U.S. patent application number 15/485906 was filed with the patent office on 2017-10-19 for methods of monitoring for adherence to aripiprazole therapy.
The applicant listed for this patent is AMERITOX, LLC. Invention is credited to Gregory L. McIntire, Ayodele Morris.
Application Number | 20170299574 15/485906 |
Document ID | / |
Family ID | 51537707 |
Filed Date | 2017-10-19 |
United States Patent
Application |
20170299574 |
Kind Code |
A1 |
McIntire; Gregory L. ; et
al. |
October 19, 2017 |
METHODS OF MONITORING FOR ADHERENCE TO ARIPIPRAZOLE THERAPY
Abstract
Methods for helping to monitor subject adherence with a
prescribed antipsychotic drug treatment regimen are disclosed.
Inventors: |
McIntire; Gregory L.;
(Greensboro, NC) ; Morris; Ayodele; (Midland,
TX) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AMERITOX, LLC |
Baltimore |
MD |
US |
|
|
Family ID: |
51537707 |
Appl. No.: |
15/485906 |
Filed: |
April 12, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14854354 |
Sep 15, 2015 |
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15485906 |
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14213392 |
Mar 14, 2014 |
9170264 |
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14854354 |
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61798443 |
Mar 15, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
G01N 33/70 20130101;
G01N 33/6893 20130101; G01N 30/72 20130101; Y10T 436/147777
20150115; H01J 49/0027 20130101; Y10T 436/24 20150115; A61P 25/18
20180101; G01N 2800/30 20130101; G01N 2800/52 20130101; G01N
2800/302 20130101; G01N 33/493 20130101 |
International
Class: |
G01N 33/493 20060101
G01N033/493; G01N 33/68 20060101 G01N033/68 |
Claims
1.-16. (canceled)
17. A method of identifying a schizophrenic subject suitable for
treatment with an anti-psychotic drug therapy other than
aripiprazole comprising: (a) detecting OPC3373 levels in a urine
sample obtained from the schizophrenic subject that has been
prescribed a dose of at least 2 mg aripiprazole per day for at
least 1 day; (b) terminating the prescribed aripiprazole dose and
administering an anti-psychotic drug therapy other than
aripiprazole to the schizophrenic subject wherein the schizophrenic
subject is suitable for treatment with an anti-psychotic drug
therapy other than aripiprazole when the OPC3373 urine level
detected in the schizophrenic subject is lower than that observed
in a control subject administered the same prescribed dose regimen
of aripiprazole over the same time period as the schizophrenic
subject, and wherein the control subject exhibits an OP3373 urine
level of at least 25 ng/mL.
18. The method of claim 17, wherein OPC3373 urine levels are
detected via LC/MSMS, LC/MS(TOF) or direct administration to a mass
spectrometry.
19. The method of claim 18, wherein direct administration comprises
Rapidfire or laser diode thermal desorption ("LDTD").
20. The method of claim 17, wherein the schizophrenic subject has
been prescribed an aripiprazole dose selected from the group
consisting of 2 mg/day, 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day,
or 30 mg/day.
21. The method of claim 17, wherein the schizophrenic subject
suitable for treatment with an anti-psychotic drug therapy other
than aripiprazole exhibits a dehydroaripiprazole urine level that
is lower than 5 ng/mL.
22. The method of claim 17, wherein the schizophrenic subject
suitable for treatment with an anti-psychotic drug therapy other
than aripiprazole exhibits an aripiprazole urine level that is
lower than 5 ng/mL.
23. The method of claim 17, further comprising detecting the levels
of one or more of dehydroaripiprazole, aripiprazole, and OPC-3952
in the urine of the schizophrenic subject.
24. The method of claim 23, wherein the schizophrenic subject
suitable for treatment with an anti-psychotic drug therapy other
than aripiprazole exhibits a dehydroaripiprazole urine level of at
least 5 ng/mL.
25. The method of claim 23, wherein the schizophrenic subject
suitable for treatment with an anti-psychotic drug therapy other
than aripiprazole exhibits an aripiprazole urine level of at least
5 ng/mL.
26. A method for detecting aripiprazole in a urine sample obtained
from a schizophrenic subject that has been prescribed aripiprazole
comprising detecting OPC3373 in the urine sample via LC/MSMS,
LC/MS(TOF) or direct administration to a mass spectrometry,
detecting aripiprazole in the urine sample when at least 25 ng/mL
of OPC3373 is detected in the urine sample.
27. The method of claim 26, wherein direct administration comprises
Rapidfire or laser diode thermal desorption ("LDTD").
28. The method of claim 26, wherein the urine sample exhibits a
dehydroaripiprazole urine level that is lower than 5 ng/mL.
29. The method of claim 26, wherein the urine sample exhibits an
aripiprazole urine level that is lower than 5 ng/mL.
30. The method of claim 26, further comprising detecting the levels
of one or more of dehydroaripiprazole, aripiprazole, and OPC-3952
in the urine sample.
31. The method of claim 30, wherein the urine sample exhibits a
dehydroaripiprazole urine level of at least 5 ng/mL.
32. The method of claim 30, wherein the urine sample exhibits an
aripiprazole urine level of at least 5 ng/mL.
33. The method of claim 26, wherein the schizophrenic subject has
been prescribed an aripiprazole dose selected from the group
consisting of 2 mg/day, 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day,
or 30 mg/day.
34. The method of claim 26, further comprising measuring the
creatinine level, pH and/or specific gravity value of the urine
sample.
35. A method for detecting aripiprazole in a urine sample obtained
from a schizophrenic subject that has been prescribed aripiprazole
comprising detecting OPC-3952 in the urine sample via LC/MSMS,
LC/MS(TOF) or direct administration to a mass spectrometry.
36. The method of claim 34, further comprising detecting the levels
of one or more of dehydroaripiprazole, aripiprazole, and OPC3373 in
the urine sample.
