U.S. patent application number 17/034419 was filed with the patent office on 2021-01-14 for use of tradipitant in motion sickness.
The applicant listed for this patent is Vanda Pharmaceuticals Inc.. Invention is credited to Mihael H. Polymeropoulos.
Application Number | 20210008037 17/034419 |
Document ID | / |
Family ID | 1000005109708 |
Filed Date | 2021-01-14 |
United States Patent
Application |
20210008037 |
Kind Code |
A1 |
Polymeropoulos; Mihael H. |
January 14, 2021 |
USE OF TRADIPITANT IN MOTION SICKNESS
Abstract
Disclosed herein is a method of treating or preventing motion
sickness or at least one symptom thereof, comprising treatment with
the NK-1 receptor antagonist, tradipitant.
Inventors: |
Polymeropoulos; Mihael H.;
(Potomac, MD) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Vanda Pharmaceuticals Inc. |
Washington |
DC |
US |
|
|
Family ID: |
1000005109708 |
Appl. No.: |
17/034419 |
Filed: |
September 28, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16591927 |
Oct 3, 2019 |
10821099 |
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17034419 |
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PCT/US19/53107 |
Sep 26, 2019 |
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16591927 |
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62874927 |
Jul 16, 2019 |
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62737992 |
Sep 28, 2018 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 1/08 20180101; A61K
31/4192 20130101 |
International
Class: |
A61K 31/4192 20060101
A61K031/4192; A61P 1/08 20060101 A61P001/08 |
Claims
1. A method of treating a subject about to engage in an activity
involving sickness-inducing motion comprising: administering
tradipitant to said subject, prior to the commencement of said
activity, in an amount effective to prevent motion sickness or at
least one symptom of motion sickness in said subject.
2. The method of claim 1, wherein said activity is vehicle
travel.
3. The method of claim 2, wherein said administration occurs about
30 minutes prior to entering a vehicle.
4. The method of claim 2, wherein said administration occurs about
30 minutes prior to commencement of vehicle travel.
5. The method of claim 1, wherein said effective amount is 100-400
mg.
6. The method of claim 5, wherein said effective amount is 100-300
mg.
7. The method of claim 6, wherein said effective amount is 100-200
mg.
8. The method of claim 7, wherein said effective amount is about
170 mg.
9. The method of claim 1, further comprising orally administering
said effective amount of tradipitant.
10. The method of claim 9, wherein said tradipitant is orally
administered in a solid immediate release form such as a capsule or
tablet comprising tradipitant and one or more pharmaceutically
acceptable excipients.
11. The method of claim 2, wherein said vehicle travel is via
automobile, airplane, helicopter, boat, train, or bus.
12. The method of claim 1, wherein said at least one symptom is
nausea, vomiting, dizziness, headache, fullness, or
disorientation.
13. A method of treating a subject with motion sickness or at least
one symptom of motion sickness, comprising: administering
tradipitant to said subject in an amount effective to treat said
sickness or a symptom thereof.
14. The method of claim 13, wherein said effective amount is
100-400 mg.
15. The method of claim 14, wherein said effective amount is
100-300 mg.
16. The method of claim 15, wherein said effective amount is
100-200 mg.
17. The method of claim 16, wherein said effective amount is about
170 mg.
18. The method of claim 13, wherein said administration further
comprises oral administration of tradipitant.
19. The method of claim 18, wherein said tradipitant is orally
administered in a solid immediate release form such as a capsule or
tablet comprising tradipitant and one or more pharmaceutically
acceptable excipients.
20. The method of claim 13, wherein said at least one symptom is
nausea, vomiting, dizziness, headache, fullness, or disorientation.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation of co-pending U.S.
application Ser. No. 16/591,927, filed Oct. 3, 2019, which is a
continuation of co-pending International Application No.
PCT/US19/53107, filed Sep. 26, 2019, which in turn claims the
benefit of U.S. Provisional Application No. 62/737,992, filed Sep.
28, 2018, and U.S. Provisional Application No. 62/874,927, filed
Jul. 16, 2019. Each of the foregoing applications is incorporated
by reference as though fully set forth herein.
BACKGROUND
[0002] The application relates generally to the use of NK-1
receptor antagonists. More particularly, the application relates
the use of the NK-1 antagonist, tradipitant in motion sickness.
[0003] Motion sickness is a disorder defined by a constellation of
symptoms that can result from real or perceived sickness-inducing
motion. Such motion may include, e.g., motion involving the head of
a subject that can produce one or more symptoms characteristic of
motion sickness. The sickness-inducing motion that gives rise to
motion sickness may commonly include riding in any form of
transportation such as, e.g., automobiles, buses, trains, other
ground or rail transportation, boats under power, ferries, cruise
ships, sailboats, personal water craft, canoes, kayaks, row boats,
airplanes and helicopters, amusement rides, and certain gymnastic
maneuvers such as somersaults. The symptoms of motion sickness
typically can include, but are not limited to, nausea, vomiting,
dizziness, headache, fullness, cold sweats, sweating, pallor,
disorientation, and anorexia. Motion sickness has been reported to
affect up to 30% of the general population under ordinary travel
conditions that include sea, air, and land travel. The prevalence
of motion sickness in one epidemiological study during bus travel
found 28% of passengers reporting feeling ill while 13% reported
experiencing nausea.
