35 mmHg or at least about 40 mmHg.
[0161] In various aspects of this embodiment, the subject can
experience, during or following the treatment period, at least one
of:
[0162] (a) adjustment of one or more hemodynamic parameters
indicative of improvement of the cardiopulmonary hypertension
condition towards a more normal level versus baseline;
[0163] (b) improvement in cardiopulmonary function; illustratively
an increase in exercise capacity or surrogate thereof (e.g., CPET
measures such as VO.sub.2 peak, VE/VCO.sub.2, PETCO.sub.2 and the
like) or lowering of BDI versus baseline;
[0164] (c) improvement of one or more quality of life parameters
versus baseline; and/or
[0165] (d) maintenance of or movement to a lower WHO functional
class.
[0166] For example, in one aspect the subject can experience
improvement in cardiopulmonary function versus baseline. Any
measure of cardiopulmonary function can be used; illustratively
6MWD is increased or BDI is lowered.
[0167] In one such aspect, 6MWD is improved from baseline by at
least about 10 m, for example, at least about 20 m or at least
about 30 m. In many instances, the method of the present embodiment
will be found effective to increase 6MWD by as much as 50 m or even
more.
[0168] In another such aspect, BDI, illustratively as measured
following a 6MWT, is lowered from baseline by at least about 0.5
point. In many instances, the method of the present embodiment will
be found effective to lower BDI by as much as 1 full index point or
even more.
[0169] In another aspect, the subject can experience improvement in
quality of life, illustratively as measured by one or more of the
health parameters recorded in an SF-36.RTM. survey. For example, an
improvement versus baseline can be obtained in at least one of the
SF-36 physical health related parameters (physical health,
role-physical, bodily pain and/or general health) and/or in at
least one of the SF-35 mental health related parameters (vitality,
social functioning, role-emotional and/or mental health). Such an
improvement can take the form of an increase of at least 1, for
example at least 2 or at least 3 points, on the scale for any one
or more parameters.
[0170] In another aspect, the subject can experience maintenance or
improvement in WHO functional class.
C. Prolongation of Life
[0171] In yet another embodiment, the treatment methods of the
present disclosure can prolong the life of a subject having a
pulmonary hypertension condition, from a time of initiation of
treatment, by at least about 30 days. Variants and illustrative
modalities of this method are as set forth above.
D. Extending Time to Clinical Worsening
[0172] Still in another embodiment, the present methods can extend
time to clinical worsening in a subject having a pulmonary
hypertension condition, and decrease the probability of a clinical
worsening event by at least about 25%. Variants and illustrative
modalities of this method are as set forth above.
E. Other Treatment Objectives
[0173] In any of the methods described hereinabove, the subject can
be male or female. For example, the combined drugs can be
administered to a female subject according to any of the above
methods, including the indicated variants and illustrative
modalities thereof. Alternatively, ambrisentan can be administered
to a male subject, for example a reproductively active male
subject, according to any of the above methods, including the
indicated variants and illustrative modalities thereof.
[0174] In another embodiment, the methods provided herein are
useful for treating a pulmonary hypertension condition in a
reproductively active male subject, wherein fertility of the
subject is not substantially compromised. "Not substantially
compromised" in the present context means that spermatogenesis is
not substantially reduced by the treatment and that no hormonal
changes are induced that are indicative of or associated with
reduced spermatogenesis. Male fertility can be assessed directly,
for example, by sperm counts from semen samples, or indirectly by
changes in hormones such as follicle stimulating hormone (FSH),
luteinizing hormone (LH), inhibin B and testosterone.
[0175] In one embodiment, a method is provided for treating PAH in
a subject, wherein the PAH is associated with one or more of (a) a
congenital heart defect, (b) portal hypertension, (c) use of a drug
or toxin other than an anorexigen, (d) thyroid disorder, (e)
glycogen storage disease, (f) Gaucher disease, (g) hereditary
hemorrhagic telangiectasia, (h) hemoglobinopathy, (i)
myeloproliferative disorder, (j) splenectomy, (k) pulmonary
veno-occlusive disease and/or (l) pulmonary capillary
hemangiomatosis. Variants and illustrative modalities of this
method are as set forth hereinabove.