Description
PRIORITY CLAIM
[0001] This application is a continuation of U.S. patent
application Ser. No. 14/213,392, filed on Mar. 14, 2014, which
claims priority to U.S. provisional patent application Ser. No.
61/798,443, filed on Mar. 15, 2013, the entire contents of each of
which are incorporated herein by reference and relied upon.
FIELD
[0002] The present invention provides methods for helping monitor
patient adherence to aripiprazole therapy in the treatment of
Schizophrenia and other Mental Health Disorders.
SUMMARY
[0003] In various embodiments, the present invention provides
methods for helping monitor patient adherence to aripiprazole
therapy in the treatment of Schizophrenia and other Mental Health
Disorders. In one embodiment, the method involves the use of
OPC3373 as a biomarker in urine.
[0004] These and other embodiments of the invention will be
disclosed in further detail herein below.
BRIEF DESCRIPTION OF THE FIGURE
[0005] FIG. 1 depicts a proposed metabolic pathway for
aripiprazole.
DETAILED DESCRIPTION
[0006] While the present invention is capable of being embodied in
various forms, the description below of several embodiments is made
with the understanding that the present disclosure is to be
considered as an exemplification of the invention, and is not
intended to limit the invention to the specific embodiments
illustrated. Headings are provided for convenience only and are not
to be construed to limit the invention in any manner. Embodiments
illustrated under any heading may be combined with embodiments
illustrated under any other heading.
[0007] The use of numerical values in the various quantitative
values specified in this application, unless expressly indicated
otherwise, are stated as approximations as though the minimum and
maximum values within the stated ranges were both preceded by the
word "about." Also, the disclosure of ranges is intended as a
continuous range including every value between the minimum and
maximum values recited as well as any ranges that can be formed by
such values. Also disclosed herein are any and all ratios (and
ranges of any such ratios) that can be formed by dividing a
disclosed numeric value into any other disclosed numeric value.
Accordingly, the skilled person will appreciate that many such
ratios, ranges, and ranges of ratios can be unambiguously derived
from the numerical values presented herein and in all instances
such ratios, ranges, and ranges of ratios represent various
embodiments of the present invention.
[0008] Aripiprazole (Abilify.RTM., Abilitat.TM.) is an atypical
antipsychotic prescribed for the treatment of schizophrenia.
Adherence has been shown, for example by Velligan, et al.,
(Psychiatric Services, 54:665, 667 (2003)), to be particularly low
in patients with schizophrenia. Urine drug testing has been
employed by behavioral health clinicians such as described by
Baselt, Disposition of Toxic Drugs and Chemicals in Man (2004) to
monitor patient adherence through analysis of aripiprazole itself
and the major plasma metabolite, dehydroaripiprazole. Typical
dosing of aripiprazole is 2-30 mg/day. It is well absorbed after
oral administration with an oral bioavailability of 87%. The mean
elimination half-life is 75 hours. Steady state serum
concentrations for aripiprazole are achieved after two weeks of
dosing.
[0009] Aripiprazole is metabolized in the liver primarily by
dehydrogenation and hydroxylation by both CYP2D6 and CYP3A4 and by
N-dealkylation by CYP3A4. The dehydrogenation biotransformation
pathway produces the pharmacologically active metabolite
dehydroaripiprazole. N-dealkylation splits aripiprazole into
metabolites, OPC3373 and DCPP. OPC3373 is an acid product with a
quinoline moiety and butyl side chain. Hydroxylation produces
metabolites, DM-1452 and DM-1451. Secondary biotransformations
include N-dealkylation, hydroxylation, glucuronidation and
sulfation. The proposed metabolic pathway for aripiprazole is shown
in FIG. 1. In plasma, aripiprazole is the predominant species,
representing 57% of a dose, followed by dehydroaripiprazole at 20%,
as the major metabolite and OPC-3373 as the second major metabolite
at 2%. Aripiprazole is eliminated by renal and biliary routes in
humans. Less than 1% of an oral dose is excreted as unchanged
aripiprazole in urine, with 8-18% in faeces. The N-dealkylation
metabolites OPC3373 and DCPP and related metabolites are excreted
predominantly in urine. Baselt, supra, reports that OPC3373 is the
major urinary metabolite, with 19% being recovered from a dose. It
is therefore an ideal biomarker for monitoring adherence to
aripiprazole by urine drug testing. The larger hydroxylation and
dehydrogenation metabolites are excreted predominantly in
faeces.
[0010] In one embodiment, the present disclosure provides a method
for monitoring aripiprazole therapy in a subject. In some
embodiments, the method comprises identifying a subject who is
prescribed aripiprazole therapy, measuring a concentration of
OPC3373 in urine of the subject, and identifying the subject as
non-adherent to aripiprazole therapy if the concentration of
OPC3373 is less than a predetermined level, and as adherent to
aripiprazole therapy if the concentration of OPC3373 is greater
than the predetermined level. In some embodiments, the method
further comprises counseling the subject on dangers of
non-adherence to aripiprazole therapy if the subject is identified
as non-adherent. In some embodiments, the predetermined level is 25
ng/mL.
[0011] In some embodiments, the aripiprazole therapy includes
prescribing to the subject and/or administering to the subject
aripiprazole in an amount selected from the group consisting of: 2
mg/day, 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, or 30
mg/day.
[0012] In some embodiments, the method further comprises measuring
a concentration of aripiprazole in urine of the subject, and
identifying the subject as non-adherent if the concentrations of
aripiprazole and OPC3373 are both less than predetermined levels of
aripiprazole and OPC3373, respectively. In some embodiments the
predetermined level of aripiprazole is 5 ng/mL. In some
embodiments, the predetermined level of OPC3373 is 25 ng/mL.
[0013] In some embodiments, the method further comprises measuring
a concentration of dehydroaripiprazole in urine of the subject, and
identifying the subject as non-adherent if the concentrations of
dehydroaripiprazole and OPC3373 are both less than predetermined
levels of dehydroaripiprazole and OPC3373, respectively. In some
embodiments, the predetermined level of dehydroaripiprazole is 5
ng/mL. In some embodiments, the predetermined level of OPC3373 is
25 ng/mL.