[0004] Under the sensory conflict theory, motion sickness is
described as arising due to a mismatch between the perceptions of
motion, or lack thereof, by the visual, vestibular, and
somatosensory systems. A discrepancy between actual body position
and perceived body position is believed to trigger the maladaptive
response of motion sickness. Motion sickness is one of the most
prevalent episodic disorders in the world, and its prevalence has
dramatically increased with world population mobility. Despite the
increasing prevalence of the disorder, the treatments available
today, which are primarily antihistamines and anticholinergics,
were first discovered in the 1940's.
[0005] The mammalian tachykinins (neurokinins [NKs]) are a family
of peptide neurotransmitters that share a common C-terminal
sequence. This group includes substance P (SP), neurokinin-A (NKA),
and neurokinin-B (NKB). SP, the most abundant NK, preferentially
binds to the neurokinin type-1 (NK-1) receptor and is involved in
the regulation of many physiological processes. NK-1 receptors have
been mapped in the central nervous system and were found to have a
broad distribution in the brain, including the mid-brain, basal
ganglia, hypothalamus, and limbic system. Neurokinin receptors are
also widely distributed in the gut, the bronchial tree, and the
vascular system.
[0006] The NK-1 receptor has been identified as a potential
therapeutic target for the treatment of motion sickness.
Maropitant, another neurokinin 1 receptor antagonist, is approved
for the prevention of vomiting due to motion sickness in dogs and
cats. A crossover study showed that the therapy reduced the
occurrence of vomiting in over 75% of dogs as compared to placebo.
This data supports the exploration of the effects of NK-1
antagonists on motion sickness in humans, though maropitant has a
different molecular composition and pharmacokinetics from other
NK-1 antagonists. Another NK1-receptor antagonist, aprepitant, is
approved for postoperative nausea and vomiting (PONV) in adults,
and for use with other medications in children and adults to
prevent nausea and vomiting caused by certain anti-cancer
(chemotherapy) medicines. Currently, tradipitant is being tested in
clinical trials for the treatment of nausea and vomiting in
patients with gastroparesis. Currently, available therapies are not
effective for all patients and some of the medications used have
significant side effect profiles.
[0007] Tradipitant is a highly potent, selective, centrally
penetrating, and orally active neurokinin-1 (NK-1) receptor
antagonist, depicted below as the compound of Formula (I)
##STR00001##
Tradipitant is disclosed in U.S. Pat. No. 7,320,994, and contains
six main structural components: the 3,5-bis-trifluoromethylphenyl
moiety, two pyridine rings, the triazol ring, the chlorophenyl
ring, and the methanone. Tradipitant is known by the chemical
names:
2-[1-[[3,5-bis(trifluoromethyl)phenyl]methyl]-5-(4-pyridinyl)-1H-1,2,3-tr-
iazol-4-yl]-3-pyridinyl](2-chlorophenyl)-methanone, and
{2-[1-(3,5-bistrifluoromethylbenzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-y-
l]-pyridin-3-yl}-(2-chlorophenyl)-methanone, and has also been
known as LY686017 and as VLY-686. Crystalline Forms IV and V of
tradipitant are disclosed in U.S. Pat. No. 7,381,826, and a process
for preparing crystalline
{2-[1-(3,5-bistrifluoromethylbenzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-y-
l]-pyridin-3-yl}-(2-chlorophenyl)-methanone, Form IV is disclosed
in U.S. Pat. Nos. 8,772,496; 9,708,291; and 10,035,787.
[0008] In preclinical and clinical studies, tradipitant produces a
long-lasting blockade of brain NK-1 receptors. Although the
distinct pathways of nausea and vomiting are largely undetermined,
a definitive role of SP acting at NK-1 receptors in the nucleus
tractus solitarus has been confirmed. Previous clinical studies
have demonstrated the efficacy of NK-1 antagonism in the prevention
of chemotherapy induced and post-operative nausea and vomiting
(CINV and PONY).
BRIEF DESCRIPTION OF THE INVENTION
[0009] A first aspect of the invention provides a method of
prevention of motion sickness or one or more symptoms thereof, in
an individual anticipating experiencing sickness-inducing motion,
comprising administering tradipitant to said individual in an
amount effective to prevent manifestation of motion sickness or one
or more symptoms thereof. In practicing the foregoing method, the
amount of tradipitant that is effective to prevent motion sickness
or a symptom thereof may be, e.g., 100-400 mg, 100-300 mg, or
100-200 mg. For example, the effective amount can be about 170 mg.
The effective amount may be administered in a single dose, such as
a single oral dose, and may or may not be in a single dosage unit
form. The dose may be administered in advance of engaging in a
sickness-inducing motion, typically about 30 minutes before
commencing such motion. Administration of such an effective amount
prior to commencing sickness-inducing motion can prevent or reduce
the severity or frequency of one or more symptoms of motion
sickness, including the prevention of nausea, vomiting, dizziness,
headache, fullness, cold sweats, sweating, pallor, or
disorientation.
[0010] A second aspect of the invention provides a method of
treating motion sickness or one or more symptoms thereof, in an
individual experiencing the manifestation of motion sickness,
comprising administering tradipitant to said individual in an
amount effective to treat the motion sickness or the symptom
thereof. Treatment of motion sickness may be considered to include
a reduction in severity of symptoms, the prevention of progression,
or the complete resolution of one or more symptoms of motion
sickness after such symptom or symptoms have manifest in the
individual. In practicing the foregoing method, the amount of
tradipitant that is effective to treat motion sickness or a symptom
thereof may be, e.g., 100-400 mg, 100-300 mg, or 100-200 mg. For
example, the effective amount can be about 170 mg. The effective
amount may be administered in a single dose, such as a single oral
dose, and may or may not be in a single dosage unit form. The dose
may be administered after the onset of at least one symptom of
motion sickness, preferably soon after the onset of the at least
one symptom, and more preferably, immediately after the onset of
the at least one symptom. Administration of such an effective
amount after motion sickness has begun to manifest can reduce the
severity of the symptom(s), eliminate the symptom(s), prevent the
progression or intensification of the symptom(s) of motion
sickness, for example from dizziness to nausea, from nausea to
vomiting, etc.