[0176] Further, in another embodiment, a method is provided for
treating a pulmonary hypertension condition classified in WHO
Groups 2-5 in a subject. Variants and illustrative modalities of
this method are as set forth hereinabove. In one aspect, the
condition comprises left-sided atrial or ventricular heart disease
and/or left-sided valvular heart disease. In another aspect, the
condition is associated with one or more of chronic obstructive
pulmonary disease (COPD), interstitial lung disease (ILD),
sleep-disordered breathing, an alveolar hypoventilation disorder,
chronic exposure to high altitude, a developmental abnormality,
thromboembolic obstruction of proximal and/or distal pulmonary
arteries, a non-thrombotic pulmonary embolism, sarcoidosis,
histiocytosis X, lymphangiomatosis, and/or compression of pulmonary
vessels.
2.3 Other Uses of the Combinations
[0177] Increased or abnormal release of endothelin causes
persistent vasoconstriction in the peripheral, renal and cerebral
blood vessels, which may lead to illnesses. It has been reported in
the literature that elevated plasma levels of endothelin were found
in patients with hypertension, acute myocardial infarct, pulmonary
hypertension, Raynaud's syndrome, atherosclerosis and in the
airways of asthmatics (see, e.g., U.S. Pat. No. 7,601,730).
Accordingly, substances which specifically inhibit the binding of
endothelin to the receptor ought also to antagonize the various
abovementioned physiological effects of endothelin and therefore be
valuable drugs, such as ambrisentan and tadalafil. Likewise, the
combination of such drugs can also be effective in treating such
diseases and conditions.
[0178] Thus, in one aspect, the present disclosure provides a
method for treating or preventing a disease in a patient in need
thereof comprising administering to the patient therapeutic amounts
of a selective type-A ERA and a PDE5 inhibitor, wherein the disease
is selected from the group consisting of hypertension, pulmonary
hypertension, myocardial infarction, angina pectoris, acute kidney
failure, renal insufficiency, cerebral vasospasms, cerebral
ischemia, subarachnoid hemorrhages, asthma, atherosclerosis,
intravascular coagulation, restenosis after angioplasty,
hypertension caused by ischemia or intoxication, kidney failure
caused by ischemia or intoxication, Raynaud's syndrome and
asthmatic airway condition.
[0179] Also provided is a method for inhibiting vasoconstriction in
a patient in need thereof comprising administering to the patient
therapeutic amounts of ambrisentan and tadalafil or
pharmaceutically acceptable salt thereof. In one aspect, the
vasoconstriction is endothelin-induced.
[0180] It is also contemplated that by combining ambrisentan and
tadalafil any undesired side effects may be reduced. For example,
administration of ambrisentan to a patient already receiving
tadalafil therapy reduces the side effects of tadalafil. The
co-action effect of combined administration will allow for a
reduction in amount of tadalafil necessary to achieve a therapeutic
effect, thereby resulting in a reduced incidence of undesirable
side effects. As such, in one embodiment, the disclosure is
directed to a method for reducing the undesirable side effects of
tadalafil or a salt thereof comprising administering a therapeutic
amount of ambrisentan or a salt thereof.
[0181] As discussed above, by administration of ambrisentan, the
therapeutically effective amount of tadalafil is reduced. As such,
the disclosure, in one embodiment, is directed to a method for
reducing the therapeutically effective dose of tadalafil or a salt
thereof comprising administering to a patient a therapeutic amount
of ambrisentan or a salt thereof.
2.3 Dosing
[0182] For all of the methods just described, at least one of
either ambrisentan or a salt thereof or tadalafil or a salt thereof
is administered in a less than standard therapeutic dose which
becomes therapeutically effective as a consequence of its
administration with the other drug. However, it is also
contemplated that tadalafil and ambrisentan may also both be
administered in a therapeutically effective amount. In some
embodiments, the tadalafil is administered in an effective dose and
ambrisentan is administered in a standard therapeutically effective
dose. In other embodiment, ambrisentan is administered in a less
than standard therapeutic dose and tadalafil is administered in a
standard therapeutically effective dose. In still other
embodiments, both ambrisentan and tadalafil are administered in
less than standard therapeutic doses. The expression "therapeutic
amounts of tadalafil and ambrisentan or a salt thereof" is intended
to encompass all possible combinations of standard and less than
standard therapeutic doses of ambrisentan and its therapeutically
acceptable salt and tadalafil or its therapeutically acceptable
salt.
[0183] In some embodiments, tadalafil or a salt thereof and
ambrisentan or a salt thereof are administered separately or
sequentially within a time period effective to provide enhanced
efficacy.