[0014] In some embodiments, the method comprises measuring
concentrations of aripiprazole, dehydroaripiprazole and OPC3373 in
urine of the subject, and identifying the subject as non-adherent
if the concentrations of aripiprazole, dehydroaripiprazole and
OPC3373 are each less than predetermined levels of aripiprazole,
dehydroaripiprazole and OPC3373, respectively. In some embodiments,
the predetermined level of aripiprazole is 5 ng/mL. In some
embodiments, the predetermined level of dehydroaripiprazole is 5
ng/mL. In some embodiments, the predetermined level of OPC3373 is
25 ng/mL.
[0015] In some embodiments, the method comprises measuring
concentrations of aripiprazole, dehydroaripiprazole and OPC3373 in
urine of the subject, and identifying the subject as non-adherent
if the concentrations of any one, any two, or all three of
aripiprazole, dehydroaripiprazole and OPC3373 are less than
predetermined levels of aripiprazole, dehydroaripiprazole and
OPC3373, respectively. In some embodiments, the predetermined level
of aripiprazole is 0.05 ng/mL. In some embodiments, the
predetermined level of dehydroaripiprazole is 0.05 ng/mL. In some
embodiments, the predetermined level of OPC3373 is 0.25 ng/mL.
[0016] The concentration of any analyte described in the present
disclosure may be determined (e.g., measured) by any suitable
quantification method. In some embodiments, the concentration of an
analyte (e.g., aripiprazole, dehydroaripiprazole, and/or OPC3373)
is measured by tandem liquid chromatography-mass spectrometry-mass
spectrometry ("LC/MSMS"). In some embodiments, the concentration of
an analyte (e.g., aripiprazole, dehydroaripiprazole, and/or
OPC3373) is measured by tandem liquid chromatography-High
Resolution mass spectrometry (Time of Flight (TOF)) ("LC/MS(TOF)").
In some embodiments, the concentration of an analyte (e.g.,
aripiprazole, dehydroaripiprazole, and/or OPC3373) is measured by
direct injection mass spectrometry-mass spectrometry ("LC/MSMS")
e.g., such systems as RapidFire.TM. (Agilent) or Laser Diode
Thermal Desorption ("LDTD") (Phytronix) to introduce samples into
the mass spectrometer; either triple quadrupole (i.e., MSMS) or
exact mass (i.e., Time of Flight, Orbitrap, etc.) instruments
[0017] In some embodiments, the method further comprises measuring
a creatinine level in urine of the subject and normalizing the
OPC3373 concentration as a function of the creatinine
concentration, wherein the predetermined level comprises a ratio of
the OPC3373 concentration to the creatinine concentration.
[0018] In some embodiments, the method further comprises measuring
a specific gravity value of the urine of the subject, and
normalizing the OPC3373 concentration as a function of the specific
gravity value, wherein the predetermined level comprises a ratio of
the OPC3373 concentration to the specific gravity value.
[0019] In some embodiments, the method further comprises measuring
a creatinine level in urine of the subject and normalizing the
aripiprazole concentration as a function of the creatinine
concentration, wherein the predetermined level comprises a ratio of
the aripiprazole concentration to the creatinine concentration.
[0020] In some embodiments, the method further comprises measuring
a specific gravity value of the urine of the subject, and
normalizing the aripiprazole concentration as a function of the
specific gravity value, wherein the predetermined level comprises a
ratio of the aripiprazole concentration to the specific gravity
value.
[0021] In some embodiments, the method further comprises measuring
a creatinine level in urine of the subject and normalizing the
dehydroaripiprazole concentration as a function of the creatinine
concentration, wherein the predetermined level of the
dehydroaripiprazole comprises a ratio of the dehydroaripiprazole
concentration to the creatinine concentration.
[0022] In some embodiments, the method further comprises measuring
a specific gravity value of the urine of the subject, and
normalizing the dehydroaripiprazole concentration as a function of
the specific gravity value, wherein the predetermined level of the
dehydroaripiprazole comprises a ratio of the dehydroaripiprazole
concentration to the specific gravity value.
[0023] In some embodiments, the method further comprises measuring
a creatinine value in urine of the subject and a specific gravity
value of urine of the subject and normalizing the aripiprazole,
dehydroaripiprazole and/or OPC3373 ("analyte") concentration(s) as
a function of the creatinine and specific gravity values, wherein
the predetermined level of the analyte comprises a ratio of the
analyte concentration to the creatinine and specific gravity
values.
[0024] In some embodiments, the method further comprises generating
a normal distribution of OPC3373 in aripiprazole subjects using the
log(OPC3373 concentration) from a plurality of measured OPC3373
concentrations in urine from a plurality of subjects, for example a
plurality of subjects known to be adherent to aripiprazole therapy.
In some embodiments, the method further comprises identifying a
concentration of OPC3373 in urine of a second (test) subject as
normal if it falls within the normal distribution (e.g., within 2
standard deviations of the mean) of OPC3373 of the plurality of
known adherent aripiprazole subjects, and/or identifying the
concentration of OPC3373 in urine of the second (test) subject as
not normal if it falls outside the normal distribution of OPC3373
in the plurality of known adherent aripiprazole subjects. In some
embodiments, the concentration of OPC3373 in urine of the second
(test) subject is incorporated into the distribution model, that
is, the OPC3373 concentration from the second (test) subject is
used along with the OPC3373 concentrations from the plurality of
aripiprazole subjects to generate a second, refined normal
distribution of OPC3373 in aripiprazole subjects.