[0011] A third aspect of the invention provides tradipitant for use
in any of the methods of treatment or prevention described in the
preceding aspects.
[0012] A fourth aspect of the invention provides a pharmaceutical
composition comprising tradipitant for use in any of the preceding
methods of treatment or prevention.
[0013] A fifth aspect of the invention provides tradipitant for use
in the manufacture of a pharmaceutical composition comprising
tradipitant for use in any of the preceding methods of treatment or
prevention.
[0014] These and other aspects, advantages and salient features of
the invention will become apparent from the following detailed
description, which, when taken in conjunction with the annexed
figure(s) disclose embodiments of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIG. 1 illustrates the effect of tradipitant on NK-1 agonist
(GR73632, 3 pmol, icv)-induced foot-tapping behavior after oral
administration.
[0016] FIG. 2 illustrates the effect of tradipitant on NK-1 agonist
(GR73632, 3 pmol, icv)-induced foot-tapping behavior after oral
administration: comparison with other NK-1 antagonists, aprepitant
and CP-122721: dose response.
[0017] FIG. 3 illustrates the effect of tradipitant on NK-1 agonist
(GR73632, 3 pmol, icv)-induced foot-tapping behavior after oral
administration: comparison with other NK-1 antagonists, aprepitant
and CP-122721: time course.
[0018] FIG. 4 illustrates the effect of tradipitant on
GR73632-induced vocalization in guinea pigs across a concentration
range of 0.05 to 10 mg/kg.
[0019] FIG. 5 illustrates the duration of activity, i.e.
suppression of NK-1 agonist-induced vocalization in guinea pigs,
following a 0.1 mg/kg dose of tradipitant.
[0020] FIG. 6 illustrates the dose-dependent effects of
tradipitant, and the effects of various NK-1 antagonists in the
guinea pig vocalization assay.
[0021] The drawings are intended to depict only typical aspects of
the disclosure, and therefore should not be considered as limiting
the scope of the disclosure.
DETAILED DESCRIPTION OF THE INVENTION
[0022] The method of using tradipitant as described herein requires
administering an amount of tradipitant that is effective to prevent
or treat motion sickness or a symptom thereof. The amount
administered to a subject being treated depends upon a number of
factors, including the species being treated, the weight of the
subject being treated, and the subject's condition otherwise. The
method specifically involves the prevention and amelioration of
motion sickness in human beings, including adult human beings. In
adult human beings the typical dose effective to prevent motion
sickness or a symptom thereof is 100-400 mg, 100-300 mg, or 100-200
mg. One specific regime involves administration of about 85-170 mg,
or more particularly about 170 mg.
[0023] As used herein, the terms "patient," "subject," and
"individual" refer to a mammal who is administrated tradipitant.
Guinea pigs, dogs, cats, gerbils, horses, cattle, sheep, and humans
are within the scope of the terms "patient," "subject," and
"individual." The most preferred subject is a human being. The term
"effective amount," i.e., dose, of tradipitant refers to an amount
that is effective in treating or preventing the disorders described
herein, or symptoms thereof.
[0024] As indicated above, a method is provided herein for
preventing motion sickness or a symptom thereof, in an individual
anticipating experiencing sickness-inducing motion. Such method
comprises prophylactically administering tradipitant to said
individual in an amount effective to prevent the manifestation of
motion sickness or one or more symptoms thereof. The effective
amount of tradipitant to prevent motion sickness or a symptom
thereof may be, e.g., 100-400 mg, 100-300 mg, 100-200 mg, or 85-170
mg, and may particularly be about 170 mg. The effective amount may
be administered in a single dose such as, e.g., a single oral dose,
and may or may not be in a single dosage unit form. The dose may be
administered in advance of engaging in a sickness-inducing motion,
for example, in advance of boarding an airplane, train, boat, or
other vehicle, or getting into an automobile, or before an
anticipated airplane takeoff or commencement of motion on board any
other type of vehicle. Particularly, the dose may be administered
about thirty (30) minutes prior to commencement of the potentially
motion sickness-inducing motion or activity. Such administration of
an effective amount of tradipitant can prevent the manifestation of
one or more symptoms of motion sickness, including the prevention
of nausea, vomiting, dizziness, headache, fullness, or
disorientation, or may limit the symptom(s) experienced by the
individual and the severity thereof.
