U.S. patent application number 10/129892 was filed with the patent office on 2003-01-09 for treatment of congestive heart failure.
Invention is credited to Bakker-Arkema, Rebecca Guggemos, Pressler, Milton Lethan.
Application Number | 20030008860 10/129892 |
Document ID | / |
Family ID | 22442080 |
Filed Date | 2003-01-09 |
United States Patent
Application |
20030008860 |
Kind Code |
A1 |
Bakker-Arkema, Rebecca Guggemos ;
et al. |
January 9, 2003 |
Treatment of congestive heart failure
Abstract
Combinations of diuretics and vasopressin antagonists are useful
to slow and reverse the symptoms and process of congestive heart
failure, to increase the excretion of water in the urine, and to
decrease the excretion of sodium and potassium ions in urine.
Preferred vasopressin antagonists have the formula (I) wherein R
and R.sup.5 are hydrogen or lower alkyl; R.sup.1, R.sup.2, and
R.sup.3 are hydrogen, halo, alkyl, alkoxy, and amino; and R.sup.4
is hydrogen or phenyl, and a pharmaceutically acceptable salt
thereof
Inventors: |
Bakker-Arkema, Rebecca
Guggemos; (Ann Arbor, MI) ; Pressler, Milton
Lethan; (Saline, MI) |
Correspondence
Address: |
Charles W Ashbrook
Warner Lambert Company
2800 Plymouth Road
Ann Arbor
MI
48105
US
|
Family ID: |
22442080 |
Appl. No.: |
10/129892 |
Filed: |
May 9, 2002 |
PCT Filed: |
March 22, 2001 |
PCT NO: |
PCT/US01/09265 |
Current U.S.
Class: |
514/215 ;
514/471 |
Current CPC
Class: |
A61K 31/55 20130101;
A61K 31/55 20130101; A61K 31/635 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 31/635 20130101 |
Class at
Publication: |
514/215 ;
514/471 |
International
Class: |
A61K 031/55; A61K
031/34 |
Claims
What is claimed is:
1. A pharmaceutical composition comprising an effective amount of a
diuretic agent and an effective amount of a vasopressin
antagonist.
2. A composition according to claim 1 employing a loop diuretic
agent.
3. A composition according to claim 1 employing a vasopressin
antagonist of Formula I 4wherein R and R.sup.5 are hydrogen or
lower alkyl; R.sup.1, R.sup.2, and R.sup.3 independently are
hydrogen, halo, lower alkyl, lower alkoxy, amino, alkylamino, or
dialkylamino; and R.sup.4 is hydrogen, phenyl or substituted
phenyl, and pharmaceutically acceptable salts thereof.
4. A composition according to claim 3 in which the vasopressin
antagonist is conivaptan.
5. A composition to claim 2 employing furosemide.
6. A composition to claim 5 employing the vasopressin antagonist
conivaptan.
7. A method for preventing and treating congestive heart failure
and other edematous conditions in a mammal comprising administering
an effective amount of a combination of at least one diuretic agent
and at least one vasopressin antagonist.
8. A method according to claim 7 wherein furosemide is administered
in combination with conivaptan.
9. A method for inhibiting excretion of sodium ions in the urine of
an animal comprising administering to the animal an effective
amount of a diuretic in combination with a vasopressin
antagonist.
10. A method according to claim 9 wherein the diuretic administered
is a loop diuretic.
11. A method according to claim 10 wherein furosemide is
administered in combination with conivaptan.
12. A method for inhibiting the excretion of potassium ions in the
urine of an animal comprising administering to the animal an
effective amount of a diuretic in combination with a vasopressin
antagonist.
13. A method according to claim 12 wherein the diuretic is a loop
diuretic.
14. A method according to claim 13 wherein furosemide is
administered in combination with conivaptan.
15. A method for treating edematous states in an animal comprising
administering an effective amount of a diuretic agent in
combination with a vasopressin antagonist.
Description
FIELD OF THE INVENTION
[0001] This invention relates to combinations of vasopressin
antagonists and diuretic agents for use in treating edematous
conditions such as congestive heart failure.
BACKGROUND OF THE INVENTION
[0002] Congestive heart failure (CHF) is a pathophysiological state
in which the heart is unable to pump sufficient blood to meet the
metabolic needs of the body. The underlying basis of this disorder
is a deficiency of mvocardial contractility, resulting in a
decreased mechanical ability to pump blood and in turn, a decreased
cardiac output. Congestive heart failure may result from a number
of factors affecting the myocardium, altering systolic and/or
diastolic function. As the condition progresses, activation of both
the sympathetic nervous system and the
renin-angiotensin-aldosterone system lead to an increase in the
total peripheral resistance. In addition, elevated levels of
arginine vasopressin (AVP) have been reported in some patients with
heart failure, although its pathophysiologic role is unknown. It
has been postulated that the increase in AVP may provide increased
systemic vascular resistance and impaired water excretion as a
compensatory mechanism to the low cardiac output associated with
CHF.
[0003] Arginine vasopressin, also known as antidiuretic hormone
(ADH), is synthesized in the magnocellular neurosecretory cells of
the paraventricular and supraoptic nuclei of the hypothalamus and
stored in the posterior pituitary. There are 2 classes of AVP
receptors. V.sub.1 and V.sub.2. There are 2 subclasses of V.sub.1
receptors, V.sub.1A and V.sub.1B. V.sub.1A receptors are found in
the vasculature, and mediate the pressor response of AVP by
increasing the contraction of blood vessels. V.sub.1A receptors are
also found on platelets, where they mediate platelet aggregation.
V.sub.1B receptors are located in the anterior pituitary, and
mediate adrenocorticotropic hormone (ACTH ) release. V.sub.2
receptors are located in the collecting ducts of the kidney: they
are coupled to aquaporine channels and modulate free water
clearance. Arginine vasopressin is released into the circulation in
response to an increase in plasma osmolality (mediated by
osmoreceptors) or a decrease in plasma volume or blood pressure
(mediated by baroceptors). However, there are other stimuli for AVP
release, including norepinephrine, angiotensin II, emotion, nausea
and vomiting, and fever.