[0025] In some embodiments, the method further comprises generating
a normal distribution of aripiprazole in aripiprazole subjects
using the log(aripiprazole concentration) from a plurality of
measured aripiprazole concentrations in urine from a plurality of
subjects, for example a plurality of subjects known to be adherent
to aripiprazole therapy. In some embodiments, the method further
comprises identifying a concentration of aripiprazole in urine of a
second (test) subject as normal if it falls within the normal
distribution (e.g., within 2 standard deviations of the mean) of
aripiprazole of the plurality of known adherent aripiprazole
subjects, and/or identifying the concentration of aripiprazole in
urine of the second (test) subject as not normal if it falls
outside the normal distribution of aripiprazole in the plurality of
known adherent aripiprazole subjects. In some embodiments, the
concentration of aripiprazole in urine of the second (test) subject
is incorporated into the distribution model, that is, the
aripiprazole concentration from the second (test) subject is used
along with the aripiprazole concentrations from the plurality of
aripiprazole subjects to generate a second, refined normal
distribution of aripiprazole in aripiprazole subjects.
[0026] In some embodiments, the method further comprises generating
a normal distribution of dehydroaripiprazole in aripiprazole
subjects using the log(dehydroaripiprazole concentration) from a
plurality of measured dehydroaripiprazole concentrations in urine
from a plurality of subjects, for example a plurality of subjects
known to be adherent to aripiprazole therapy. In some embodiments,
the method further comprises identifying a concentration of
dehydroaripiprazole in urine of a second (test) subject as normal
if it falls within the normal distribution (e.g., within 2 standard
deviations of the mean) of dehydroaripiprazole of the plurality of
known adherent aripiprazole subjects, and/or identifying the
concentration of dehydroaripiprazole in urine of the second (test)
subject as not normal if it falls outside the normal distribution
of dehydroaripiprazole in the plurality of known adherent
aripiprazole subjects. In some embodiments, the concentration of
dehydroaripiprazole in urine of the second (test) subject is
incorporated into the distribution model, that is, the
dehydroaripiprazole concentration from the second (test) subject is
used along with the dehydroaripiprazole concentrations from the
plurality of aripiprazole subjects to generate a second, refined
normal distribution of dehydroaripiprazole in aripiprazole
subjects.
[0027] Any method disclosed herein may additionally comprise
counseling a subject on dangers of non-adherence to aripiprazole
therapy if the subject is identified as non-adherent.
[0028] In some embodiments, the method further comprises modifying
the subject's prescribed dose of aripiprazole if the subject is
identified as being non-adherent with the prescribed aripiprazole
therapy. In some embodiments, the method further comprises
discontinuing aripiprazole therapy in the subject if the subject is
identified as being non-adherent. In some embodiments, the method
further comprises replacing aripiprazole therapy in the subject
with a new therapeutic regimen if the subject is identified as
being non-adherent. In some embodiments, the method further
comprises discontinuing aripiprazole therapy in the subject and
increasing a dose of a second anti-psychotic drug in the subject.
In some embodiments, the method further comprises maintaining
(e.g., not modifying or not significantly modifying) the subject's
prescribed dose of aripiprazole if the subject is identified as
being adherent with the prescribed aripiprazole therapy.
[0029] In some embodiments, the method further comprises
determining a clinical effect of a subject's aripiprazole therapy,
the method comprising identifying a subject who is prescribed
aripiprazole therapy, measuring a concentration of one or more of
OPC3373, aripiprazole, and dehydroaripiprazole in urine of the
subject, identifying the subject as adherent to aripiprazole
therapy if the concentration of OPC3373, aripiprazole and/or
dehydroaripiprazole falls within a normal distribution of OPC3373,
aripiprazole and/or dehydroaripiprazole (respectively), identifying
an inadequate clinical response to the prescribed aripiprazole
therapy in the subject, and replacing the prescribed aripiprazole
therapy with a different anti-psychotic drug therapy.
Examples
Example 1
[0030] The appearance of OPC3373
(4-[(2-Oxo-1,2,3,4-tetrahydro-7-quinolinyl)oxy]butanoic acid,
BMS-337047) as the major aripiprazole metabolite in the urine can
be used to help monitor patient adherence to aripiprazole therapy.
While analysis of both aripiprazole and the plasma metabolite,
dehydroaripiprazole, can be used to monitor patient adherence, the
relatively low levels of these molecules in the urine frequently
results in "false negatives" in patients known to be taking
aripiprazole. As shown in Table 1, the level of OPC3373 in the
urine exceeds that of both aripiprazole and the major plasma
metabolite, dehydroaripiprazole by as much as 5-120.times. and as
much as 200.times. in normally metabolizing humans who are known to
be taking chronic doses of aripiprazole.
TABLE-US-00001 TABLE 1 Levels of OPC3373 in Human Urine Relative to
Aripiprazole and Dehydroaripiprazole (ng/mL) OPC3373 Aripiprazole
LOQ = Dehydroaripiprazole LOQ = Sample ID 100 ng/mL LOQ = 5 ng/mL 5
ng/mL Specimen1 <100.0 8.8 5.0 Specimen2 5353.4 56.1 39.5
Specimen3 285.4 <5.0 9.5 Specimen4 <100.0 <5.0 <5.0
Specimen5 <100.0 5.1 <5.0 Specimen6 159.7 14.1 32.4 Specimen7
877.6 0.0 9.7 Specimen8 868.9 17.8 53.3 Specimen9 628.9 20.1 84.9
Specimen10 136.7 5.1 38.7 Specimen11 108.0 <5.0 <5.0
Specimen12 <100.0 0.0 <5.0 Specimen13 1203.6 <5.0 10
Specimen14 607.7 <5.0 <5.0 Specimen15 180.2 0.0 0.0
Specimen16 819.4 5.9 17.4 Specimen17 <100.0 0.0 0.0 Specimen18
657.3 <5.0 <5.0 Specimen19 <100.0 <5.0 <5.0
Specimen20 <100.0 0.0 <5.0 Specimen21 <100.0 0 <5.0
Specimen22 2149.2 15.8 17.9 Range 10*-1500 ng/mL 5-75 ng/mL 5-100
ng/mL % NEG at 27.2 100/5/5 ng/mL Cutoff % POS with 22.7 OPC3373
only *Below LOQ
[0031] Thus, for the purposes of helping to monitor patients for
adherence to aripiprazole therapy, testing of the metabolite,
OPC3373, provides a greater level of sensitivity and therefore the
ability to identify aripiprazole positive patients when commonly
available compounds including aripiprazole and dehydroaripiprazole
are not reflective of adherent patients in as many as 50% of the
patient positive population. Inasmuch as aripiprazole is used for
the treatment of psychotic individuals, it is important to be able
to identify drug positive patients at very low levels.