[0025] A method is also provided herein for treating motion
sickness or a symptom thereof after such motion sickness has
already manifest or begun to manifest in the individual. Such
method includes administering tradipitant to said individual in an
amount effective to treat the motion sickness or the symptom
thereof. Treatment of motion sickness in the present context
includes all processes in which there may be a slowing,
interrupting, arresting, controlling, or stopping of the
progression of motion sickness and/or symptoms thereof. For
example, such treatment may include the prevention of progression,
or the partial or complete resolution of one or more symptoms of
motion sickness after such symptom or symptoms have manifest in the
individual. In practicing the foregoing method, the amount of
tradipitant that is effective to treat motion sickness or a symptom
thereof may be, e.g., 100-400 mg, 100-300 mg, 100-200 mg, 85- 170
mg, or particularly about 170 mg. The effective amount may be
administered in a single dose, including a single oral dose, which
may or may not be in a single dosage unit form. The effective
amount of tradipitant may be administered after the onset of at
least one symptom of motion sickness. Preferably, the effective
amount is administered soon after the onset of the at least one
symptom, for example up to thirty (30) minutes after the onset of
the at least one symptom, and more preferably, the effective amount
is administered immediately or substantially immediately after the
onset of the at least one symptom. Administration of such an
effective amount after motion sickness has begun to manifest can
reduce the severity of the symptom(s), eliminate the symptom(s), or
prevent the progression or intensification of the symptom(s) of
motion sickness, for example from dizziness to nausea, from nausea
to vomiting, etc.
[0026] The skilled artisan will appreciate that additional
preferred embodiments may be selected by combining the preferred
embodiments above, or by reference to the examples given
herein.
EXAMPLES
Example 1: Pre-Clinical Studies
[0027] Tradipitant is a selective neurokinin-1 (NK-1) receptor
antagonist. In vitro, tradipitant potently inhibits NK-1 receptor
binding and antagonizes the effects of an NK-1 agonist in a
functional assay. No significant activity is observed in a panel of
74 additional receptors, enzymes, and ion channels including the
NK-2 and NK-3 receptors. By 3 different measures, tradipitant is
also a potent centrally active NK-1 antagonist in vivo.
Example 1.1: Mechanism Studies
[0028] Tradipitant inhibits [.sup.125I] substance P (SP) binding to
the NK-1 receptor expressed by IM-9 cells with a K.sub.i of 0.062
nM and inhibits the SP-induced mobilization of intracellular
calcium in U373 cells with a K.sub.b of 0.095 nM (Table 1).
TABLE-US-00001 TABLE 1 Affinity of tradipitant for NK-1 Receptors
In Vitro IM-9 Human Cell Calcium Mobilization in Antagonist
Membrane Binding K.sub.i (nM) U373 Cells K.sub.b (nM) Tradipitant
0.062 .+-. 0.012 0.095 .+-. 0.025 Aprepitant 0.14 .+-. 0.03 0.14
.+-. 0.01 CP-122721 0.027 .+-. 0.01 0.034 .+-. 0.009
These potencies are similar to those observed with the NK-1
antagonists aprepitant (MK-869) and CP-122721. In addition, results
from tradipitant evaluation in a panel of 74 other receptors,
enzymes, and ion channels indicate that, at a test concentration of
1 .mu.M, tradipitant does not exhibit any inhibition of binding
greater than 50%. At the NK-2 and NK-3 receptors, the compound
produces no significant inhibition. Therefore, tradipitant is a
highly selective NK-1 antagonist in vitro.
[0029] As shown in Table 2, several of the major metabolites of
tradipitant have an affinity for the NK-1 receptor based on a
binding assay. These metabolites have high affinity for the NK-1
receptor.
TABLE-US-00002 TABLE 2 Affinity of tradipitant metabolites for NK-1
Receptors in vitro IM-9 Human Cell Membrane Binding K.sub.i
Metabolite Designation (nM) LSN2081070 M2 (Racemic) 0.09 (n = 1)
LSN2107355 M2 (S-enantiomer) 0.08 (n = 1) LSN2107357 M2
(R-enantiomer) 0.94 (n = 1) LSN2195411 M3 0.03 (n = 1) LSN2195413
M4 (Racemic) 0.08 (n = 1)
Example 1.2: Efficacy Models for in vivo Evaluation of Brain NK-1
Receptor Occupancy and Efficacy of Tradipitant
[0030] Example 1.2.1: Effects of Tradipitant on Centrally
Administered NK-1 Agonist-Induced Foot-Tapping Behavior in
Gerbils
[0031] Introduction
[0032] Differences in species selectivity of NK-1 receptors pose
challenges to characterization of NK-1 receptor antagonists in
vivo. Gerbil NK-1 receptors have previously been shown to be
similar to those in humans. Gerbils exhibit a characteristic
stereotypic foot-tapping behavior in response to distress, fear, or
aversive stimuli. Intracerebroventricular (icy) administration of
substance P or a selective NK-1 receptor agonist such as GR73632
produces rapid rhythmic tapping of the hind feet lasting
approximately 5 minutes, which can be inhibited by systemic
administration of a brain penetrating antagonist of the NK-1
receptor. This response is selective for NK-1 agonists, since
selective NK-2 and NK-3 agonists do not elicit a similar response.
This behavioral response is further characterized and modified to
enable identification and optimization, in vivo, of potent NK-1
receptor antagonists including tradipitant.
[0033] Methods
[0034] Male Mongolian gerbils (Harlan Sprague Dawley, Indianapolis,
Ind.) weighing 26 to 40 grams are administered the selective
neurokinin-1 receptor agonist GR73632 (3 pmol) via direct,
vertical, free-hand intracerebroventricular (icy) injection to a
depth of 4.5 mm below bregma with a cuffed 27-gauge needle attached
to a 50 .mu.l Hamilton syringe. Immediately after injection,
animals are placed individually into isolated chambers with
pressure-sensitive velocimeter platform floors (San Diego
Instruments acoustic startle apparatus) that detect and quantify
vibration. The San Diego Instruments "SR" DOS-based computer
program is used on a PC to record the number of foot-taps over the
following 6 to 10 minutes, beginning 30 seconds after the floor is
lightly tapped. Raw data are converted with a Microsoft.RTM.