[0184] Ambrisentan and tadalafil may be given to the patient in
either single or multiple doses by any of the accepted modes of
administration of agents having similar utilities, for example as
described in those patents and patent applications incorporated by
reference, including buccal, by intra-arterial injection,
intravenously, intraperitoneally, parenterally, intramuscularly,
subcutaneously, orally, or via an impregnated or coated device such
as a stent, for example, or an artery-inserted cylindrical polymer.
In one embodiment, ambrisentan or a salt thereof and tadalafil or a
salt thereof are administered intravenously.
[0185] In one embodiment, ambrisentan or a salt thereof and
tadalafil or a salt thereof are administered orally. Tadalafil or a
salt thereof and ambrisentan or a salt thereof may also be
administered as a combined dosage unit, such as, for example, in a
tablet.
[0186] As mentioned above, tadalafil or a salt thereof and
ambrisentan or a salt thereof may be administered in a therapeutic
amount or an effective amount. Therefore, in some embodiments, the
amount of ambrisentan or a salt thereof administered is from about
0.5 mg to about 100 mg daily or from about 1 mg to about 100 mg
daily, or from about 2 mg to about 50 mg daily, or from about 2 mg
to about 20 mg daily. Further, the amount of tadalafil or a salt
thereof administered is from about 1 mg to about 500 mg daily or
from about 5 mg to about 500 mg daily, or from about 5 mg to about
200 mg daily, or from about 10 mg to about 200 mg daily, or from
about 10 mg to about 100 mg daily. These aggregate daily doses may
be administered to the patient either once or twice a day.
[0187] In one embodiment, whether ambrisentan and tadalafil are
administered together or separately, the ratio of the amount of
ambrisentan or a salt thereof and the amount of tadalafil or a salt
thereof can be in a range from about 1:1 to about 1:10, or
alternatively from about 1:1 to about 1:8, or alternatively from
about 1:2 to about 1:5, or alternatively from about 1:2.5 to about
1:3.5 or in a particular aspect, is about 1:3.
[0188] Additionally, ambrisentan or a salt thereof is administered
as a sustained release formulation and/or tadalafil or a salt
thereof is administered as an immediate release or sustained
release formulation. This is more thoroughly discussed in the next
section.
[0189] In one embodiment then, the patient under treatment is
already taking a maintenance dose of tadalafil ranging from 20 to
40 mg with a typical dose once daily. To this dosing regimen is
then added ambrisentan at from about 5 mg to about 10 mg. By
administering such therapeutic doses of ambrisentan the amount of
tadalafil can then be decreased to from about 20-40 to about 15-30
mg or about 10-20 mg daily thereby greatly reducing the incidence
of adverse events. Likewise, by administering such therapeutic
doses of tadalafil the amount of ambrisentan can then be decreased
to from about 5-10 to about 3-8 mg or about 2-5 mg daily thereby
greatly reducing the incidence of adverse events.
3. Active Ingredients and Compositions
3.1 Pharmaceutical Formulations
[0190] As mentioned above, a combination of tadalafil and
ambrisentan may be formulated separately. The separate dosage forms
containing each active ingredient can be administered sequentially
or at similar times (i.e., either together or one after the other).
In another embodiment, tadalafil and ambrisentan is co-formulated
into a combined dosage unit. Accordingly, in one embodiment, the
disclosure is directed to pharmaceutical formulations comprising a
therapeutic amount of tadalafil or a salt thereof, a therapeutic
amount of ambrisentan or a salt thereof, and a pharmaceutically
acceptable carrier.
[0191] In another embodiment, the formulation comprises an
effective amount of ambrisentan or a salt thereof and/or tadalafil
or a salt thereof. In certain embodiments, the formulations are
formulated for either intravenous or oral administration. In still
other embodiment, the two active ingredients are co-formulated into
a combined dosage unit. In still yet other embodiments, the two
active ingredients are formulated separately for co-therapy
administration.
3.2 Co-Formulations
[0192] In certain embodiments of the present disclosure, the
ambrisentan and tadalafil are co-formulated into a combined dosage
unit or unitary dosage form suitable for oral administration. In
certain embodiments, the ambrisentan is formulated as a sustained
release formulation. In certain embodiments, the tadalafil is
formulated for immediate release or sustained release.
