U.S. patent application number 17/039769 was filed with the patent office on 2021-01-21 for iloperidone metabolite for use in the treatment of psychiatric disorders.
The applicant listed for this patent is Vanda Pharmaceuticals Inc.. Invention is credited to Gunther Birznieks, John Joseph Feeney, Deepak Phadke, Mihael H. Polymeropoulos, Curt D. Wolfgang.
Application Number | 20210015809 17/039769 |
Document ID | / |
Family ID | 1000005121098 |
Filed Date | 2021-01-21 |
United States Patent
Application |
20210015809 |
Kind Code |
A1 |
Phadke; Deepak ; et
al. |
January 21, 2021 |
ILOPERIDONE METABOLITE FOR USE IN THE TREATMENT OF PSYCHIATRIC
DISORDERS
Abstract
R-P88 is used for the treatment of disorders amenable to
treatment with an atypical antipsychotic.
Inventors: |
Phadke; Deepak; (Olathe,
KS) ; Wolfgang; Curt D.; (Germantown, MD) ;
Polymeropoulos; Mihael H.; (Potomac, MD) ; Feeney;
John Joseph; (Olney, MD) ; Birznieks; Gunther;
(Bethesda, MD) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Vanda Pharmaceuticals Inc. |
Washington |
DC |
US |
|
|
Family ID: |
1000005121098 |
Appl. No.: |
17/039769 |
Filed: |
September 30, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
14384401 |
Sep 11, 2014 |
|
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|
PCT/US2013/031413 |
Mar 14, 2013 |
|
|
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17039769 |
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61610664 |
Mar 14, 2012 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/454 20130101;
A61P 25/18 20180101 |
International
Class: |
A61K 31/454 20060101
A61K031/454; A61P 25/18 20060101 A61P025/18 |
Claims
1. A method of treating a patient suffering from a psychiatric
disorder that comprises internally administering to the patient an
effective amount of R-P88, or a pharmaceutically acceptable salt
thereof, or an ester of R-P88 or a pharmaceutically acceptable salt
of such ester, once per day.
2. The method of claim 1 wherein the disorder is one that is
amenable to treatment with iloperidone.
3. The method of claim 1 wherein the disorder is one or more of
schizophrenia, schizoaffective disorder, bipolar disorder, (mania
and/or depression), depression, major depression, psychotic
episodes, autism, autism spectrum disorder, fragile X syndrome, and
pervasive developmental disorder.
4. The method of claim 1, wherein the R-P88, or the
pharmaceutically acceptable salt thereof or the ester of R-P88 or
the pharmaceutically acceptable salt of such ester, is orally
administered at a dose of 1 to 24 mg once per day.
5. The method of claim 1, wherein the R-P88, or the
pharmaceutically acceptable salt thereof or the ester of R-P88 or
the pharmaceutically acceptable salt of such ester, is orally
administered at a dose of 12 to 24 mg once per day.
6. The method of claim 1, wherein the R-P88, or the
pharmaceutically acceptable salt thereof or the ester of R-P88 or
the pharmaceutically acceptable salt of such ester, is orally
administered without titration.
7. A method of treating a patient suffering from a psychiatric
disorder that comprises internally administering to the patient an
effective amount of R-P88, or a pharmaceutically acceptable salt
thereof or an ester of R-P88 or a pharmaceutically acceptable salt
of such ester, twice per day.
8. The method of claim 7, wherein the disorder is one that is
amenable to treatment with iloperidone.
9. The method of claim 7, wherein the effective amount is selected
from: 1 to 24 mg/day administered twice per day (i.e., 0.5 to 12 mg
b.i.d.). 2 to 18 mg/day administered twice per day (i.e., 1 to 9 mg
b.i.d.). 2 to 12 mg/day administered twice per day (i.e., 1 to 6 mg
b.i.d.). 2 to 10 mg/day administered twice per day (i.e., 1 to 5 mg
b.i.d.).
10. A pharmaceutical composition comprising R-P88 or a
pharmaceutically acceptable salt thereof, or an ester of R-P88 or a
pharmaceutically acceptable salt of an ester of R-P88, and a
pharmaceutically acceptable carrier.
11. The pharmaceutical composition of claim 10, formulated for
administration once per day.