Excel.RTM. (Microsoft.RTM. and Excel.RTM. are registered trademarks
of Microsoft Corp., Redmond, Wash.) macro that determines the
number of events over threshold (125) in each 250-millisecond time
bin over the 5.5 minutes following onset of observation. The total
number and average intensity of events over the duration is
determined. Total number of taps is analyzed with one-way ANOVA and
post-hoc Dunnett's test using JMP statistical software.
[0035] A dose-response curve (with doses of 0.3, 1, 3 and 10 pmols,
icv) is initially generated with the NK-1 agonist GR73632. Maximal
foot-tapping behavior is achieved with 3 and 10 pmol doses; the 3
pmol dose is subsequently chosen as the dose of choice for
antagonism experiments.
[0036] NK-1 antagonists are tested for their ability to attenuate
GR73632-induced foot tapping. NK-1 antagonists are administered
(po) via oral feeding tube at doses and time points specified in
each experiment. All animals receive only one dose of NK-1
antagonists in all tests.
[0037] ED.sub.50 Determinations/Dose-Response Tests
[0038] NK-1 antagonists are administered at multiple doses (at
least 3; one dose per animal) and response to GR73632 is
measured.
[0039] Duration of Action Tests
[0040] NK-1 receptor antagonists are administered at multiple
pre-treatment times (one administration per animal) including at
0.5, 1, 2, 4, 7, 16, and 24 hours prior to GR73632 injection.
GR73632 (Peninsula Labs, Calif.) is dissolved in saline.
Tradipitant is dissolved in 1% CMC/0.5% SLS/0.085% PVP vehicle.
CP-122721 and aprepitant are synthesized at Lilly Laboratories and
dissolved in 10% ethanol/emulphor and 1% CMC/0.5% SLS/0.085% PVP
respectively.
[0041] Results
[0042] As shown in FIG. 1, orally administered tradipitant potently
inhibits NK-1 agonist-induced foot-tapping behavior in gerbils 2
hours after administration of drug in a dose-dependent manner, with
an ED.sub.50 of 0.03.+-.0.004 mg/kg (*p<0.05 compared to vehicle
for 0.1 mg/kg and 0.3 mg/kg doses). Data shown in FIG. 1 are
expressed in number of foot-tapping events occurring in five (5)
minutes.
[0043] FIG. 2 depicts a comparison of the efficacy of tradipitant
to that of other NK-1 antagonists, with data expressed as percent
control of vehicle (vehicle response to 3 pmol GR73632).
Tradipitant is found to be more potent than aprepitant (Merck,
ED.sub.50=0.42 mg/kg.+-.0.05 mg/kg) and CP-122721 (Pfizer,
ED.sub.50=2.2 mg/kg.+-.0.5 mg/kg).
[0044] FIG. 3 depicts the effects of tradipitant over a time course
on NK-1 agonist (GR 73632, 3 pmol, icv)-induced foot-tapping
behavior after oral administration, compared with that of NK-1
antagonists aprepitant and CP-122721. Tradipitant (0.1 mg/kg, po)
is found to significantly inhibit foot-tapping behavior up to 7
hours after administration but the effect is significantly
diminished by 16 hours after administration at this dose. However,
at a higher dose of 1 mg/kg, tradipitant shows greater than 50%
inhibition of foot-tapping behavior 16 hours after administration.
The duration of effect of tradipitant is longer than that of
CP-122721 (up to 2 hours after administration, 3 mg/kg) while
aprepitant (1 mg/kg) shows inhibition of foot-tapping behavior up
to 24 hours after administration. Data are expressed as percent
control of vehicle (vehicle response to 3 pmol GR73632).
[0045] Discussion
[0046] The effect of tradipitant on NK-1 agonist-induced
foot-tapping behavior in gerbils suggests that tradipitant is a
very potent, centrally acting NK-1 receptor antagonist in vivo in
the gerbil with a relatively long duration of action.
[0047] Example 1.2.2: Emetic Challenge Study in Beagle Dogs with
Tradipitant
[0048] Introduction
[0049] Five male dogs are administered a single oral dose of 3
mg/kg aprepitant (a positive control), or tradipitant at 0.3, 1.0,
and 3.0 mg/kg in a Latin-square design. An intravenous injection of
0.1 mg/kg apomorphine, a known emetic, is given alone, or 2 hours
after administration of tradipitant or aprepitant. Each animal is
administered a different dose on a particular dosing day, so that
each dose of tradipitant, aprepitant, and apomorphine alone is
represented. Over the five (5) weeks of the study, each animal
receives each of the treatments, but only one per week. The purpose
of this study is to determine if tradipitant suppresses
apomorphine-induced emesis.
[0050] The low dose of tradipitant is 10 times the ED.sub.50 in the
gerbil foot-tapping model of NK-1 receptor antagonism (Example
1.2.1). The high dose is 100 times this efficacious dose, and is
also the dose of aprepitant that has previously been determined to
be efficacious against apomorphine-induced emesis in the dog. The
mid dose of tradipitant is the approximate half-log interval
between the low and high doses.
[0051] The oral route of administration is selected for tradipitant
because this is the route proposed or currently used clinically.
The intravenous route is typically used for experimental
apomorphine administration. The beagle dog is considered an
effective species for demonstration of antagonism of
apomorphine-induced emesis.