[0004] Heart failure is characterized by increased sympathetic
nervous system activity and changes in several neurohormonal
factors, such as angiotensin II, aldosterone. endothelin-1, and
atrial natriuretic factor. In patients with advanced CHF, plasma
levels of AVP are also increased. While the mechanism of AVP
release in CHF is not well-understood, infusion of AVP into CHF
patients results in an increase in systemic vascular resistance and
a redistribution of cardiac output. These observations suggest that
the increased levels of AVP observed in patients with severe CHF
play a role in the pathogenesis of this disease. Several compounds
are known which antagonize the hormonal effects of AVP, for example
the benzazepines disclosed in U.S. Pat. No. 5,723,606.
[0005] The cardiac dysfunction underlying CHF results in a
decreased effective tissue perfusion, which in turn stimulates the
renin-angiotensin-aldosterone and sympathetic nervous systems to
promote Na.sup.+ retention by the kidney, which can result in the
formation of edema. Patients with CHF and evidence of pulmonary
congestion or peripheral edema are routinely treated with
diuretics. Thiazide diuretics, which act on the distal convoluted
tubule of the kidney by inhibiting the Na.sup.+--Cl.sup.-
cotransporter, may initially be employed. However. they produce
only a slight increase (5%-8%) in the amount of sodium excretion by
the kidney, and subject the patient to risk of hypokalemia (low
blood potassium) and hyponatremia. In patients with more advanced
heart failure and signs of extracellular fluid accumulation, loop
diuretics are generally used. Loop diuretics, such as furosemide,
act at the thick ascending limb of the loop of Henle by competing
for the Cl.sup.31 site on the Na.sup.+--K.sup.+--Cl.sup.-
transporter. These diuretics are capable of increasing the
fractional sodium excretion to more than 20% of the filtered load,
albeit at an even greater risk of potassium wasting in the urine
and hypokalemia and hyponatremia in the serum.
[0006] We have now discovered that the use of diuretics in
combination with compounds which inhibit vasopressin enzymes is
surprisingly effective in promoting increased clearance of fluid by
the kidney, and decreased excretion of sodium and potassium in the
urine, thereby minimizing the risk of electrolyte disturbance such
as hypokalemia and hyponatremia. An object of this invention is
thus to provide compositions comprising a vasopressin antagonist in
combination with a loop diuretic agent, and a method for treating
edematous conditions such as CHF using such compositions.
SUMMARY OF THE INVENTION
[0007] This invention provides a composition comprising a diuretic
agent and a vasopressin antagonist. The invention also provides a
method for treating edematous conditions such as CHF, and promoting
increased fluid clearance by the kidney, and maintenance of
electrolyte balance in a mammal by decreasing excretion of sodium
and potassium in the urine otherwise caused by the diuretic agent
alone.
[0008] Any diuretic agent can be used in combination with any
vasopressin antagonist according to this invention. In a preferred
embodiment, the diuretic agent is a loop diuretic agent. Loop
diuretics are compounds that act on the ascending limb of the loop
of Henle and on the proximal and distal tubes in the kidneys of
animals. The compounds are routinely used to treat edema associated
with CHF, cirrhosis of the liver, and renal disease. Typical loop
diuretics include bumetinide, ethacrynic acid, furosemide,
piretanide, and torsemide. Other diuretics can also be used in this
invention, including agents such as chlorothiazide,
hydrochlorothiazide, triamterene, spironolactone, eplerenone,
metolazone, acetazolamide, amiloride, and polythiozide. A preferred
loop diuretic is furosemide (see U.S. Pat. No. 5.256,687).
[0009] The vasopressin antagonist to be employed is any chemical
compound that is effective in inhibiting the biological activity of
any arginine vasopressin or antidiuretic hormone. Numerous
compounds are knout to be vasopressin antagonists, and any of such
compounds can be utilized in the composition of this invention.
[0010] In a preferred embodiment the vasopressin antagonist to be
utilized is a condensed benzazepine such as those described in U.S.
Pat. No. 5.723.606, incorporated herein by reference. In a further
preferred embodiment, the vasopressin antagonist is an imidazo
benzazepine of the Formula I 1
[0011] wherein R and R.sup.5 are hydrogen or lower alkyl;
[0012] R.sup.1, R.sup.2, and R.sup.3 independently are hydrogen,
halo, lower alkyl, lower alkoxy, amino, alkylamino, or
dialkylamino; and
[0013] R.sup.4 is hydrogen, phenyl or substituted phenyl, and
pharmaceutically acceptable salts thereof.
[0014] An especially preferred vasopressin antagonist to be used in
accordance with this invention is conivaptan, which is
N-[4-(2-methyl-4,5,6-tetrahydromidazo[4,5-d][1]benzazepin-6-ylcarbonyl)ph-
enyl]biphenyl-2-carboxamide hydrochloride. Conivaptan is also
referred to as CI-1025 and YM087, and has the structural formula
below 2
[0015] Other vasopressin antagonists that can be employed
accordingly to this invention include the benzoheterocyclic
compounds described in U.S. Pat. No. 5,258,510, incorporated herein
by reference. Preferred compounds from this class to be used herein
include the following:
[0016]
5-Dimethylamino-1-[4-(2-methylbenzoylamino)-benzoyl]-2,3,4,5-tetrah-
ydro-1H-benzazepine;
[0017]
5-Dimethylamino-1-[2-chloro-4-(2-methylbenzoylamino)benzoyl]-2,3,4,-
5-tetrahydro-1H-benzazepine;
[0018]
5-Methylamino-1-[2-chloro4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-t-
etrahydro-1H-benzazepine;
[0019]
5-Cyclopropylamino-1-[2-chloro4-(2-methylbenzoylamino)benzoxyl]-2,3-
,4,5-tetrahydro-1H-benzazepine;
[0020]
5-Cyclopropylamino-1-[2-chloro-4-(2-chlorobenzoylamino)benzoxyl]-2,-
3,4,5-tetrahydro-1H-benzazepine;
[0021]
5-Dimethylamino-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,-
5-tetrahydro-1H-benzazepine;
[0022]
5-Dimethylamino-1-[2-methoxy4-(2-methylbenzoylamino)benzoyl]-1,2,3,-
4-tetrahydroquinoline;
[0023]
7-Chloro-5-methylamino-1-[4-(2-methylbenzoylamino)benzoxyl]-2,3,4,5-
-tetrahydro-1H-benzazepine; and
[0024]
7-Chloro-5-methylamino-1-[4-(2-chlorobenzoylamino)benzoxyl]-2,3,4,5-
-tetrahydro-1H-benzazepine.