12. The pharmaceutical composition of claim 10, formulated for
administration twice per day.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of co-pending U.S.
patent application Ser. No. 14/384,401, filed 11 Sep. 2014 as the
US National Phase of then-co-pending International Patent
Application Ser. No. PCT/US2013/031413, filed 14 Mar. 2013, which
claims priority to US Provisional Patent Application No.
61/610,664, filed 14 Mar. 2012, each of which is hereby
incorporated herein.
FIELD OF THE INVENTION
[0002] This invention is in the field of treatment of disorders
amenable to treatment with an atypical antipsychotic such as
iloperidone.
BACKGROUND OF THE INVENTION
[0003] Iloperidone (1-[4-[3-[4-(6
flouro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]
ethanone) is disclosed in U.S. Pat. No. 5,364,866, which is
incorporated herein by reference. Active metabolites of
Iloperidone, e.g., S-P88 (also referred to as (S)-P-88-8891), are
useful in the present invention. See, e.g., WO2003020707, which is
incorporated herein by reference. In some cases, it may be
advantageous to use iloperidone preferentially in patients with
certain genotypes as disclosed, e.g., in WO2006039663 and in
WO2003054226, which are incorporated herein by reference.
[0004] Fanapt.RTM. iloperidone is currently approved in the United
States for the acute treatment of schizophrenia. The recommended
target dosage of Fanapt.RTM. tablets is 12 to 24 mg/day,
administered b.i.d., i.e., twice per day. The target dosing range
is achieved by daily dosage adjustments, alerting patients to
symptoms of orthostatic hypotension. Fanapt.RTM. must be titrated
slowly from a low starting dose to avoid orthostatic hypotension
due to its alpha andrenergic blocking properties. The recommended
starting dose for Fanapt.RTM. tablets is 1 mg taken twice daily.
Increases to reach the target dose range of 6-12 mg twice daily,
may be made with daily dosage adjustments to 2 mg twice daily, 4 mg
twice daily, 6 mg twice daily, 8 mg twice daily, 10 mg twice daily,
and 12 mg twice daily on days 2, 3, 4, 5, 6, and 7, respectively.
The maximum recommended dose is 12 mg twice daily (24 mg/day).
SUMMARY OF THE INVENTION
[0005] This invention relates to the treatment of disorders that
are amenable to treatment with an atypical antipsychotic, in
particular, iloperidone, that comprises administering to the
patient R-P88 according to a dosing that is derived from the
pharmacokinetics of R-P88 in the body.
[0006] In a particular illustrative embodiment, the invention
provides a method of treating a patient suffering from a disorder
amenable to treatment with iloperidone that comprises internally
administering to the patient an effective amount of R-P88 once per
day.
[0007] In another embodiment, the invention provides a method of
treating a patient suffering from a disorder amenable to treatment
with iloperidone that comprises internally administering to the
patient an effective amount of R-P88 twice per day, wherein the
effective amount is 3 to 9 mg twice daily (totaling 6 to 18
mg/day.
[0008] The illustrative aspects of the present invention are
designed to solve the problems herein described and other problems
not discussed, which are discoverable by a skilled artisan.
DETAILED DESCRIPTION OF THE INVENTION
[0009] There are three major metabolic pathways by which
iloperidone is cleared in humans. Specifically, iloperidone is:
[0010] (1) converted to S-P88, which both (a) converts back to
iloperidone, creating a dynamic equilibrium
(P88.revreaction.Iloperidone), and (b) is further metabolized and
eliminated via the CYP2D6 pathway; [0011] (2) metabolized via the
CYP2D6 pathway to P95, which is then eliminated; [0012] (3)
metabolized via the CYP3A4 pathway to P89, which is then
eliminated.
[0013] This invention relates to a method of treating a patient
suffering from a disorder that is amenable to treatment with an
antipsychotic, such as iloperidone, that comprises orally
administering R-P88.
[0014] P88, by its chemical name, is known as 1-[4-[3-[4-(6
Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]etha-
nol and, alternatively, as
4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxyl]-3-methox-
y-a-methylbenzenemethanol. In humans, P-88 is found only in the
S-enantiomeric form, which has the following structure:
##STR00001##
However, P-88 can also be synthesized in its R enantiomeric form,
which has the structure:
##STR00002##
[0015] P88 and the S and R forms thereof are described in U.S. Pat.
No. 7,977,356, which is incorporated herein by reference as though
fully set forth.