[0052] Methods
[0053] A single oral dose of 0, 0.3, 1.0, or 3.0 mg/kg tradipitant,
or 3.0 mg/kg aprepitant is administered to each male dog once a
week in gelatin capsules. All animals are dosed over a period of
five (5) weeks, with each dog receiving one of five different
treatments on each day of dosing. A dose of 0.1 mg/kg apomorphine
is administered by intravenous injection approximately two (2)
hours after each administration of tradipitant or aprepitant. In
cases where apomorphine is administered alone, without prior
treatment with tradipitant or aprepitant, apomorphine is given at
approximately the same time as when given in combination with
tradipitant or aprepitant.
[0054] All dogs are fasted overnight prior to each treatment day
and then fed approximately one (1) hour after oral dosing
(approximately one (1) hour prior to administration of
apomorphine). Individual doses are adjusted weekly for changes in
body weight.
[0055] The dose regimen consists of a 5.times.5 Latin square
design, in which each subject receives 1 dose or dose combination
per week (6 day washout) as shown in Table 3 below.
TABLE-US-00003 TABLE 3 Latin Square Design Study Study Study Study
Study week 1 week 2 week 3 week 4 week 5 Dog 1 APO + 0.3 APO + APO
+ 3 APO APO + 1 mg/kg aprepitant mg/kg mg/kg tradipitant
tradipitant tradipitant Dog 2 APO + APO + 1 APO APO + 0.3 APO + 3
aprepitant mg/kg mg/kg mg/kg tradipitant tradipitant tradipitant
Dog 3 APO + 3 APO APO + APO + 1 APO + 0.3 mg/kg aprepitant mg/kg
mg/kg tradipitant tradipitant tradipitant Dog 4 APO APO + 0.3 APO +
1 APO + 3 APO + mg/kg mg/kg mg/kg aprepitant tradipitant
tradipitant tradipitant Dog 5 APO + 1 APO + 3 APO + 0.3 APO + APO
mg/kg mg/kg mg/kg aprepitant tradipitant tradipitant
tradipitant
The number of emetic episodes is recorded for approximately one
hour following the injection of apomorphine, and plasma
concentrations at anticipated Tmax of tradipitant (2 hours
post-dosing) are evaluated.
[0056] Results
[0057] Table 4 provides individual and mean and standard deviation
values for the 2 hour plasma concentrations of tradipitant. All
animals administered tradipitant have measurable levels at 2 hours
post-dose. In general, plasma concentrations at 2 hours post-dose
increase with increasing dose in a sub-proportional manner. As
observed in other studies in dogs, the exposure to tradipitant is
variable between animals. Individual animal data reveal no
relationship between plasma concentrations and week of
administration.
TABLE-US-00004 TABLE 4 Plasma concentrations of tradipitant (ng/ml)
Administered Dose 0.3 mg/kg 1.0 mg/kg 3.0 mg/kg Concentration of
Concentration of Concentration of tradipitant (ng/ml) tradipitant
(ng/ml) tradipitant (ng/ml) Dog 1 51.20 175.58 122.73 Dog 2 41.33
86.49 256.58 Dog 3 90.93 240.84 316.20 Dog 4 83.38 100.97 682.91
Dog 5 22.59 61.56 119.79 Mean (SD) 57.89 (28.75) 133.09 (73.71)
299.64 (230.58)
[0058] As shown in Table 5, emesis occurs after each treatment,
with the largest incidence of emesis occurring in the apomorphine
alone group. One dog (Dog 3) has a single episode of emesis at each
dose of tradipitant and aprepitant; this dog also has the greatest
number of emetic episodes with apomorphine alone (12). No emesis
occurs in the remaining four (4) dogs at any dose of tradipitant or
aprepitant. These dogs have an average of four (4) emetic episodes
with apomorphine alone. The antiemetic effect of aprepitant
supports the validity of this model.
TABLE-US-00005 TABLE 5 Emetic episodes by treatment group Total No.
Emetic Test article* Dose level (mg/kg) Episodes APO (control) 0 28
aprepitant 3.0 1** tradipitant 0.3 1** tradipitant 1.0 1**
tradipitant 3.0 1** *Apomorphine is administered as a challenge
dose to all groups. **All episodes occur in same dog (Dog 3).
[0059] Results of this study indicate that tradipitant is effective
against apomorphine-induced emesis at each dose tested (0.3, 1.0,
and 3.0 mg/kg).
[0060] Example 1.2.3: Tradipitant Inhibits Substance P-Induced
Vocalization in Guinea Pigs
[0061] Introduction
[0062] When introduced into the brain, the NK-1 receptor agonist
substance P (SP) elicits distress vocalizations in the guinea pig
that can be inhibited by NK-1 antagonists.
[0063] This behavioral assay is used to demonstrate potency and CNS
penetration of NK-1 antagonists in the guinea pig, a species that
has receptor affinity for NK-1 antagonists that is similar to
humans.
[0064] Methods
[0065] Male Dunkin/Hartley guinea pigs (200 to 250 grams) are
orally administered either vehicle or an NK-1 antagonist.
Approximately 45 minutes later (for dose response studies), the
animals are anesthetized and 0.1 nmol of GR73632 (SP analog) in a
vehicle volume of 5 .mu.l is injected into the cerebral ventricle
at the intersection of bregma and the midline of the skull. Animals
are placed in a dark testing chamber located inside of a sound
attenuation cubicle and vocalizations are recorded for 30 minutes
following recovery from anesthesia. The time spent vocalizing is
quantified for each animal. In the duration of action study, 0.1
mg/kg of tradipitant or vehicle solution is administered orally and
then 2, 4, or 7 hours later, 0.1 nmol of GR73632 is administered
into the cerebral ventricle as described above. Vocalizations are
recorded and quantified as indicated above. Vehicle solutions are
either CMC (FIG. 4 data) or an ethanol/emulphor solution (FIGS. 5
and 6). Data is analyzed using one-tailed t-tests.