[0025] Other vasopressin antagonists that can be employed according
to this invention include those described in U.S. Pat. Nos.
5,225,402: 5,258,510: 5,338,755; 5,719,155; and 5,710,150, all of
which are incorporated herein by reference. Specific vasopressin
antagonists include YM471, OPC-331260, OPC-21268, OPC-41061,
SR-121463, SR49059, VPA-985. CL-385004, FR-161282, JVT-605, VP-339,
WAY-140288, and the like.
[0026] The compositions provided by this invention will contain a
diuretic agent. preferably a loop diuretic, and a vasopressin
antagonist in a weight ratio of about 0.05:1 to about 1000:1, and
typically about 1:1 to about 500:1 and ideally about 1:1 to about
10:1. A typical composition, for example, will comprise about 40 mg
to about 80 mg of the loop diuretic furosemide together with about
5 mg to about 40 mg of conivaptan. Such compositions w ill be
administered to adult humans suffering from edematous conditions
such as CHF.
[0027] A further embodiment of this invention is a method for
treating CHF comprising administering to a patient suffering from
CHF and in need of treatment an effective amount of a diuretic
agent in combination with an effective amount of vasopressin
antagonist.
[0028] Another embodiment is a method for decreasing the excretion
of sodium and potassium ions in the urine of an animal comprising
administering a diuretic agent in combination with a vasopressin
antagonist.
[0029] Still another embodiment of the invention is a method for
increasing the amount of fluids secreted by an animal via the
kidney comprising administering an effective amount of diuretic
agent in combination with a vasopressin antagonist.
[0030] Another embodiment is a method for treating edematous
states.
[0031] All that is required to practice the methods of this
invention is to administer amounts of a diuretic agent and a
vasopressin antagonist that are effective to treat CHF and to
reduce electrolyte imbalance in mammals. The agents can be
administered individually, or they can be formulated together into
a single composition.
DESCRIPTION OF FIGURES
[0032] FIG. 1 shows the change in urine osmolality (mOsm/kg) in
patients receiving various dose combinations of furosemide and
conivaptan.
[0033] FIG. 2 shows the percentage reduction in urine osmolality
caused by various dose combinations of furosemide and conivaptan
and the synergy between the two agents.
[0034] FIG. 3 shows the total urine sodium concentration (mEq)
following various dose combinations of furosemide and conivaptan
(conivaptan antagonizes the excretion of sodium).
[0035] FIG. 4 shows the total urine potassium concentration (mEq)
following various dose combinations of furosemide and conivaptan.
Conivaptan antagonizes the urinary excretion of potassium by
furosemide.
DETAILED DESCRIPTION OF THE INVENTION
[0036] The ability of a combination of a diuretic agent together
with a vasopressin antagonist to reduce electrolyte imbalance and
to treat CHF has been established in a controlled clinical
trial.
[0037] Preclinical pharmacologic studies have demonstrated potent
binding of YM087 conivaptan to AVP receptors and antagonism of the
vascular and renal effects of AVP. YM087 has high affinity for
V.sub.1A-and V.sub.2-receptors with pKi (negative log of the
binding inhibition constant) of 8.20 for human V.sub.1A-receptors
and 8.95 for human V.sub.2-receptors expressed in COS-1 cells.
[0038] Clinical Pharmacology
[0039] YM087 given orally to rats antagonizes the AVP-induced
pressor response (V.sub.1A antagonism) in a dose-related manner,
with the dose that reduced the AVP response by 50% (ID.sub.50)
being 0.32 mg/kg; ID.sub.50 for a similar experiment using
intravenous (IV) YM087 in dogs was 0.026 mg/kg. In conscious dogs,
oral YM087 (0.03 to 0.3 mg/kg) increased urinary output (V.sub.2
antagonism) and reduced urinary osmolality (from 1500 to<100
mOsm/kg H.sub.2O) in a dose-related manner. Unlike furosemide.
YM087 has little or no effect on urinary sodium (Na) or potassium
(K) excretion. In dogs with heart failure induced by rapid right
ventricular pacing, intravenous administration of YM087 (0.1 mg/kg)
significantly improved the depressed cardiac function and produced
a water diuresis.
[0040] Oral absorption of YM087 is rapid (peak concentrations
reached between 0.5 to 1 hour in the rat and dog, respectively) and
occurs predominantly in the small intestine. There is a marked food
effect with absorption reduced by>50% in dogs after a meal. The
elimination half-life is 1 hour in rats and 2 hours in dogs. Mass
balance studies show the majority of radioactive tracer excreted in
the feces. The preclinical toxicologic potential of YM087 has been
extensively evaluated. and all findings were evaluated for
relevance to human risk assessment and impact on clinical trial
design. Findings of potential concern were bone marrow changes in
dogs and effects on fertility in rats.
[0041] Histopathologic changes in bone marrow were observed in both
2- and 13-week oral studies in dogs with systemic exposures 28- to
87-fold higher than the maximum anticipated human exposure.
Decreased peripheral erythrocyte, leukocyte, and/or platelet counts
occurred in affected dogs in the 13-week study. Bone marrow and
peripheral blood changes were reversible.
[0042] YM087 did not affect reproductive performance of male rats.