Example 2
[0032] An additional set of aripiprazole positive patients was
monitored for levels of aripiprazole, dehyrdroaripiprazole, and
OPC3373 in their urine. Table 2 details the results of testing on
these subjects, and demonstrates that OPC3373 is a much better
biomarker for adherence to aripiprazole therapy than the parent
compound or the primary plasma metabolite, dehydroaripiprazole.
Sample number 3 in Table 2 demonstrated very low levels of
creatinine and as is well known in the industry may have been
severely diluted such that the aripiprazole metabolite, OPC3373,
was below levels of quantitation.
[0033] For these data the Lower Level of Quantitation (LLOQ) for
the analytes in question were: [0034] Aripiprazole: 5 ng/mL [0035]
Dehydroaripiprazole: 5 ng/mL [0036] OPC3373: 25 ng/mL
[0037] These analyses were completed using LC/MSMS.
TABLE-US-00002 TABLE 2 Results from Testing Urine from Aripiprazole
Positive Patients in a Controlled Study Specimen Validity Results
Abilify Urine Results (ng/mL) Sample Specific Dehydro- # Dose ID pH
Creatinine Gravity OPC3373 aripiprazole Aripiprazole Comments 1 5
mg q 001CK 5.3 97.3 1.015 410.7 5.2 19.4 day 2 5 mg q 002CF 6.6
366.1 1.031 2338.8 6.4 11.6 day 3 5 mg q 003MS 4.8 9.0 1.004 0 0 0
Peaks detected, day but less than LOD/LOQ 4 5 mg q 004TJ 5.2 172.7
1.023 175.0 0 11.1 Peak detected, day but less than LOD/LOQ 5 5 mg
q 006NT 5.5 182.5 1.028 1213.6 6.5 22.3 day 6 5 mg q 007ET 5.0 87.7
1.015 79.0 0 9.4 Peak detected, day but less than LOD/LOQ
Example 3
[0038] The urine of 5 patients who were prescribed 30 mg of
Abilify.RTM. (aripiprazole) was tested for compliance over 5 days
(Table 3). The data in Table 4 demonstrate the "normal" nature of
the sample validity criteria (i.e., pH, specific gravity, and
creatinine). The preponderance of OPC3373 in the urine as the major
metabolic urine compound is clearly demonstrated in Table 3.
Assuming 15 opportunities to determine the patient to be either
positive or negative for Abilify.RTM. dosing, the use of OPC3373
resulted in 100% correct identification of those taking the
prescribed medicine. Without OPC3373, only 93% were determined to
be positive with one patient either having stopped taking their
medicine between day 4 and 5 or just being below the reporting
cutoffs for both aripiprazole and dehydroaripiprazole. Thus, use of
OPC3373 as a urine biomarker even at this relatively high dose adds
value to compliance monitoring for Abilify.RTM..
TABLE-US-00003 TABLE 3 Test Results from Patients Prescribed 30
mg/day Abilify .RTM. Creatinine Specific Aripi- Dehydro- Sub Day pH
(mg/dL) Gravity prazole aripiprazole OPC3373 A 1 5.1 152.6 1.013
45.7 14.1 981.5 4 5.6 227.6 1.015 34.0 16.6 1935.4 5 5.6 293.8
1.016 55.5 28.1 2248.8 B 1 7.1 38.7 1.006 16.5 11.5 371.3 4 5.4
55.9 1.006 16.9 14.1 515.6 5 5.0 34.4 1.004 0 0 260.1 C 1 5.8 220.3
1.015 30.8 29.2 3050.9 4 5.5 254.6 1.018 53.4 84.8 3128.9 5 7.0
142.1 1.011 12.6 17.0 1601.0 D 1 6.7 126.9 1.010 0 6.8 1688.0 4 7.3
243.1 1.011 0 11.0 4160.0 5 6.1 186.3 1.012 10.6 8.9 2417.9 E 1 6.5
188.5 1.013 83.3 56.9 4383.3 4 5.0 39.4 1.005 113.0 36.3 481.0 5
5.4 177.1 1.019 199.8 89.7 3141
TABLE-US-00004 TABLE 4 Sample Validity and Urine Results Summary at
30 mg/day Dehydro- OPC3373 Creatinine Specific Aripi- aripiprazole
(ng/mL) pH (mg/dL) Gravity prazole (ng/mL) 3373 Avg 5.94 158.75
1.01 44.81 28.33 2024.31 Std 0.79 84.97 0.00 53.76 27.69 1356.01
Dev n 15.00 Max 7.30 293.80 1.02 199.80 89.70 4383.30 Min 5.00
34.40 1.00 0.00 0.00 260.10
Example 4
[0039] The urine of 22 patients who were prescribed 20 mg of
Ability (e.g., aripiprazole) was tested for compliance over 5 days
(Table 5). The data in Table 6 demonstrate the "normal" nature of
the sample validity criteria (i.e., pH, specific gravity, and
creatinine). The preponderance of OPC3373 in the urine as the major
metabolic urine compound is clearly demonstrated in Table 5.
Assuming 66 opportunities to determine the patient to be either
positive or negative for Abilify.RTM. dosing, the use of OPC3373
resulted in 100% correct identification of those taking the
prescribed medicine. Without OPC3373, only 85% were determined to
be positive with patients just being below the reporting cutoffs
for both aripiprazole and dehydroaripiprazole. Thus, use of OPC3373
as a urine biomarker even at this relatively high dose adds value
to compliance monitoring for Abilify.RTM..