[0016] Although R-P88 is not found in humans, it has a receptor
binding profile for relevant receptors that is similar to that of
iloperidone and S-P88 in important ways and is therefore useful as
an atypical antipsychotic.
[0017] In human plasma, in vitro, R-P88 converts back to
iloperidone more slowly than does S-P88. This invention takes
advantage of this unexpected finding by using R-P88 in place of
iloperidone, or in place of racemic P88 or S-P88, in the treatment
of conditions for which an atypical antipsychotic is indicated.
Specifically, while iloperidone is administered twice per day at a
maximum daily dose of 24 mg/day, R-P88 can be administered once per
day or, at lower doses than iloperidone (or S-P88), twice per
day
[0018] Thus, in an illustrative aspect of this invention, an
effective amount of R-P88, or a salt or solvate thereof, is orally
administered to a human suffering from a psychiatric disorder,
e.g., schizophrenia, schizoaffective disorder, bipolar disorder
(mania and/or depression), depression, major depression, psychotic
episodes, autism, autism spectrum disorder, fragile X syndrome ,
and pervasive developmental disorder. An effective amount is an
amount that during the course of therapy will have a preventive or
ameliorative effect on a psychiatric disorder, such as
schizophrenia, or a symptom thereof, or of bipolar disorder. An
effective amount, quantitatively, may vary depending upon, for
example, the patient, the severity of the disorder or symptom being
treated, and the route of administration.
[0019] It will be understood that the dosing protocol including the
amount of R-P88 or salt or solvate thereof actually administered
will be determined by a qualified healthcare professional in the
light of the relevant circumstances including, for example, the
condition to be treated, the chosen route of administration, the
age, weight, and response of the individual patient, and the
severity of the patient's symptoms. Patients should of course be
monitored for possible adverse events, including, e.g., those
adverse events associated with administration of iloperidone, e.g.,
QT prolongation and orthostatic hypotension.
q.d. Dosing Protocols
[0020] In an illustrative embodiment of the invention, the patient
swallows a pharmaceutical composition comprising an effective
amount of R-P88 once per day (q.d.), e.g., in an amount of 1 to 24
mg/day, 6 to 24 mg/day, 12 to 24 mg/day, 6 to 18 mg/day, or 6 to 12
mg/day, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18,
20, 22, or 24 mg/day. At the initiation of treatment, the amount of
R-P88 administered each day can be titrated upwards until a final
dose, i.e., a maximum dose, is reached, similar to the way in which
iloperidone is titrated upon initiation of treatment. For example,
a patient can be administered R-P88 once per day titrated in
accordance with the following increments:
[0021] 1 mg once daily, 2 mg once daily, 4 mg once daily, 6 mg once
daily, 8 mg once daily, 10 mg once daily, 12 mg once daily, to
reach a maximum, i.e., final, dose of 12 mg/day, or
[0022] 2 mg once daily, 4 mg once daily, 8 mg once daily, 12 mg
once daily, 16 mg once daily, 20 mg once daily, 24 mg once daily,
to reach a maximum dose of 24 mg/day, or
[0023] 2 mg once daily, 4 mg once daily, 8 mg once daily, 12 mg
once daily, to reach a maximum dose of 12 mg/day.
[0024] In other illustrative q.d. dosing protocols of the
invention, upward titration to a final dose may be made more
quickly, e.g., more quickly than for iloperidone, or upward
titration may be omitted entirely, with a final dose administered
to a patient at the first administration. For example, in an
illustrative embodiment of the invention, an abbreviated upward
titration may include:
[0025] 1 mg once daily, 4 mg once daily, 8 mg once daily, and 12 mg
once daily, on days 1, 2, 3, and 4 to reach a maximum dose of 12
mg/day, or
[0026] 2 mg once daily, 6 mg once daily, and 12 mg once daily, on
days 1, 2, and 3 to reach a maximum dose of 12 mg/day, or
[0027] 4 mg once daily, 8 mg once daily, 16 mg once daily, and 24
mg once daily, on days 1, 2, 3, and 4 to reach a maximum dose of 24
mg/day, or
[0028] 8 mg once daily and 24 mg once daily, on days 1 and 2 to
reach a maximum dose of 24 mg/day.