In the 13-week, repeated oral dose study in rats, more females at
10 mg/kg were in diestrus or proestrus and fewer were in estrus
than in controls, and uterine weights were decreased at all doses;
associated systemic exposures were 0.06- to 3.2-fold the maximum
anticipated human exposure. In the female fertility study in rats,
reduced fertility index, increased implantation loss, and decreased
live fetuses were observed in females given 100 mg/kg orally for 2
weeks prior to mating with untreated males. Effects on estrous
cycle and fertility in female rats may be related to alterations in
serum hormone levels resulting from pharmacologic activity of
YM087. YM087 was not teratogenic in rats or rabbits.
[0043] Other drug-related effects, including diuresis and
hepatocellular hypertrophy, were of less concern due to the nature
of the effects or the high exposures at which the effects occurred
compared to exposures anticipated in clinical trials.
[0044] YM087 was not mutagenic in bacteria, and was not clastogenic
in human lymphocytes in vitro or in bone marrow of rats. No
toxicity was observed in 4-week, IV studies with the glycerin
formulation at maximum achievable doses. 2.5 mg/kg in rats and 2
mg/kg in dogs.
[0045] In summary, toxicological findings of potential concern for
human risk assessment were reversible effects on bone marrow in
dogs and reversible effects on estrus cycle and decreased fertility
in rats. Findings in bone marrow were observed at exposures in
excess of 23 times exposure expected in humans given the maximum
dose of 120 mg once daily (QD), while effects on estrus cycle
occurred at exposures from 0.05- to 3-fold the expected human
exposure at 120 mg QD. Other drug-related findings in toxicology
studies were considered secondary to pharmacologic activity or a
functional adaptation to exposure to YM087.
[0046] YM087 has been given to approximately 250 healthy patients
who participated in a total of 15 Phase 1 studies (8 in Japan and 7
in Europe). Subjects taking oral medication received either a
single dose of YM087 (dose range 0.2 through 120 mg) QD or 30 or
120 mg YM087 administered as a divided dose twice daily (BID).
Subjects received YM087 as a single IV injection once daily over a
dose range of 0.2 to 250 .mu.g/kg or up to a maximum of 50 mg.
[0047] Inhibition of AVP-induced platelet aggregation (evidence of
V.sub.1A antagonist activity) was seen among subjects who received
YM087 at 20 mg/day orally or 2.5 mg IV. Total inhibition of
AVP-induced dermal vasoconstriction was observed among subjects who
received YM087 50 mg IV.
[0048] Normal subjects have demonstrated aquaretic action (evidence
of V.sub.2-receptor antagonism) accompanied by a decrease in urine
osmolarity starting at 15 mg oral or 50 .mu.g/kg IV. At higher
doses aquaretic effects were more pronounced and at 120 mg QD or 60
mg BID given orally or 50 mg given IV were considered too
uncomfortable in normal subjects to be tolerable. YM087 at IV doses
up to 250 .mu.g/kg and 50 mg/day increased urine production rate
for up to 3 and 6 hours postdosing, respectively.
[0049] Under fasting conditions, YM087 is rapidly absorbed, time to
maximum plasma concentration (tmax) being reached at around 1 hour.
The mean oral bioavailability of a 60-mg dose is 44% under fasting
conditions: bioavailability is decreased after intake with food. A
high-fat breakfast reduced bioavailability of single 15- to 90-mg
doses of YM087 to 43% to 59% of the fasted value, and peak plasma
levels were reduced to 24% to 54% of the fasting value. Oral YM087
demonstrated a nonlinear pharmacokinetic profile. Repeated BID oral
doses of YM087.60 mg. result in unexpectedly high plasma levels
after the second dose. possibly caused by reduced first-pass
metabolism. YM087 displays 2 compartment pharmacokinetics, with an
elimination half-life of 4 to 5 hours. Elderly subjects have a
similar elimination half-life as healthy, young volunteers.
[0050] The pharmacokinetics of orally administered YM087 (20 mg)
were not affected when combined with either 0.5 mg IV digoxin or 25
mg oral captopril (each given as a single dose).
[0051] Safety
[0052] Among approximately 250 subjects treated, no major safety
concerns were identified. One patient with severe CHF who received
YM087 80 mg/day for 4 days experienced a generalized tonic clonic
seizure, which the investigator could not exclude as related to
study drug. The most frequent adverse events regardless of
treatment association were mild or moderate thirst and mild
headache. Other adverse events included flushes, a sensation of
cold extremities, abdominal complaints, abnormal stools, syncope,
dizziness, palpitations, and postural hypotension. Three subjects
who received YM087 and one subject who received placebo developed
minor, reversible decreases in white blood cell counts. No
drug-related trend was observed in biochemical or hematological
laboratory parameters. At higher doses, urinary osmolarity
decreased and plasma osmolarity increased with or without an
increase in plasma sodium. These observations were considered
related to antagonism of V.sub.2 receptors and not a safety
concern. Vital signs (blood pressure and heart rate) were
unaffected by YM087.
[0053] Study Rationale
[0054] The edematous condition resulting from CHF develops from a
decreased effective tissue perfusion, which in turn stimulates the
renin-angiotensin-aldosterone and sympathetic nervous systems to
promote Na.sup.+ retention by the kidney. which can result in the
formation of edema. Patients with CHF and evidence of edema are
routinely treated with diuretics. Thiazide diuretics, which act on
the distal convoluted tubule of the kidney by inhibiting the
Na.sup.+--Cl.sup.- cotransporter. may initially be employed.
However, they produce only a slight increase (5%-8%) in the amount
of sodium excretion by the kidney and expose the patient to risk of
hypokalemia and other disorders associated with electrolyte
disorders. In patients with more advanced heart failure and signs
of extracellular fluid accumulation, loop diuretics are generally
used. Loop diuretics, such as furosemide, act at the thick
ascending limb of the loop of Henle by competing for the Cl.sup.-
site on the Na.sup.+--K.sup.+--Cl.sup.- transporter. These
diuretics are capable of increasing the fractional sodium excretion
to more than 20% of the filtered load. albeit at an even greater
risk of hypokalemia and other electrolyte disorders.