TABLE-US-00005 TABLE 5 Test Results from Patients Prescribed 20
mg/day Abilify .RTM. Creatinine Specific Aripi- Dehydro- Sub. pH
(mg/dL) Gravity prazole aripiprazole OPC3373 A 5.5 55.7 1.005 28.5
14.6 626.3 7.1 60.3 1.007 9.9 8.7 696.2 6.2 57.2 1.008 11.1 7.1
883.5 B 5.2 69.1 1.037 6.5 7.2 213.7 5.5 59.0 1.037 6.1 7.7 187.7
5.2 109.8 1.013 9.6 16.9 487.7 C 5.0 67.1 1.017 36.7 16.5 865.5 5.5
124.7 1.016 40.5 17.9 1561.5 5.0 56.8 1.005 27.6 12.2 744.8 D 6.5
219.2 1.015 21.6 20.5 1648.5 5.8 249.0 1.017 57.6 91.4 1287.4 5.5
195.8 1.013 50.4 71.3 710 E 8.9 314.9 0.993* 17.7 17.2 1442.2 8.9
199.9 0.986* 10.9 15.3 1379.3 8.8 180.5 0.998* 0 7.3 1248.6 F 5.7
129.3 1.008 7.1 6.2 1087.2 5.3 80.3 1.008 14.3 8.5 464.5 5.6 59.1
1.007 6.9 0 435.6 G 6.0 87.3 1.011 16.4 11.4 1248.9 5.9 39.7 1.006
13.6 5.6 448.1 6.8 90.2 1.007 5.2 6.6 1174.0 H 5.5 37.9 1.006 16.2
0 280.1 6.8 32.8 1.004 0 0 230.4 7.1 17.2* 1.003 0 0 100.8 I 5.6
264.1 1.015 36.6 25.5 4199.1 6.6 147.4 1.013 5.6 7.2 2524.6 6.3
141.8 1.013 14.3 12.6 2008.2 J 6.4 46.3 1.005 10.4 0 416.1 7.6 99.7
1.014 16.1 7.0 1527.5 5.9 149.2 1.017 24.1 11.8 2191.8 K 5.5 189.0
1.013 58.7 27.4 1649.1 5.2 75.5 1.009 42.4 16.6 556.6 6.0 162.2
1.017 51.1 32.5 1516.8 L 5.1 133.3 1.016 84.9 34.2 2667.1 7.1 143.4
1.013 0 7.5 2225.5 6.2 199.0 1.016 25.0 16.5 2447.1 M 5.7 22.0
1.002* 6.9 0 267.1 5.3 14.7* 1.003 5.2 0 202.1 5.5 15.0* 1.002* 0 0
167 N 5.4 226.1 1.011 5.6 6.5 284.2 5.5 364.9 1.019 21.5 13.9
1007.7 5.3 354.7 1.018 26.7 18.0 913.8 O 5.8 172.6 1.016 36.5 9.9
4092.7 5.9 104.4 1.012 16.2 5.0 1240.3 5.8 273.5 1.017 41.3 12.4
4927.7 P 6.5 41.6 1.008 13.8 0 700.7 5.1 69.4 1.012 49.3 11.1
1499.6 6.3 53.3 1.009 29.7 6.9 765.3 Q 5.4 181.1 1.019 64.0 12.8
4156.0 5.4 50.6 1.007 21.3 10.3 1697.6 7.1 59.1 1.010 0 0 2210.8 R
6.8 26.8 1.003 0 0 497.3 7.0 25.6 1.003 5.3 0 406.3 7.0 25.7 1.003
0 0 570.0 S 5.2 317.2 1.020 87.2 27.7 2562.9 5.2 324.2 1.021 75.0
25.7 2702.1 5.3 350.4 1.021 137.6 64.6 4591.0 T 5.4 52.4 1.008 28.3
6.2 732.1 6.6 48.8 1.007 14.9 0 296.2 7.1 59.1 1.008 0 0 442.5 U
5.4 112.6 1.011 7.8 5.5 182 7.0 109.6 1.005 0 0 160.4 7.3 27.6
1.005 0 0 38.2 V 6.8 17.7 1.003 0 0 91.4 5.4 60.0 1.008 8.4 0 469.0
5.3 96.3 1.012 18.8 6.6 1128.1 *Measurement is below limits for
specimen validity parameter; specimen still valid.
TABLE-US-00006 TABLE 6 Sample Validity and Urine Results Summary at
20 mg/day Abilify .RTM. Creatinine Specific Aripi- Dehydro- pH
(mg/dL) Gravity prazole aripiprazole OPC3373 Avg 6.08 121.22 1.01
22.80 12.30 1248.25 Std 0.93 95.66 0.01 25.72 16.58 1163.41 Dev n
66.00 Max 8.90 364.90 1.04 137.60 91.40 4927.70 Min 5.00 14.70 0.99
0.00 0.00 38.20
Example 5
[0040] The urine of 23 patients who were prescribed 15 mg of
Abilify.RTM. (aripiprazole) was tested for compliance over 5 days
(Table 7). The data in Table 8 demonstrate the "normal" nature of
the sample validity criteria (i.e., pH, specific gravity, and
creatinine). The preponderance of OPC3373 in the urine as the major
metabolic urine compound is clearly demonstrated in Table 7.
Assuming 69 opportunities to determine the patient to be either
positive or negative for Abilify.RTM. dosing, the use of OPC3373
resulted in 99% correct identification of those taking the
prescribed medicine. Without OPC3373, only 78% were determined to
be positive with patients just being below the reporting cutoffs
for both aripiprazole and dehydroaripiprazole. Notably, subject N
demonstrated very dilute urine (i.e., creatinine <10 mg/dL) and
yet, the level of OPC3373 confirmed that subject's adherence to
aripiprazole therapy. Thus, use of OPC3373 as a urine biomarker at
this dose adds value to compliance monitoring for Abilify.RTM..