[0193] In one embodiment, the formulation is in tablet form or
capsule form. In embodiment, the tablet or capsule comprises from
about 1 mg to about of 500 mg of tadalafil or a pharmaceutically
acceptable salt thereof. In another embodiment, the tablet or
capsule comprises from about 5 mg to about 500 mg of tadalafil or a
pharmaceutically acceptable salt thereof. In yet another
embodiment, the tablet or capsule comprises from about 5 mg to
about 200 mg of tadalafil or a pharmaceutically acceptable salt
thereof. In still yet another embodiment, the tablet or capsule
comprises from about 10 mg to about 200 mg of tadalafil or a
pharmaceutically acceptable salt thereof. In still yet another
embodiment, the tablet or capsule comprises from about 10 mg to
about 100 mg of tadalafil or a pharmaceutically acceptable salt
thereof.
[0194] In one embodiment, the tablet or capsule comprises from
about 0.5 mg to about 100 mg of ambrisentan or a pharmaceutically
acceptable salt thereof. In another embodiment, the tablet or
capsule comprises from about 1 mg to about 100 mg of ambrisentan or
a pharmaceutically acceptable salt thereof. In yet another
embodiment, the tablet or capsule comprises from about 2 mg to
about 50 mg of ambrisentan or a pharmaceutically acceptable salt
thereof. In yet another embodiment, the tablet or capsule comprises
from about 2 mg to about 20 mg of ambrisentan or a pharmaceutically
acceptable salt thereof.
[0195] In one embodiment, the ratio of the amount of ambrisentan or
a salt thereof and the amount of tadalafil or a salt thereof, in
the formulation, can be from about 1:1 to about 1:10, or
alternatively from about 1:1 to about 1:8, or alternatively from
about 1:2 to about 1:5, or alternatively from about 1:2.5 to about
1:3.5 or in a particular aspect, is about 1:3.
[0196] In one such embodiment, the ambrisentan composition is
placed in a portion of the tablet which is separate from, but in
contact with, the portion of the tablet containing the tadalafil
composition. It will be understood that the unitary dosage form may
comprise simply compressing the ambrisentan composition and the
tadalafil composition into a multilayer tablet or conventionally
processed into other conventional unitary dosage forms such as a
capsules. The multilayer tablets and capsules suitable for use in
the present disclosure can be fabricated using methods known in the
art using standard machinery.
[0197] The tablets may comprise two layers, i.e. a first layer
which comprises the tadalafil and is formulated for immediate
release or sustained release, and a second layer which comprises
the ambrisentan and is formulated for sustained release.
Alternatively, the multilayer tablet may comprise an inner layer
and an outer layer, where the inner layer comprises the sustained
release ambrisentan formulation and where the outer layer comprises
the immediate release or sustained release tadalafil layer. In
another embodiment, the ambrisentan and tadalafil are co-formulated
into a capsule, where the capsule allows for the immediate release
or sustained release of tadalafil and the sustained release of
ambrisentan. For example, the capsule may contain granules of both
tadalafil and ambrisentan, where the granules have been formulated
such that the tadalafil is available for immediate release or
sustained release and the Ambrisentan is formulated for sustained
release. Alternatively, the capsule may contain a liquid immediate
release or sustained release formulation of tadalafil and a solid
sustained release formulation of ambrisentan. However, such
embodiments are exemplary and are not intended to limit the
formulations of the present disclosure.
[0198] A multilayer tablet can be made by compression or molding,
optionally with one or more accessory ingredients. Compressed
tablets may be prepared by compressing in a suitable machine the
active ingredient in a free-flowing form such as a powder or
granules, optionally mixed with a binder, lubricant, inert diluent,
preservative, surface active agent or dispersing agent. Molded
tablets may be made by molding in a suitable machine a mixture of
the powdered active ingredient moistened with an inert liquid
diluent. The tablets may optionally be coated or scored.
[0199] The tablets may contain one or more agents including
sweetening agents, flavoring agents, coloring agents and preserving
agents, in order to provide a palatable preparation. Tablets
containing the active ingredients in admixture with non-toxic
pharmaceutically acceptable excipients which are suitable for
manufacture of tablets are acceptable. These excipients may be, for
example, inert diluents, such as calcium or sodium carbonate,
lactose, lactose monohydrate, croscarmellose sodium, povidone,
calcium or sodium phosphate; granulating and disintegrating agents,
such as maize starch, or alginic acid; binding agents, such as
cellulose, microcrystalline cellulose, starch, gelatin or acacia;
and lubricating agents, such as magnesium stearate, stearic acid or
talc. Tablets may be uncoated or may be coated by known techniques
including microencapsulation to delay disintegration and adsorption
in the gastrointestinal tract and thereby provide a sustained
action over a longer period. For example, a time delay material
such as glyceryl monostearate or glyceryl distearate alone or with
a wax may be employed.