[0055] At the kidney, AVP acts via the V.sub.2 receptors in the
principal cells of the collecting duct to increase water
reabsorption. The binding of AVP to V.sub.2 receptors results in an
increase in cytosolic cAMP (via a linked G protein) which acts as a
second messenger, and results in an increase in the "trafficking"
of aquaporin 2 (AQP2) water channels from intracellular vesicles to
the apical plasma membrane of the principal cells. While this
shuttling of AQP2 occurs shortly following stimulation of the
V.sub.2 receptor, longer-term chances also occur in the form of an
increase in AQP2 proteins. As YM087 antagonizes the binding of AVP
to the V.sub.2 receptor, it is reasonable to postulate that its
mechanism of action is via the decrease in the trafficking and
production of AQP2 to the plasma membrane of the principal cells of
the collecting duct.
[0056] These findings indicate that furosemide and YM087 act at
different segments of the nephron, and act via different mechanisms
of action. Agents that act at different portions of the kidney can
be of importance in patients with CHF and other edematous states
who sometimes develop resistance to loop diuretics, especially when
they have been used chronically for some time. The addition of a
hormone antagonist which would increase the excretion of
solute-free water (and thus not increase sodium loss) and
simultaneously limit potassium losses, might produce an added
benefit in the treatment of CHF patients who are currently on a
loop diuretic. Therefore, this study will be conducted to assess
the effect of concomitant treatment with the vasopressin
antagonist. YM087, and a commonly used diuretic, furosemide, in
patients with a prototypical edematous condition, namely CHF.
[0057] Study Objectives
[0058] The objectives of this study are:
[0059] To assess the effect of concomitant treatment with YM087 and
furosemide in CHF patients;
[0060] To determine the safety of giving these two agents
concomitantly to CHF patients: and
[0061] To assess the pharmacodynamic parameters of oral YM087 when
given with furosemide
[0062] Study Design
[0063] This is an open-label, randomized study assessing the effect
on the safety and efficacy of oral YM087 (20 or 40 mg QD) when
given concomitantly with oral furosemide (40 or 80 mg QD) to
patients with CHF.
[0064] This study is comprised of 4 phases: Screening, Furosemide
Balance, Baseline, and Treatment (Scheme 1, Study Design). Patients
will be randomized to 1 of 4 treatment combinations: (a) furosemide
40 mg QD and YM087 20 mg QD; (b) furosemide 40 mg QD and YM087 40
mg QD; (c) furosemide 80 mg QD and YM087 20 mg QD; or (d)
furosemide 80 mg QD and YM087 40 mg QD. Patients will be treated on
an outpatient basis, and will come for clinic visits at Screening
and on Study Days 1, end of Day 4 (beginning of Day 5), and each
day of treatment (Days 5 through 9 [beginning of Day 10]). All
tests scheduled to be done at the 24-hour time point will be done
prior to the next dose of study medication. Urine collections will
be done for the 24 hours prior to the visit. 3
[0065] Study Schedule
[0066] Screening Phase (1 Week)
[0067] The Screening Phase allows the investigator to evaluate
patients who qualify for entry into the study and to assess initial
values for a number of study parameters (ie. clinical laboratory
and urinalysis values including serum and urine electrolytes). An
informed consent will be signed and patients will provide medical
history, including documentation of New York Heart Association
(NYHA) Class II/III CHF. A physical examination will also be
performed at this time.
[0068] Furosemide Balance Phase (4 Days)
[0069] This phase allows the patient to achieve sodium and fluid
balance on the background dose of furosemide. The patient will be
randomized to 1 of the 4 arms of the study, and during this phase,
will receive the dose of furosemide (either 40 or 80 mg/day) to
which he/she is randomized. The dose should be given in the morning
(before breakfast). During this phase and throughout the remainder
of the study, patients will monitor their weight daily.
[0070] Baseline Phase (2 Days)
[0071] During the Baseline Phase, the patient will continue to
receive the dose of furosemide (either 40 or 80 mg/day) to which
he/she has been randomized. Patients will be given their dose of
furosemide in the clinic for each of these days. This phase will be
used to establish baseline values for a number of study parameters.
Various clinical laboratory parameters (eg, serum and urine sodium.
and plasma and urine osmolalities), free water clearance, effective
water clearance, and safety profiles will be obtained. On Day 6,
patients will remain in the clinic during the first 6 hours of the
study, in order to collect blood and urine samples at various time
points. Patients will then be allowed to return home overnight
(continuing to collect their urine for the 24-hour urine sample),
and will return to the clinic the following morning at their
scheduled visit.
[0072] Treatment Phase (3 Days)
[0073] This phase is used to determine the effect of concomitant
treatment with furosemide and YM087. In addition to the background
dose of furosemide (40 or 80 mg/day), patients will receive YM087
at the dose to which they have been randomized (20 or 40 mg QD) for
3 days (Study Days 7-9). Both drugs will be administered at the
same time orally once daily 1 hour before breakfast with 100 mL
water. Furosemide and YM087 will be dispensed in the clinic on
these days (Study Days 7, 8, and 9). On Day 9, patients will remain
in the clinic during the first 6 hours of the study, in order to
collect blood and urine samples at various time points. Patients
will then be allowed to return home overnight (continuing to
collect their urine for the 24-hour urine sample), and will return
to the clinic the following morning for their scheduled visit.
[0074] If at any time, the investigator judges the patient's volume
status to be abnormally decreased, the next dose of furosemide may
be decreased by one-half. The dose of furosemide can be further
decreased by one-half at any later assessment in which the volume
status is still abnormal.
[0075] Fluid and Sodium Intake
[0076] Patients will have their sodium and fluid intake assessed
prior to the Baseline Phase. CHF patients should be maintained on
the sodium-restricted diet that is typically prescribed for these
patients. A dietician or nurse coordinator will determine the
contents of diet and daily calorie intake, salt consumption, and
volume of water consumed in the diet. These levels will be
maintained throughout the study period. Total fluid intake (not
including water in food) may not exceed 2.0 L/day. Fluid intake
will be assessed on a daily basis.