TABLE-US-00007 TABLE 7 Test Results from Patients Prescribed 15
mg/day Abilify .RTM. Creatinine Specific Dehydro- Sub Day pH
(mg/dL) Gravity Aripiprazole aripiprazole OPC3373 A 1 7.0 64.7
1.008 14.6 6.6 586.4 4 7.6 81.0 1.013 19.0 8.0 586.3 5 6.1 38.6
1.007 9.6 0 333.4 B 1 5.3 242.3 1.025 52.2 27.9 1273.6 4 5.4 225.2
1.024 31.7 16.8 1401.6 5 5.4 260.1 1.027 22.8 12.8 1723.1 C 1 7.8
36.9 1.007 0 0 347.3 4 5.6 35.8 1.006 19.5 7.4 353.5 5 7.1 11.0*
1.002* 0 0 83.6 D 1 7.4 243.4 1.024 5.3 21 2736.7 4 5.2 98.1 1.012
39.3 20.7 814.5 5 7.0 60.3 1.006 0 5.2 335.3 E 1 6.6 255.2 1.014
15.1 10.1 829.8 4 7.7 154.5 1.012 10.2 7.5 431.6 5 8.4 172.5 1.008
16.4 17.0 624.3 F 1 5.2 76.1 1.013 31.2 0 1969.0 4 5.4 115.3 1.014
8.9 0 512.6 5 5.9 171.9 1.016 9.3 0 1113.8 G 1 7.5 22.9 1.003 15.4
5.9 212.8 4 6.0 29.8 1.004 12.3 0 193.6 5 7.4 23.6 1.003 6.9 0
173.2 H 1 5.6 67.5 1.009 17.9 11.4 658.8 4 6.2 29.6 1.004 0 0 213.7
5 5.4 71.6 1.012 32.1 24.1 723.2 I 1 6.2 86.8 1.013 20.0 12.8 474.6
4 6.1 157.9 1.015 40 24 820.2 5 6.1 159.9 1.016 37.1 23.1 973.7 J 1
6.4 274.3 1.020 31.5 25.4 1755.0 4 6.0 21.1 1.003 0 0 77.1 5 6.5
249.4 1.014 16.7 23.9 2238.0 K 1 5.3 13.2* 1.002* 0 0 59.1 4 7.1
31.9 1.004 0 0 185.5 5 6.1 79.7 1.011 7.4 0 852.2 L 1 6.4 283.6
1.015 9.8 12.3 354.3 4 6.7 307.4 1.019 26.7 21.0 1208.1 5 5.2 318.2
1.023 57.3 33.3 819.6 M 1 5.4 74.0 1.006 8.9 6.7 214.4 4 6.9 177.4
1.011 0 10.1 842.0 5 5.1 67.0 1.006 12.3 12.3 292.6 N 1 6.8
7.41.sup..dagger. 1.001.sup..dagger. 0 0 0 4 6.5 9.8* 1.002* 0 0
30.3 5 6.4 9.61.sup..dagger. 1.001.sup..dagger. 0 0 33.8 O 1 6.7
229.7 1.024 0 0 891.5 4 7.1 229.9 1.013 0 0 1378.1 5 7.8 169.0
1.011 0 0 615.8 P 1 5.2 31.3 1.004 17.5 6.1 317.8 4 5.1 47.7 1.006
45.3 25.8 612.4 5 4.8 11.7* 1.001* 14.2 0 168.4 Q 1 5.6 137.9 1.012
15.0 5.5 784.0 4 5.6 194.5 1.014 14.5 8.6 1316.1 5 6.1 178.1 1.015
7.5 6.5 1126.1 R 1 6.8 92.0 1.013 10.1 9.6 997.1 4 8.5 17.8* 1.003
6.2 0 112.4 5 5.7 208.5 1.023 17.7 24.1 2372.0 S 1 6.4 97.4 1.018
5.4 5.2 1182.2 4 6.8 86.4 1.019 5.7 8.1 1693.6 5 7.3 139.1 1.022
14.2 11.2 938.0 T 1 7.1 69.4 1.012 19.4 11.4 526.4 4 5.6 63.2 1.009
7.9 0 466.0 5 5.5 132.3 1.016 25.3 16.6 725.7 U 1 6.8 237.3 1.013 0
0 22.5 4 7.2 319.1 1.011 0 0 616.6 5 5.6 178.4 1.019 5.1 0 313.3 V
1 6.9 143.7 1.013 0 5.1 1086.0 4 7.6 98.3 1.010 0 0 559.0 5 7.6
114.6 1.011 0 0.0 742.6 W 1 6.0 172.6 1.014 27.6 14.6 1825.0 4 5.6
182.2 1.017 62.3 14.3 1805.1 5 5.3 138.6 1.015 76.7 24.9 1329.2
*Measurement is below limits for specimen validity parameter;
specimen still valid. .sup..dagger.Invalid sample.
TABLE-US-00008 TABLE 8 Sample Validity and Urine Results Summary at
15 mg/day Abilify .RTM. Creatinine Specific Aripi- Dehydro- pH
(mg/dL) Gravity prazole aripiprazole OPC3373 Avg 6.34 125.18 1.01
15.29 8.76 782.39 Std 0.89 89.22 0.01 16.56 9.29 619.17 Dev n 69.00
Max 8.50 319.10 1.03 76.70 33.30 2736.70 Min 4.80 7.40 1.00 0.00
0.00 0.00
Example 6
[0041] The urine of 37 patients who were prescribed 10 mg of
Abilify.RTM. (aripiprazole) was tested for compliance over 5 days
(Table 9). The data in Table 10 demonstrate the "normal" nature of
the sample validity criteria (i.e., pH, specific gravity, and
creatinine). The preponderance of OPC3373 in the urine as the major
metabolic urine compound is clearly demonstrated in Table 9.
Assuming 111 opportunities to determine the patient to be either
positive or negative for Abilify.RTM. dosing, the use of OPC3373
resulted in 99% correct identification of those taking the
prescribed medicine. Without OPC3373, only 61% were determined to
be positive with patients just being below the reporting cutoffs
for both aripiprazole and dehydroaripiprazole. Thus, use of OPC3373
as a urine biomarker at this dose adds value to compliance
monitoring for Abilify.RTM..