[0029] Thus, illustrative titration schedules for q.d.
administration include, e.g.:
[0030] 1 mg q.d. on day 1, 2 mg q.d.on day 2, 4 mg q.d.on day 3, 6
mg q.d.on day 4, 8 mg q.d.on day 5, 10 mg q.d.on day 6, and 12 mg
q.d.on day 7 and thereafter, or
[0031] 2 mg q.d.on day 1, 4 mg q.d.on day 2, 8 mg q.d.on day 3, 12
mg q.d.on day 4, 16 mg q.d.on day 5, 20 mg q.d.on day 6, and 24 mg
q.d.on day 7 and thereafter, or
[0032] 2 mg q.d.on days 1 and 2, 4 mg q.d.on days 3 and 4, 8 mg
q.d.on days 5 and 6, and 12 mg q.d.on day 7 and thereafter,
[0033] 1 mg q.d.on day 1, 4 mg q.d.on day 2, 8 mg q.d.on day 3, and
12 mg q.d.on day 4 and thereafter, or
[0034] 2 mg q.d.on days 1 and 2, 6 mg q.d.on days 3 and 4, and 12
mg q.d.on day 5 and thereafter, or
[0035] 4 mg q.d.on day 1, 8 mg q.d.on day 2, 16 mg q.d.on day 3,
and 24 mg q.d.on day 4 and thereafter, or
[0036] 8 mg q.d.on days 1 and 2 and 24 mg q.d.on day 3 and
thereafter.
b.i.d. Dosing Protocols
[0037] In an illustrative embodiment of the invention, the patient
swallows a pharmaceutical composition comprising an effective
amount of R-P88 twice per day (b.i.d.) in the amount of 1 to 24
mg/day, e.g., 2 to 18 mg/day, e.g., 6 to 18 mg/day, e.g., 6 mg/day,
12 mg/day, 16 mg/day, or 18 mg/day. In such illustrative
embodiment, at the initiation of treatment, the amount R-P88
administered each day can be titrated upwards until a final dose is
reached. For example, a patient can be administered R-P88 once per
day titrated in accordance with the following increments: [0038] 1
mg twice daily, 2 mg twice daily, and 3 mg twice daily, to reach a
maximum dose of 6 mg/day, or [0039] 1 mg twice daily, 2 mg twice
daily, 3 mg twice daily, 4 mg twice daily, 5 mg twice daily and 6
mg twice daily, to reach a maximum dose of 12 mg/day, or [0040] 1
mg twice daily, 2 mg twice daily, 4 mg twice daily, 6 mg twice
daily, 8 mg twice daily, to reach a maximum dose of 16 mg/day, or
[0041] 1 mg twice daily, 2 mg twice daily, 4 mg twice daily, 6 mg
twice daily, 8 mg twice daily, 10 mg twice daily, and 12 mg twice
daily, to reach a maximum dose of 24 mg/day.
[0042] In other illustrative b.i.d. dosing protocols of the
invention, upward titration to a final dose may be made more
quickly, e.g., more quickly than for iloperidone, or upward
titration may be omitted entirely, with a final dose administered
to a patient at the first administration. For example, in an
illustrative embodiment of the invention, an abbreviated upward
titration may include: [0043] 1 mg twice daily, 4 mg twice daily,
and 6 mg twice daily, on days 1, 2, 3, and 4 to reach a maximum
dose of 12 mg/day, or [0044] 2 mg twice daily and 6 mg twice daily,
on days 1 and 2 to reach a maximum dose of 12 mg/day, or [0045] 1
mg twice daily, 4 mg twice daily, and 12 mg twice daily, on days 1,
2, and 3 to reach a maximum dose of 24 mg/day, or [0046] 2 mg twice
daily, 6 mg twice daily, and 12 mg twice daily, on days 1, 2, and 3
to reach a maximum dose of 24 mg/day.
[0047] Thus, illustrative titration schedules for b.i.d.
administration include, e.g.: [0048] 1 mg b.i.d. on day 1, 2 mg
b.i.d. on day 2, 3 mg b.i.d. on day 3 and thereafter or [0049] 1 mg
b.i.d. on day 1, 2 mg b.i.d. on day 2, 3 mg b.i.d. on day 3, 4 mg
b.i.d. on day 4, 5 mg b.i.d. on day 5, 6 mg b.i.d. on day 6 and
thereafter or [0050] 1 mg b.i.d. on day 1, 2 mg b.i.d. on day 2, 4
mg b.i.d. on day 3, 6 mg b.i.d. on day 4, 8 mg b.i.d. on day 5 and
thereafter or [0051] 1 mg b.i.d. on day 1, 2 mg b.i.d. on day 2, 4
mg b.i.d. on day 3, 6 mg b.i.d. on day 4, 8 mg b.i.d. on day 5, 10
mg b.i.d. on day 6, 12 mg b.i.d. in day 7 and thereafter.