[0066] Results
[0067] As shown in FIG. 4, oral administration of tradipitant
produces significant inhibition of agonist-induced vocalization at
doses of 10 mg/kg (p<.001), 1.0 mg/kg (p<0.001), 0.1 mg/kg
(p<.001), and 0.05 mg/kg (p<.001). Data shown parenthetically
in FIG. 4 indicate percent of control response. Activity of
tradipitant does not wane at the lower doses, indicating that even
lower doses would be required to produce a dose response
function.
[0068] As shown in FIG. 5, the effect of 0.1 mg/kg tradipitant is
significantly active in suppressing agonist-induced vocalization at
7 hours following oral administration of the antagonist
compound.
[0069] A second dose-response study compares potencies of
tradipitant, aprepitant, and CP-122721. As shown in FIG. 6, all
NK-1 antagonists tested produce significant inhibition of
vocalization at 1 mg/kg. Only tradipitant retains significant
inhibitory activity at and below 0.1 mg/kg. The minimum effective
dose of tradipitant is found to be 0.025 mg/kg which produces
highly significant (p<.001) inhibition of vocalization compared
to controls. (Vehicle was ethanol/emulphor; vehicle groups were
n=5-14 per compound.)
[0070] Discussion
[0071] Tradipitant significantly inhibits NK-1 agonist-induced
vocalization in guinea pigs, indicating that this compound is an
orally available and brain-penetrant NK-1 antagonist. The minimum
effective dose (MED) that produces this effect is 0.025 mg/kg.
Tradipitant, administered orally, is shown to have a duration of
activity that exceeds 7 hours. In this experimental paradigm,
tradipitant is substantially more potent than aprepitant and
CP-122721.
[0072] Example 1.2.4: Occupancy of NK-1 Receptors
[0073] A tracer NK-1 antagonist compound (GR205171) is used to
evaluate the ability of other NK-1 antagonists to occupy the brain
NK-1 receptors. In these studies, the test compounds are
administered orally and the tracer compound is administered
intravenously afterward. The occupancy of the NK-1 receptors is
evaluated by quantitating the amount of the tracer compound bound
to the brain NK-1 receptors after increasing doses of the test
compounds. Using this paradigm, tradipitant has an estimated
ED.sub.50 of 0.04 mg/kg p.o. and is substantially more potent than
the other antagonists evaluated.
Example 2: Clinical Study of Gastrointestinal Motility
[0074] A single-center, randomized, double-blind,
placebo-controlled study is conducted to investigate the effect of
tradipitant on small bowel transit time. A total of 15 healthy
subjects, including 12 men and 3 women between the ages of 19 and
63 years, are enrolled in the study and receive at least 1 dose of
study medication. A total of 13 subjects complete the study.
Subjects are randomized to receive 20 mg of tradipitant, 200 mg of
tradipitant, or placebo as a single oral dose within each of 3
periods, co-administered with a capsule radiolabeled with a maximum
of 1 MBq .sup.111In. Four hours post-dose, all subjects also
receive a second capsule radiolabeled with a maximum of 4 MBq
.sup.99mTc. Each subject receives all 3 doses during the study. For
all dosing regimens, in vivo gamma scintigraphic studies are
performed at predetermined intervals, and the following
scintigraphic parameters are analyzed: onset and completion of
gastric emptying, onset and completion of colon arrival, initiation
and completion of small bowel transit, and initial and complete
disintegration of the capsule (anatomical location and time).
[0075] A statistically significant effect of tradipitant on small
bowel transit time is observed in the study. No effect on gastric
emptying is observed in this study. However, the study is
underpowered with respect to this parameter.
Example 3: Motion Sickness Prevention
[0076] A randomized, double blind, placebo-controlled clinical
study of motion sickness is conducted, in which 126 human subjects
("study participants"), each having a prior history of motion
sickness, are subjected to sea travel in the Pacific Ocean under
varied weather conditions.
[0077] Methods
[0078] Study participants are distributed over seven boat trips off
the coast of Los Angeles, Calif., USA. For each trip, sea
conditions and participant self-evaluation of symptoms of motion
sickness are recorded. Among the seven trips, three are under
"rough" sea conditions, conducive to producing motion sickness with
wave heights above one meter. The remaining four trips are made
under "calm" conditions, with wave heights less than one meter, and
are less likely to produce motion sickness. Under "rough" sea
conditions, 72.2% of the placebo treated patients experience
vomiting compared to only 26.7% under "calm" conditions.
[0079] Subjects are randomized to receive either tradipitant 170 mg
or placebo by mouth in a blinded fashion, prior to travel
initiation. Participants report their symptoms at predetermined
time intervals during the travel period. Primary end points of the
study include: percentage of participants vomiting, and Motion
Sickness Severity Scale (MSSS) Worst score. The MSSS is a 7 point
scale ranging from 0 ("no symptoms") to 6 ("vomiting"). An
exploratory analysis is also performed to evaluate the effects of
tradipitant under "calm" and "rough" seas.