3.3 Additional Formulations
[0200] Formulations also contemplated by the present disclosure may
also be for administration by injection include aqueous or oil
suspensions, or emulsions, with sesame oil, corn oil, cottonseed
oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a
sterile aqueous solution, and similar pharmaceutical vehicles.
Aqueous solutions in saline are also conventionally used for
injection, but less preferred in the context of the present
disclosure. Ethanol, glycerol, propylene glycol, liquid
polyethylene glycol, and the like (and suitable mixtures thereof),
cyclodextrin derivatives, and vegetable oils may also be employed.
The proper fluidity can be maintained, for example, by the use of a
coating, such as lecithin, by the maintenance of the required
particle size in the case of dispersion and by the use of
surfactants. The prevention of the action of microorganisms can be
brought about by various antibacterial and antifungal agents, for
example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal,
and the like. The same formulations are contemplated for separate
administration of ambrisentan and tadalafil.
[0201] Sterile injectable solutions are prepared by incorporating
the component in the required amount in the appropriate solvent
with various other ingredients as enumerated above, as required,
followed by filtered sterilization. Generally, dispersions are
prepared by incorporating the various sterilized active ingredients
into a sterile vehicle which contains the basic dispersion medium
and the required other ingredients from those enumerated above. In
the case of sterile powders for the preparation of sterile
injectable solutions, the preferred methods of preparation are
vacuum-drying and freeze-drying techniques which yield a powder of
the active ingredient plus any additional desired ingredient from a
previously sterile-filtered solution thereof.
[0202] The ideal forms of the apparatus for administration of the
novel combinations for pulmonary hypertension and other methods of
the disclosure consist therefore of (1) either a syringe comprising
2 compartments containing the 2 active substances ready for use or
(2) a kit containing two syringes ready for use.
[0203] In making a pharmaceutical composition including ambrisentan
and tadalafil, the active ingredients are usually diluted by an
excipient or carrier and/or enclosed within such a carrier that can
be in the form of a capsule, sachet, paper or other container. When
the excipient serves as a diluent, in can be a solid, semi-solid,
or liquid material (as above), which acts as a vehicle, carrier or
medium for the active ingredient. Thus, the compositions can be in
the form of tablets, pills, powders, lozenges, sachets, cachets,
elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a
solid or in a liquid medium), ointments containing, for example, up
to 10% by weight of the active compounds, soft and hard gelatin
capsules, sterile injectable solutions, and sterile packaged
powders.
[0204] Some examples of suitable excipients include lactose,
dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,
calcium phosphate, alginates, tragacanth, gelatin, calcium
silicate, microcrystalline cellulose, polyvinylpyrrolidone,
cellulose, sterile water, syrup, and methyl cellulose. The
formulations can additionally include: lubricating agents such as
talc, magnesium stearate, and mineral oil; wetting agents;
emulsifying and suspending agents; preserving agents such as
methyl- and propylhydroxy-benzoates; sweetening agents; and
flavoring agents.
[0205] The compositions of the disclosure can be formulated so as
to provide quick, sustained or delayed release of the active
ingredient after administration to the patient by employing
procedures known in the art. As discussed above, given the reduced
bioavailabity of ambrisentan, sustained release formulations are
generally preferred. Controlled release drug delivery systems for
oral administration include osmotic pump systems and dissolutional
systems containing polymer-coated reservoirs or drug-polymer matrix
formulations. Examples of controlled release systems are given in
U.S. Pat. Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345.
[0206] The compositions are preferably formulated in a unit dosage
form. The term "unit dosage forms" or "combined dosage unit" refers
to physically discrete units suitable as unitary dosages for human
subjects and other mammals, each unit containing a predetermined
quantity of the active materials calculated to produce the desired
therapeutic effect, in association with a suitable pharmaceutical
excipient (e.g., a tablet, capsule, ampoule). The active agents of
the disclosure are effective over a wide dosage range and are
generally administered in a pharmaceutically effective amount. It
will be understood, however, that the amount of each active agent
actually administered will be determined by a physician, in the
light of the relevant circumstances, including the condition to be
treated, the chosen route of administration, the actual compounds
administered and their relative activity, the age, weight, and
response of the individual patient, the severity of the patient's
symptoms, and the like.