[0077] Urine Output
[0078] A 24-hour urine specimen will be collected on Study Days 4
through 9. Samples will be collected at intervals on Study Days 6
and 9, and subsequently pooled to obtain the total 24-hour sample.
Urine collection will begin following the administration of
furosemide alone or furosemide and YM087 (at approximately 7
AM).
[0079] Study Population
[0080] Source and Number of Patients
[0081] Number of Patients: 3 to 6 patients per arm; 12 to 24
patients total Source: Outpatients
[0082] Patient-selection Criteria
[0083] Inclusion Criteria p These criteria are mandatory and must
be met to provide evaluable data.
[0084] Males or females 18 to 85 years of age
[0085] Females must be postmenopausal, surgically sterilized or
practicing a barrier method of birth control so that in the opinion
of the investigator, they will not become pregnant during the
study;
[0086] Congestive heart failure with Class II or III functional
impairment by New York Heart Association criteria (Appendix C);
[0087] At screening, current therapy for chronic heart failure
consisting of at least 2 months duration of an ACE inhibitor.
.beta.-blocker (optional), and digoxin (optional);
[0088] Doses of digoxin, ACE inhibitors, and/or .beta.-blockers,
must have been held constant for 7 days prior to the Balance Phase:
and
[0089] At screening, patients must have been receiving a dose of
furosemide of between 40 and 160 mg/day.
[0090] Exclusion Criteria
[0091] Breast-feeding or pregnant;
[0092] Excessive peripheral edema (>2+, ie, above the knee) or
lack of peripheral edema, suggesting volume depletion;
[0093] Significant renal impairment (serum creatinine>2.5 mg/dL
or creatinine clearance<30 mL/min); or nephrotic syndrome;
[0094] Known urinary outflow obstruction (eg, stenosis, stone.
tumor. etc):
[0095] Alanine aminotransferase (ALT) or aspartate aminotransferase
(AST) >3.times.upper limit of normal (ULN) and/or bilirubin
.gtoreq.2.5 mg/dL: or cirrhosis with ascites:
[0096] Active myocarditis, constrictive pericarditis, or active
vasculitis due to collagen vascular disease;
[0097] Uncontrolled hyper- or hypothyroidism;
[0098] Adrenal insufficiency (AM cortisol<7 .mu.g/dL);
[0099] Serious hematological diseases (eg, severe anemia, Hgb<10
g/dL; leukopenia, WBC<4000/.mu.L);
[0100] Significant hypotension (SBP<95) or uncontrolled
hypertension:
[0101] Concurrent enrollment in a chemotherapy or radiation
regimen;
[0102] Unstable angina or acute myocardial infarction within 30
days of the screening visit;
[0103] Treatment with inotropic drugs (eg, dobutamine, dopamine,
milrinone, amrinone, etc) within 30 days of the screening
visit;
[0104] Participation in another clinical trial of an
investigational drug (including placebo) within the 30 days prior
to screening for entry into the present study;
[0105] History of current or past use of illicit drugs or
alcoholism unless abstinence can be documented for .gtoreq.6
months:
[0106] Other medical conditions, such as significant obstructive
cardiac valvular disease and/or hypertrophic subaortic stenosis,
obstructive lung disease, dementia, or significant abnormalities
that the investigator feels may compromise the patient's safety or
successful participation in the study: and
[0107] Inability to understand and sign the Informed Consent to
participate in this study.
[0108] Prohibited Drugs
[0109] The following medications may not be taken during this
study:
[0110] Any antineoplastic agent;
[0111] Any medication known to cause leukopenia:
[0112] Parenteral inotropic agents;
[0113] Nonsteroidal anti-inflammatory drugs, with the exception of
low-dose aspirin (.ltoreq.325 mg/day); and
[0114] Smoking pattern should not be altered for the duration of
the investigation as smoking has been found to stimulate the
secretion of AVP from the posterior pituitary gland. Patients must
not smoke immediately prior to blood sampling.
[0115] Allowable Medications
[0116] Digitalis, ACE inhibitors, beta blockers, or other
vasodilators are allowed but should be at a stable dose for at
least 7 days prior to the Furosemide Balance Phase. The dosage and
regimen of any other chronic, permitted concurrent medications (eg.
hormone replacement therapy, hormone contraceptives, thyroid
replacement therapy, or H2 antagonists) should be stabilized before
the Furosemide Balance Phase and held constant throughout the
study. Any medications prescribed chronically or intermittently
during the study or dose adjustments of these medications must be
reported on the concurrent medication Case Report Form (CRF). It is
recommended that concurrent medications not be taken at the same
time as the study drug (eg, within 1-2 hours).
[0117] Efficacy Assessments
[0118] Primary Efficacy Parameter(s)
[0119] The primary efficacy measure is change in urine output from
baseline (obtained on Day 2 of the Baseline Phase [Study Day 6]) to
end of treatment (Study Day 9).
[0120] Secondary Efficacy Parameter(s)
[0121] Similarly, secondary efficacy parameters will be
evaluated:
[0122] Change from baseline in body weight; and
[0123] Change from baseline in free water clearance. calculated as
1 C H 2 O = V ( 1 - Uosm Posm )
[0124] where:
[0125] V=Urine volume (mL/day):
[0126] Uosm=Urine osmolality, and
[0127] Posm=Plasma osmolality.
[0128] Change from baseline in effective water clearance,
calculated as
V-[2(U.sub.Na+U.sub.K).times.V/2(P.sub.Na+P.sub.K)]
[0129] where:
[0130] V=Urine volume;
[0131] U.sub.Na=Urine sodium concentration;
[0132] U.sub.K=Urine potassium concentration:
[0133] P.sub.Na=Plasma sodium concentration; and
[0134] P.sub.K=Plasma potassium concentration.