Pharmaceutical Compositions & Administration
[0052] For therapeutic or prophylactic use, R-P88 or a salt or
solvate thereof will normally be administered as a pharmaceutical
composition comprising R-P88 as the (or an) essential active
pharmaceutical ingredient with a solid or liquid pharmaceutically
acceptable carrier and, optionally, with pharmaceutically
acceptable excipients employing standard and conventional
techniques.
[0053] Pharmaceutical compositions useful in the practice of this
invention include suitable dosage forms for oral administration.
Thus, if a solid carrier is used, the preparation may be tableted,
placed in a hard gelatin capsule in powder or pellet form, or in
the form of a troche or lozenge. The solid carrier may contain
conventional excipients such as binding agents, fillers, tableting
lubricants, disintegrants, wetting agents and the like. The tablet
may, if desired, be film coated by conventional techniques. If a
liquid carrier is employed, the preparation may be in the form of a
syrup, emulsion, soft gelatin capsule, sterile vehicle for
injection, an aqueous or non-aqueous liquid suspension, or may be a
dry product for reconstitution with water or other suitable vehicle
before use. Liquid preparations may contain conventional additives
such as suspending agents, emulsifying agents, wetting agents,
non-aqueous vehicle (including edible oils), preservatives, as well
as flavoring and/or coloring agents.
[0054] The pharmaceutical compositions may be prepared by
conventional techniques appropriate to the desired preparation
containing appropriate amounts of R-P88. See, for example,
Remington's Pharmaceutical Sciences, Mack Publishing Company,
Easton, Pa., 17th edition, 1985.
[0055] Some examples of suitable carriers and diluents include
lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum
acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium
silicate, microcrystalline cellulose, polyvinylpyrrolidone,
cellulose, water, syrup, methyl cellulose, methyl- and
propylhydroxybenzoates, talc, magnesium stearate and mineral oil.
The formulations can additionally include lubricating agents,
wetting agents, emulsifying and suspending agents, preserving
agents, sweetening agents or flavoring agents. The compositions of
the invention may be formulated so as to provide quick, sustained
or delayed release of the active ingredient after administration to
the patient.
[0056] The compositions can be formulated in a unit dosage form.
The term "unit dosage form" refers to physically discrete units
suitable as unitary dosages for human subjects and other mammals,
each unit containing a predetermined quantity of active material
calculated to produce the desired prophylactic or therapeutic
effect over the course of a treatment period, in association with
the required pharmaceutical carrier. Such unit dosage form can be
formulated with an amount of R-P88 required to administer R-P88 in
accordance with any of the dosing protocols described in this
specification or claims. For example, if a patient is being treated
with R-P88, 6 mg/day b.i.d., each unit dosage form can comprise 6
mg of R-P88 and the patient would take one unit dose form in the
morning and one in the afternoon or evening. Or, if a patient is
being treated with R-P88, 12 mg/day b.i.d., each unit dosage form
can comprise 6 mg of R-P88 and the patient would take two unit
dosage forms in the morning and two in the afternoon or
evening.
[0057] Methods for the administration of iloperidone directed
toward, inter alia, eliminating or minimizing the prolongation of a
corrected electrocardiographic QT (QTc) interval associated with
increased concentrations of iloperidone or iloperidone derivatives
are described in WO 2006/039663, WO 2008/121899, WO 2009/036056, WO
2009/036100, WO 2010/117931, WO 2010/117937, WO 2010/117941, WO
2010/117943, and WO2010/132866, all of which are incorporated
herein by reference. Such methods can also be applied to R-P88
administered in accordance with the method of this invention.
[0058] The invention thus includes R-P88, as well as a
pharmaceutical composition comprising R-P88, for the treatment of
disorders that are amenable to treatment with an atypical
antipsychotic in accordance with the dosing regiments generally and
specifically described above.