[0207] For preparing solid compositions such as tablets, the
principal active ingredients are mixed with a pharmaceutical
excipient to form a solid preformulation composition containing a
homogeneous mixture of a compound of the present disclosure. When
referring to these preformulation compositions as homogeneous, it
is meant that the active ingredients are dispersed evenly
throughout the composition so that the composition may be readily
subdivided into equally effective unit dosage forms such as
tablets, pills and capsules.
[0208] The tablets or pills of the present disclosure may be coated
or otherwise compounded to provide a dosage form affording the
advantage of prolonged action, or to protect from the acid
conditions of the stomach. For example, the tablet or pill can
comprise an inner dosage and an outer dosage element, the latter
being in the form of an envelope over the former. Ambrisentan and
the co-administered agent(s) can be separated by an enteric layer
that serves to resist disintegration in the stomach and permit the
inner element to pass intact into the duodenum or to be delayed in
release. A variety of materials can be used for such enteric layers
or coatings, such materials including a number of polymeric acids
and mixtures of polymeric acids with such materials as shellac,
cetyl alcohol, and cellulose acetate.
[0209] Additional embodiments of the disclosure include kits
comprising a therapeutic amount of ambrisentan or a salt thereof
and a therapeutic amount of tadalafil or a salt thereof.
[0210] The following examples are included to demonstrate preferred
embodiments of the disclosure. It should be appreciated by those of
skill in the art that the techniques disclosed in the examples
which follow represent techniques discovered by the inventor to
function well in the practice of the disclosure, and thus can be
considered to constitute preferred modes for its practice. However,
those of skill in the art should, in light of the present
disclosure, appreciate that many changes can be made in the
specific embodiments which are disclosed and still obtain a like or
similar result without departing from the spirit and scope of the
disclosure.
EXAMPLES
[0211] Tadalafil as used in this disclosure is commercially
available and can be prepared by conventional methods such as in
the manner disclosed in U.S. Pat. No. 5,859,006. Ambrisentan is
also commercially available or may be prepared by conventional
methods such as in the manner disclosed in U.S. Pat. No. 5,703,017.
The entire disclosure of both patents is hereby incorporated by
reference. Additionally, the abbreviations used throughout have the
following meanings: [0212] .mu.M=micromolar [0213] .mu.m=micrometer
[0214] cm=centimeter [0215] kg=kilogram [0216] mA=milliamp [0217]
min=minute [0218] mm=millimeter [0219] mM=millimolar [0220]
mpk=milligram per kilogram (body weight) [0221] ms=millisecond
[0222] nM=nanomolar [0223] AMB=ambrisentan [0224] TAD=tadalafil
[0225] BOS=bosentan [0226] MAC=macitentan [0227]
ET-1=endothelin-1
Example 1
[0228] Ambrisentan and Tadalafil Relax Endothelin-Induced
Contraction of Rat Pulmonary Arteries and Aortas
[0229] This example examines the pharmacological effects of the
combination of ambrisentan and tadalafil in comparison with either
of them alone, with respect to their capability to relax isolated
rat pulmonary artery and thoracic aorta preparations.
[0230] The selective type-A endothelin receptor antagonist,
ambrisentan (Letairis.RTM.), and the phosphodiesterase type 5
inhibitor, tadalafil (Adcirca.RTM.), are currently used to treat
pulmonary arterial hypertension. Isolated rat intact intrapulmonary
arterial rings contracted with 8 nM endothelin-1 (ET-1) were
relaxed by 10 nM ambrisentan (from Gilead Sciences, Inc.) and 30 nM
tadalafil (from Sequoia Research Products Ltd, Pangbourne, UK) by
30.+-.13% (mean.+-.SEM, n=3) and 12.+-.5% (n=3), respectively,
whereas both drugs in combination relaxed the intact intrapulmonary
arterial rings by 77.+-.5% (FIG. 1, n=3, P<0.01 vs.
mono-administration of ambrisentan or tadalafil).
[0231] Similarly, mono-administration of 10 nM ambrisentan and 30
nM tadalafil relaxed isolated rat intact thoracic aortic rings in
the presence of 8 nM ET-1 by 32.+-.3% (n=3) and 16.+-.4% (n=3),
respectively. The combination of both 10 nM ambrisentan and 30 nM
tadalafil relaxed the ET-1-induced contraction of the intact
thoracic aortic rings by 81.+-.7% (FIG. 1, n=3; P<0.01 vs.
mono-administration of ambrisentan or tadalafil). The IC.sub.50
value for tadalafil to relax ET-1 constricted aortic rings was
reduced from 79 nM to 16 nM in the presence of 10 nM
ambrisentan.