[0135] This formula can be reduced to: 2 V .times. ( 1 - U Na + U K
P Na + P K )
[0136] Change from baseline in serum and urine sodium;
[0137] Change from baseline in fractional sodium excretion,
calculated as: 3 Fe Na % = CL Na CL CR .times. 100
[0138] where:
[0139] CL.sub.Na=sodium clearance; and
[0140] CL.sub.CR=creatinine clearance.
[0141] Number of back-titrations of furosemide
[0142] Laboratory Evaluation
[0143] Full clinical laboratory assessments will be performed at
screening and at the end of Study Days 6 and 9. A clinically
significant laboratory abnormality occurring during the study that
has been verified by repeat testing will be reported as an adverse
event and followed until the abnormality has resolved or a
satisfactory explanation has been obtained (see Appendix B for a
listing of the clinical laboratory determinations to be
performed).
[0144] Urinalysis
[0145] A urinalysis will be performed at screening and at the end
of the study (Day 9).
[0146] Other Assessments
[0147] Pharmacokinetic/Pharmacodynamic Analysis
[0148] Plasma concentrations of YM087 and plasma and urine
concentrations of furosemide will be determined throughout the
study as outlined in Appendix A. YM087 concentrations will be
measured using a validated LC/MS/MS method in the positive
ionization mode. Furosemide concentrations will be determined using
a validated HPLC method. For both assays, sensitivity, specificity,
linearity, and reproducibility will be determined before analysis
of samples.
[0149] A pharmacokinetic/pharmacodynamic analysis will be utilized
to evaluate the potential effect of concomitant treatment with
YM087 and furosemide in comparison to furosemide alone. In
addition, plasma concentrations of furosemide during baseline and
treatment phases, will give information about a potential
pharmacokinetic interaction between YM087 and furosemide.
[0150] Study Medication
[0151] Description
[0152] Furosemide tablets (40 and 80 mg) and YM087 tablets (10 mg)
will be prepared for the study by the Clinical Pharmaceutical
Operations Department. Medication for this protocol will be
dispensed according to the randomization code. All study
medications should be stored in a secure, locked area. A detailed
set of dispensing instructions will be included with the drug
shipment.
[0153] Data Analysis and Statistical Considerations
[0154] Power and Sample Size
[0155] This is an exploratory study. Patient numbers are not based
on considerations of power, but are thought to be adequate to
provide preliminary. assessment of the safety and tolerability of
YM087 when administered concomitantly with furosemide.
[0156] Efficacy Parameters
[0157] The efficacy parameters and changes from baseline will be
summarized by treatment group at each collection time. Baseline
values are defined as those values obtained at the 24 hour time
point of Study Day 6 (end of Baseline Phase). Descriptive
statistics will include mean, standard error, median, minimum,
maximum, and others as appropriate.
[0158] A urine creatinine will be obtained on all 24-hour urine
specimens in order to determine the accuracy of urine collection.
Results will be summarized on those urine samples determined to be
complete 24-hour collections. Additionally, results from all
patients will be summarized.
[0159] Twenty-four patients ranging in age from 41 to 87 with Class
II/Class III CHF (as defined by the New York Heart Association)
were randomized into 1 of 4 treatment groups. Group I received 40
mg of furosemide alone, once a day for 6 days, followed by
concomitant treatment with 20 mg of conivaptan once a day for 3
days. Group II received initial dosing with 40 mg of furosemide.
followed by concomitant dosing with 40 mg of conivaptan. Group III
received 80 mg of furosemide initially, then concomitant dosing
with 20 mg of conivaptan. Group IV received 80 mg of furosemide
alone, and then in continuation with 40 mg of conivaptan.
[0160] Baseline measurements of urine volume, osmolality, sodium,
and potassium content were obtained on Day 6 (steady state for
background furosemide use), and evaluations of the combination
therapy were done on Day 9. The data shown in FIGS. 1 and 2 and in
Table 1 below establish that the aquaretic effects of conivaptan
not only persist but are amplified with concurrent use of a loop
diuretic. This surprising result establishes synergism between the
two drugs on urinary water excretion. In addition, the results of
urinary sodium excretion shown in FIG. 3 and in Table 1 below
establish that combination therapy lessens the loss of sodium in
the urine, particularly as the dose of furosemide is increased.
This surprising result renders the claimed combination particularly
useful in treatment or prevention of hyponatremia in edematous
states like CHF in which therapy with a diuretic is standard care.
Finally, the results on urinary potassium excretion shown in FIG. 4
establishes that the combination substantially reduces potassium
loss, particularly as the dose of furosemide is increased. This
surprising result indicates the claimed combination is especially
useful in treatment or prevention of hypokalemia in edematous
states like CHF in which therapy with a diuretic is standard care.
In total, the data establish that conivaptan in combination with a
loop diuretic such as furosemide can provide increased therapeutic
excretion of water in edematous conditions like CHF. Furthermore,
the data establish that the deleterious effects of a loop diuretic
on electrolyte loss, particularly potassium, can be diminished to a
surprising extent by concomitant treatment with a vasopressin
antagonist such as conivaptan.
1TABLE 1 Change From Baseline in Pharmacodynamic Parameters (0-6
Hours Postdose) Urine Total Urine Total Urine Urine Osmolality
Sodium Potassium Volume (mOsm/kg) (mEq) (mEq) (mL) Mean % Mean %
Mean % Mean % Treatment Group Change Change Change Change F 40 mg/C
20 mg -25.0 -13.8 -1.3 54.4 F 40 mg/C 40 mg -13.4 27.6 14.0 79.9 F
80 mg/C 20 mg -43.2 -9.2 -23.1 13.7 F 80 mg/C 40 mg -45.5 -32.3
-45.0 -7.8 F = Furosemide; C = Conivaptan.