[0080] Results
[0081] Results are reported in Table 6 below. In the overall intent
to treat (ITT) population (n=126), a significantly higher
percentage of participants experience vomiting in the placebo arm
of the study (39.7%) as compared to the tradipitant arm (17.5%), p
value=0.0039. The MSSS Worst score endpoint also favors tradipitant
(3.4) vs. placebo (3.75), although the difference does not reach
statistical significance, p value=0.293. Under "calm" sea
conditions, only a small percentage of participants in either arm
experience vomiting, 26.7% in the placebo arm and 18.2% in the
tradipitant treatment arm (not significant). A similar MSSS Worst
score is seen between the two groups under "calm" conditions, 3.32
(placebo arm) and 3.40 (tradipitant treatment arm) (not
statistically significant). Under "rough" sea conditions, 72.2% of
the placebo treated patients vomit as compared to 15.8% of those
treated with tradipitant, p value=0.0009. A significant effect is
also seen under "rough" conditions in the MSSS Worst score, 4.57
(placebo) and 3.19 (tradipitant), p value=0.0235.
TABLE-US-00006 TABLE 6 Results for the Overall population and for
the Calm and Rough Sea sub-populations. Tradipitant Placebo
Difference P-value ITT* n = 63 n = 63 % Vomiting 17.5% 39.7% 22.2%
0.0039 Worst MSSS 3.40 3.75 0.35 0.2936 Calm Sea n = 44 n = 45 %
Vomiting 18.2% 26.7% 8.5% 0.3123 Worst MSSS 3.4 3.32 -0.09 0.8271
Rough Sea n = 19 n = 18 % Vomiting 15.8% 72.2% 56.4% 0.0009 Worst
MSSS 3.19 4.57 1.38 0.0235
[0082] Conclusions
[0083] The foregoing data show that treatment with 170 mg
tradipitant by mouth prior to travel initiation provides a
significant reduction in the incidence of vomiting and in MSSS
Worst score during travel under rough sea conditions and in overall
conditions, as well as modest (not statistically significant)
reductions during travel under calm conditions. These findings show
that tradipitant at a dose of 170 mg provides an effective
treatment for motion sickness.
EMBODIMENTS
[0084] In addition to other illustrative embodiments, this
invention can be seen to comprise one or more of the following
illustrative embodiments:
[0085] 1. A method of treating a subject about to engage in an
activity involving sickness-inducing motion comprising:
administering tradipitant to said subject, prior to the
commencement of said activity, in an amount effective to prevent
motion sickness or at least one symptom of motion sickness in said
subject.
[0086] 2. The method of embodiment 1, wherein said activity is
vehicle travel.
[0087] 3. The method of either of embodiments 1 or 2, wherein said
administration occurs about 30 minutes prior to entering a
vehicle.
[0088] 4. The method of either of embodiments 1 or 2, wherein the
administration occurs about 30 minutes prior to commencement of
vehicle travel.
[0089] 5. A method of treating a subject with motion sickness or at
least one symptom of motion sickness, comprising: administering
tradipitant to said subject in an amount effective to treat said
sickness or a symptom thereof.
[0090] 6. The method of any of embodiments 1-5, wherein the
effective amount is 100-400 mg.
[0091] 7. The method of any of embodiments 1-5, wherein the
effective amount is 100-300 mg.
[0092] 8. The method of any of embodiments 1-5, wherein the
effective amount is 100-200 mg.
[0093] 9. The method of any of embodiments 1-5, wherein the
effective amount is about 170 mg.
[0094] 10. The method of any preceding embodiment, wherein the
administration further comprises oral administration of the
effective amount of tradipitant.
[0095] 11. The method of embodiment 10, wherein the tradipitant
administered to the subject is in a solid immediate release form
such as a capsule or tablet comprising tradipitant and one or more
pharmaceutically acceptable excipients.
[0096] 12. The method of any one of embodiments 2-4, wherein the
vehicle travel is via automobile, airplane, helicopter, boat,
train, bus, or other vehicle.
[0097] 13. The method of any preceding embodiment, wherein the at
least one symptom is nausea, vomiting, dizziness, headache,
fullness, or disorientation.
[0098] 14. Tradipitant for use in any of the preceding methods of
treatment.
[0099] 15. A pharmaceutical composition comprising tradipitant for
use in any of the preceding methods.
[0100] 16. Tradipitant for use in the manufacture of a
pharmaceutical composition comprising tradipitant for use in any of
the preceding methods.
[0101] As used herein, the terms "first," "second," and the like,
do not denote any order, quantity, or importance, but rather are
used to distinguish one element from another, and the terms "a" and
"an" herein do not denote a limitation of quantity, but rather
denote the presence of at least one of the referenced item. The
modifier "about" used in connection with a quantity is inclusive of
the stated value and has the meaning dictated by the context (e.g.,
includes the degree of error associated with measurement of the
particular quantity). The suffix "(s)" as used herein is intended
to include both the singular and the plural of the term that it
modifies, thereby including one or more of that term (e.g., the
metal(s) includes one or more metals). Ranges disclosed herein are
inclusive and independently combinable (e.g., ranges of "up to
about 25 mg, or, more specifically, about 5 mg to about 20 mg," is
inclusive of the endpoints and all intermediate values of the
ranges of "about 5 mg to about 25 mg," etc.).
[0102] While various embodiments are described herein, it will be
appreciated from the specification that various combinations of
elements, variations or improvements therein may be made by those
skilled in the art, and are within the scope of the invention. In
addition, many modifications may be made to adapt a particular
situation or material to the teachings of the invention without
departing from essential scope thereof. Therefore, it is intended
that the invention not be limited to the particular embodiment
disclosed as the best mode contemplated for carrying out this
invention, but that the invention will include all embodiments
falling within the scope of the appended claims.
* * * * *