[0232] In endothelium-denuded aortic rings, tadalafil failed to
inhibit contraction induced by ET-1 whereas 10 nM ambrisentan
reduced contraction by 26.+-.7% (n=4); the drug combination was not
more effective than mono-administration of ambrisentan.
[0233] These data suggest that the combination of ambrisentan and
tadalafil inhibit endothelin-induced vasoconstriction and
endothelium is required to produce their enhanced effect on
vasorelaxation.
Example 2
[0234] Selective Type-A ERA and PDE5 Inhibitor Shows Co-Action in
Relaxing Endothelin-Induced Contraction of Pulmonary Arteries while
Non-Selective ERA and PDE5 Inhibitor Lack Such Co-Action
[0235] This Example confirms the beneficial co-action of
ambrisentan and tadalafil as, observed in Example 1 and further
investigates the mechanism underlying such co-action.
[0236] Ambrisentan (Letairis.RTM.) is a selective type-A endothelin
receptor antagonist approved for treatment of PAH. Bosentan
(Tracleer.RTM.) is a non-selective (types A&B) endothelin
receptor antagonist for PAH. Macitentan (second generation of
Bosentan) is a non-selective endothelin receptor antagonist in
phase III for PAH. Tadalafil (Adcirca.RTM. and Clalis.RTM.) is a
PDE5 inhibitor for PAH and erectile dysfunction (ED).
Method: Ex-Vivo Vascular Function Assay
[0237] Intrapulmonary arteries (200-500 .mu.m) and aortas were
isolated from Sprague Dawley rats (300-320 g) and cut into 1-2 mm
rings. Rings were mounted in a myograph and constricted with a
submaximal concentration (8 nM) of ET-1. Ambrisentan, Bosentan,
Macitentan and Tadalafil alone and in combination were evaluated in
ET-constricted rings.
Results:
[0238] FIG. 2 shows the effects of Tadalafil with Ambrisentan,
Bosentan or Macitentan to attenuate ET-1-induced contraction of rat
pulmonary artery rings.
[0239] Isolated rat intact intrapulmonary arterial rings contracted
with 8 nM endothelin-1 (ET-1) were relaxed by 10 nM ambrisentan and
30 nM tadalafil by 29.+-.1% (mean.+-.SEM, n=4) and 22.+-.2% (n=4),
respectively, whereas both drugs in combination relaxed the intact
intrapulmonary arterial rings by 85.+-.3% (FIG. 2, n=4, P<0.01
vs. mono-administration of ambrisentan or tadalafil).
[0240] In contrast, the combination of 30 nM tadalafil with 100 nM
bosentan or 30 nM macitentan, two nonselective type-A & B
endothelin receptor antagonists, relaxed the ET-1-dependent
contraction of the intact intrapulmonary arterial rings by 50.+-.4%
(FIG. 2, n=4, P<0.05 vs. mono-administrations of bosentan and
tadalafil or combination of ambrisentan with tadalafil) or 48.+-.8%
(FIG. 2, n=7, P<0.05 vs. mono-administrations of macitentan and
tadalafil or combination of ambrisentan with tadalafil).
Mono-administrations of 100 nM bosentan and 30 nM macitentan
produced a vasorelaxant effect similar to 10 nM ambrisentan and
relaxed the isolated intact intrapulmonary arterial rings
contracted with 8 nM ET-1 by 25.+-.1% (n=4) and 31.+-.2% (n=4),
respectively.
[0241] FIG. 3 shows the effects of TAD with AMB or BOS to attenuate
ET-1-induced contraction of rat aortic rings. Again, the effect of
the combination of AMB and TAD was almost double of the sum of
mono-administration of each drug. In contrast, such enhanced
effectiveness was not observed for the combination of TAD and
BOS.
[0242] In FIG. 4, the contraction graphs show the effects of TAD in
combination with AMB or BOS on ET-1-induced contraction of rat
aortic rings (up: no treatment; middle: AMB+TAD; down: BOS+TAD).
Apparently, the combination of AMB and TAD is much more effective
than the combination of BOS and TAD.
[0243] In endothelium-denuded pulmonary arterial rings, 30 nM
tadalafil failed to inhibit contraction induced by ET-1 whereas 10
nM ambrisentan reduced contraction by 23.+-.4% (n=4); the drug
combination was not more effective than mono-administration of
ambrisentan (FIG. 5). FIG. 5 therefore shows that endothelium is
involved in additive effect of ET Receptor antagonists with
TAD.