[0161] The compositions to be employed in the present invention can
be prepared and administered in a wide variety of oral and
parenteral dosage forms for treating and preventing edematous
conditions such as CHF, and promoting electrolyte balance. The
compounds can be administered by injection, that is, intravenously,
intramuscularly, intracutaneously. subcutaneously, submucosally,
intraductally, intraduodenally, or intraperitoneally. Also, the
compounds can be administered by inhalation, for example,
intranasally. Additionally, the compositions can be administered
transdermally. It will be obvious to those skilled in the art that
the following dosage forms may comprise as the active component,
either a compound as a free base, acid, or a corresponding
pharmaceutically acceptable salt of such compound. The active
compound generally is present in a concentration of about 5% to
about 95% by weight of the formulation.
[0162] For preparing pharmaceutical compositions from the compounds
of the present invention, pharmaceutically acceptable carriers can
be either solid or liquid. Solid form preparations include powders,
tablets, pills, capsules, cachets, suppositories, and dispersible
granules. A solid carrier can be one or more substances which may
also act as diluents, flavoring agents, solubilizers, lubricants,
suspending agents, binders, preservatives, tablet disintegrating
agents, or an encapsulating material.
[0163] In powders, the carrier is a finely divided solid which is
in a mixture with the finely divided active component.
[0164] In tablets, the active component is mixed with the carrier
having the necessary binding properties in suitable proportions and
compacted in the shape and size desired.
[0165] The powders and tablets preferably contain from 5% or 10% to
about 70% of the active compound. Suitable carriers are magnesium
carbonate, magnesium stearate, talc, sugar, lactose, pectin,
dextrin, starch, gelatin, tragacanth, methylcellulose, sodium
carboxymethylcellulose, a low melting wax, cocoa butter, and the
like. The term "preparation" is intended to include the formulation
of the active compound with encapsulating material as a carrier
providing a capsule in which the active component, with or without
other carriers, is surrounded by a carrier, which is thus in
association with it, Similarly, cachets and lozenges are included.
Tablets, powders, capsules, pills, cachets, and lozenges can be
used as solid dosage forms suitable for oral administration.
[0166] For preparing suppositories, a low melting wax, such as a
mixture of fatty acid glycerides or cocoa butter, is first melted
and the active component is dispersed homogeneously therein as by
stirring. The molten homogenous mixture is then poured into
convenient sized molds, allowed to cool, and thereby to
solidify.
[0167] Liquid form preparations include solutions, suspensions, and
emulsions, for example, water or water propylene glycol solutions.
For parenteral injection, liquid preparations can be formulated in
solution in aqueous polyethylene glycol solution.
[0168] Aqueous solutions suitable for oral use can be prepared by
dissolving the active component in water and adding suitable
colorants, flavors, stabilizing, and thickening agents as
desired.
[0169] Aqueous suspensions suitable for oral use can be made by
dispersing the finely divided active component in water with
viscous material, such as natural or synthetic gums, resins,
methylcellulose, sodium carboxymethylcellulose, and other
well-known suspending agents.
[0170] Also included are solid form preparations which are intended
to be converted, shortly before use, to liquid form preparations
for oral administration. Such liquid forms include solutions,
suspensions, and emulsions. These preparations may contain, in
addition to the active component, colorants, flavors, stabilizers,
buffers, artificial and natural sweeteners, dispersants,
thickeners, solubilizing agents, and the like.
[0171] The pharmaceutical preparation is preferably in unit dosage
form. In such form, the preparation is subdivided into unit doses
containing appropriate quantities of the active component. The unit
dosage form can be a packaged preparation, the package containing
discrete quantities of preparation, such as packeted tablets,
capsules, and powders in vials or ampoules. Also, the unit dosage
form can be a capsule, tablet, cachet, or lozenge itself, or it can
be the appropriate number of any of these in packaged form.
[0172] The quantity of each active component in a unit-dose
preparation may be varied or adjusted from 1 to 1000 mg, preferably
10 to 100 mg according to the particular application and the
potency of the active component. The composition can, if desired,
also contain other compatible therapeutic agents.
[0173] The following examples illustrate typical formulations that
can be utilized in the invention.
2 Tablet Formulation Ingredient Amount (mg) Conivaptan 25
Furosemide 40 Lactose 30 Cornstarch (for mix) 10 Cornstarch (paste)
10 Magnesium stearate (1%) 5 Total 120
[0174] The conivaptan, furosemide, lactose, and cornstarch (for
mix) are blended to uniformity. The cornstarch (for paste) is
suspended in 200 mL of water and heated with stirring to form a
paste. The paste is used to granulate the mixed powders. The wet
granules are passed through a No. 8 hand screen and dried at
80.degree. C. The dry granules are lubricated with the 1% magnesium
stearate and pressed into a tablet. Such tablets can be
administered to a human from one to four times a day for treatment
of CHF and other edematous conditions.
3 Preparation for Oral Solution Ingredient Amount Conivaptan 40 mg
Furosemide 80 mg Sorbitol solution (70% N.F.) 40 mL Sodium benzoate
20 mg Saccharin 5 mg Red dye 10 mg Cherry flavor 20 mg Distilled
water q.s. 100 mL
[0175] The sorbitol solution is added to 40 mL of distilled water,
and the conivaptan and furosemide are dissolved therein. The
saccharin, sodium benzoate, flavor, and dye are added and
dissolved. The volume is adjusted to 100 mL with distilled water.
Each milliliter of syrup contains 4 mg of invention composition.
The composition is administered to animals to treat edematous
states such as heart failure, hepatic failure, and venous
insufficiency.
[0176] Parenteral Solution
[0177] In a solution of 700 mL of propylene glycol and 200 mL of
water for injection is suspended 20 g of conivaptan and 15 g of
furosemide. After suspension is complete, the pH is adjusted to 6.5
with 1 N sodium hydroxide, and the volume is made up to 1000 mL
with water for injection. The formulation is sterilized, filled
into 5.0 mL ampoules each containing 2.0 mL, and sealed under
nitrogen. The composition is administered to a patient in order to
decrease the excretion of sodium and potassium in the urine,
thereby preventing electrolyte imbalance associated with CHF and
use of a diuretic agent alone.
* * * * *