Synthesis
[0059] R-P88 can be synthesized by known methods, such as those
disclosed in U.S. Pat. No. 7,977,356. As disclosed therein, R-P88
can be synthesized by the stereospecific reduction of iloperidone,
which has formula III:
##STR00003##
with an optically active borane complex of formula IV:
##STR00004##
[0060] The reactions can be effected according to conventional
methods. Working up the reaction mixtures and purification of the
compounds thus obtained may be carried out in accordance with known
procedures.
[0061] Acid addition salts may be produced from the free bases in
known manner, and vice-versa. Suitable acid addition salts for use
in accordance with the present invention include, for example, the
hydrochloride.
[0062] The borane complexes used as starting materials can be
produced from the corresponding compounds of formulas Va and Vb,
according to known procedures.
##STR00005##
[0063] The starting materials of formulas Va and Vb are known.
EXAMPLE
[0064] The aim of this study was to evaluate the potential
conversion of (R)-P88 and (S)-P88 to iloperidone in human liver S9
fraction in the presence of NAD and NADP. A copy of the final
report from this study, entitled, "InVitro Metabolism of (R)-P88
and (S)-P88 in Human Liver S9 Fraction," ("Final Report") is
attached.
[0065] Three concentrations of (R)-P88 and (S)-P88 (1, 10 and 100
.mu.M) were incubated with human liver S9 fractions in the presence
of NAD and NADP. Under initial rate conditions, 13 concentrations
of (R)-P88 and (S)-P88 (1 to 100 .mu.M) were incubated with human
liver S9 fractions to determine the Michaelis-Menten enzyme kinetic
constants, Km and Vmax, for the formation of iloperidone.
[0066] The resultant data showed that S-P88 converted significantly
more quickly to iloperidone than did R-P88. At some substrate
concentrations, the rate of R-P88 conversion to iloperidone was
more than twice that of S-P88 to iloperidone. The data, which were
statistically significant, are shown in the following table.
TABLE-US-00001 Sub- Mean Rate of Differ- 95% Confidence strate
Iloperidone Formation ence Interval for Conc. (pmol/min/mg protein)
Between p Difference .mu.(.mu.M) R-P88 S-P88 Means value Between
Means 1 15.5 36.3 20.8 <0.001 19.8 to 21.8 2 29.8 62.1 32.4
<0.001 23.5 to 41.2 4 66.3 101 34.9 0.002 22.3 to 47.6 6 87.4
167 79.9 <0.001 61.7 to 98.1 8 126 183 57.4 0.002 35.1 to 79.8
10 158 271 112 <0.001 104 to 121 12.5 186 298 112 <0.001 96.1
to 128 15 211 340 130 <0.001 117 to 143 20 262 439 176 <0.001
142 to 211 25 307 553 247 <0.001 207 to 287 50 423 922 499
<0.001 392 to 606 75 491 1270 776 <0.001 715 to 837 100 521
1660 1139 <0.001 954 to 1324
[0067] In addition, results of the experiments include that the
conversion of (R)-P88 to iloperidone showed a slightly S-shaped
direct plot and "hook"-shaped Eadie-Hofstee plot suggesting
allosteric interactions.
[0068] In contrast, the conversion of (S)-P88 to iloperidone best
fit a biphasic saturation enzyme model suggesting two enzymes
contributing to the metabolism of (S)-P88, one high-affinity enzyme
with normal saturation kinetics and one low affinity enzyme with
linear (non-saturating) enzyme kinetics.
[0069] In addition, slower conversion of R-P88 to iloperidone is
expected to result in decreased formation of P95, which has the
following structure and chemical name:
##STR00006##
[0070]
4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-m-
ethoxy-benzoic acid, and which has been implicated in episodes of
orthostatic hypotension following initial administration of
iloperidone.
[0071] R-P88 may form pharmaceutically acceptable salts. It may
also form fatty acid esters, e.g., via the hydroxy group in the
ethanolic moiety, and pharmaceutically acceptable salts thereof,
such as described in US20070197595, which is incorporated herein by
reference. This invention comprises use of such salts, esters, or
salts of esters in place of or in addition to R-P88.
[0072] The foregoing description of various aspects of the
invention has been presented for purposes of illustration and
description. It is not intended to be exhaustive or to limit the
invention to the precise form disclosed, and obviously, many
modifications and variations are possible. Such modifications and
variations that may be apparent to a person skilled in the art are
intended to be included within the scope of the invention as
defined by the accompanying claims.
* * * * *