[0244] In the presence of 1 .mu.M BQ-788, a selective type-B
endothelin receptor antagonist, the combination effect of 10 nM
ambrisentan with 30 nM tadalafil was significantly reduced from
85.+-.3% (n=4) to 56.+-.7% (FIG. 6, n=4, P<0.05 vs. combination
of ambrisentan with tadalafil) which is close to the additive
effect of 30 nM tadalafil with 100 nM bosentan or 30 nM macitentan.
BQ-788 did not have an effect on the relaxation by combination of
tadalafil with bosentan (FIG. 6).
[0245] These data suggest that the co-action of ambrisentan and
tadalafil inhibiting endothelin-induced vasoconstriction and the
type-B endothelin receptor in endothelium contributes to their
enhanced effect on vasorelaxation. The mechanism is explained and
illustrated in FIG. 7-9. FIG. 7 illustrates the ET-1 and PDE5
signaling in endothelial cells and smooth muscle cells. A selective
type-A ERA such as AMB and a PDE5 inhibitor such as TAD target
vasorelaxation from two different pathways leading to enhanced
effectiveness (FIG. 8), whereas a non-selective ERA or a selective
type-B ERA and a PDE5 inhibitor would not have such benefits
because they target the same pathway (FIG. 9).
[0246] Based on this mechanism, therefore, the co-action observed
in the present example based on the combination of ambrisentan and
tadalafil can be extrapolated to other selective type-A ERA's and
PDE5 inhibitors.
Example 3
[0247] Selective Type-A ERA and PDE5 Inhibitor Attenuated
Hypoxia-Induced Pulmonary Arterial Hypertension (PAH)
[0248] This Example demonstrates the co-action of ambrisentan and
tadalafil in a pulmonary arterial hypertension (PAH) animal
model.
Method: Pulmonary Arterial Hypertension (PAH) Animal Model
[0249] Male SD Rats (225-250 g) were housed in chambers under
normoxic (sea level) or hypoxic (10% oxygen) conditions for 3
weeks.
[0250] Rats were dosed with vehicle (0.5% hydroxypropyl
methylcellulose (HPMC), 0.2% Tween 80, and 0.9% benzyl alcohol in
water), AMB or TAD (quaque die) beginning the day they were placed
in chambers. Plasma was collected when animals were terminated.
Table 1 lists the animals used in this study, along with the
treatments they received.
TABLE-US-00001 TABLE 1 Group N Manipulation Treatment Duration 1 8
Normoxia Vehicle 3 wks 2 12 Hypoxia Vehicle 3 wks 3 12 Hypoxia 10
mpk TAD 3 wks 4 12 Hypoxia 1 mpk AMB 3 wks 5 12 Hypoxia 10 mpk AMB
3 wks 6 12 Hypoxia 1 mpk AMB + 10 mpk TAD 3 wks 7 12 Hypoxia 10 mpk
AMB + 10 mpk TAD 3 wks
[0251] For AMB, 1 mg per kg body weight (mpk) resulted in about 17
nM free or unbounded plasma concentration when administered
separately, or about 13 nM free or unbounded plasma concentration
when administered along with TAD. The free or unbounded plasma
concentration for 10 mpk AMB dosing was about 104 nM in both cases.
The free or unbounded plasma concentrations of TAD was about 24 nM
when administered separately, or about 26 nM when administered with
AMB, whether 1 mpk or 10 mpk.
Results:
[0252] Compared to animals treated with the vehicle, treatment with
mono-administration of TAD or AMB inhibited hypoxia-induced mean
pulmonary arterial pressure (mPAP) (FIG. 10). TAD, 1 mpk AMB and 10
mpk AMB showed 23.2.+-.1.3%, 28.4.+-.1.1% and 42.1.+-.2.4%
inhibition of PAP (mPAP.+-.SEM), respectively.
[0253] When administered together, TAD and 1 mpk AMB led to a
60.8.+-.3.7% PAP inhibition, which was statistically significantly
greater than the additive effect of mono-administration of each
agent (51.6.+-.1.8%, p<0.05). Likewise, the co-administration of
TAD and 10 mpk AMB achieved a 71.7.+-.2.3% PAP inhibition, which
was also statistically significantly greater than the additive
effect of mono-administration of each agent (65.3.+-.1.9%,
p<0.05).
[0254] Therefore, this example demonstrates, in vivo, the co-action
of ambrisentan and tadalafil in inhibiting PAH.
* * * * *