TABLE-US-00009 TABLE 9 Test Results from Patients Prescribed 10
mg/day Abilify .RTM. Creatinine Specific Dehydro- Sub Day pH
(mg/dL) Gravity Aripiprazole aripiprazole OPC3373 A 1 5.7 170.9
1.017 19.5 10.0 1936.3 4 5.8 124.8 1.016 7.6 0 717.3 5 5.8 118.1
1.016 7.6 0 1002 B 1 8.9 91.6 1.017 12.8 5.0 475.1 4 8.5 138.7
1.017 5.9 0 730.9 5 9.1 212.3 1.021 18.6 8.8 1965.3 C 1 6.1 345.1
1.029 16.0 23.7 1555.6 4 6.5 170.7 1.016 5.0 7.0 639.5 5 7.0 80.9
1.008 0 6.6 259.6 D 1 5.6 147.2 1.015 14.9 0 731.9 4 5.8 169.2
1.016 8.7 0 1508.1 5 6.6 215.2 1.015 7.6 0 2397.6 E 1 6.8 90.4
1.013 0 0 86.6 4 7.3 117.5 1.014 0 0 115 5 7.8 126.9 1.006 0 0
163.8 F 1 6.5 45.1 1.005 0 0 155.9 4 5.5 44.2 1.004 4.6 0 147.9 5
5.1 45.0 1.005 0.0 0 169.8 G 1 5.1 93.2 1.011 23.7 13.0 900.6 4 5.0
217.7 1.013 39.0 16.9 2569.1 5 5.1 97.6 1.009 26.2 8.0 1089.0 H 1
5.6 162.4 1.018 58.2 14 2792.7 4 5.8 112.7 1.009 13.8 0.0 1363.5 5
6.1 73.5 1.004 10.2 0 662.9 I 1 5.6 162.4 1.018 58.2 14 2792.7 4
6.1 105.8 1.009 0 5.0 726.0 5 6.0 150.9 1.011 7.3 7.7 1402.4 J 1
5.6 241.8 1.015 15.8 14.3 2443.3 4 6.3 184.5 1.014 0 0 555.7 5 5.2
167.9 1.013 14.2 12.2 540.4 K 1 5.9 189.3 1.013 11.6 0 686.6 4 7.9
165.7 1.010 0 0 165.6 5 8.3 182.6 1.010 0 0 351.4 L 1 8.6 35.5
1.007 0 0 42.3 4 5.2 86.9 1.006 11.7 5.4 310.2 5 5.1 26.4 1.003 7.6
0 70.1 M 1 6.3 60.5 1.004 0 0 187.9 4 5.4 182.0 1.019 0 0 0 5 6.5
156.7 1.016 0 0 469.6 N 1 5.6 152.0 1.016 16.2 0 647.3 4 4.9 10.0*
1.002* 6.3 0 213.9 5 5.2 239.8 1.019 52.0 59.3 1179.8 O 1 5.5 204.1
1.017 19.8 20.3 1033.6 4 5.9 257.0 1.016 6.5 20.7 685.5 5 6.8 161.0
1.014 0 5.5 395.7 P 1 5.7 370.2 1.020 20.9 22.0 907.7 4 6.9 148.2
1.010 0.0 0.0 253.6 5 6.7 127.9 1.010 0 0 267.9 Q 1 6.5 212.8 1.012
0 0 738.6 4 7.2 77.4 1.008 0 0 1053.4 5 7.1 101.9 1.007 0 0 1286.9
R 1 7.1 50.9 1.006 0 0 536.8 4 6.9 32.4 1.003 0 0 78.9 5 7.8 193.4
1.011 6.2 0 813.9 S 1 7.6 156.0 1.005 0 0 532.4 4 5.9 33.7 1.003
14.2 0 124.9 5 5.8 58.0 1.005 21.3 0 221.6 T 1 6.0 101.3 1.007 33.1
6.7 439.6 4 6.8 114.4 1.010 0 0 204.0 5 6.8 196.2 1.011 5.9 8.0
449.1 U 1 5.9 36.8 1.004 0 0 56.0 4 6.5 118.9 1.011 0 0 156.1 5 6.7
143.7 1.007 0 0 275.8 V 1 5.7 378.9 1.017 5.6 9.4 280.5 4 5.1 248.0
1.021 102.7 64.8 4601.6 5 5.9 18.8* 1.002* 7.1 0 227.4 W 1 6.4
10.3* 1.001.sup..dagger. 9.5 0 137.0 4 7.2 60.0 1.008 0 0 260.7 5
6.4 9.3* 1.001 0 0 40.9 X 1 9.3 87.0 0.999 0 0 966.1 4 5.8 131.8
1.011 19.6 12.2 762.2 5 5.7 163.7 1.014 15.6 8.3 762.1 Y 1 5.9
248.5 1.020 28.2 17.2 1429.0 4 5.9 99.6 1.009 6.1 0 201.9 5 6.9
37.3 1.002* 0 0 135.1 Z 1 7.3 48.5 1.003 0 0 119.1 4 6.8 31.6 1.007
0 0 173.1 5 5.0 47.8 1.011 13.8 0 375.3 AA 1 6.6 27.5 1.006 0 0
238.4 4 6.5 144.8 1.011 0 0 255.3 5 7.0 88.6 1.008 0 0 105.5 BB 1
6.7 232.3 1.009 0 0 231.5 4 6.4 177.4 1.015 9.7 5.0 1640.0 5 6.6
158.6 1.014 0 0 1541.0 CC 1 5.3 230.2 1.017 30.9 9.8 1945.9 4 6.8
60.3 1.006 0.0 0.0 166.4 5 6.3 51.9 1.009 0 0 128.8 DD 1 5.6 20.4
1.006 0 0 67.3 4 5.8 130.3 1.012 28.4 24.6 2307.7 5 6.2 29.5 1.002
0 5.9 339.3 EE 1 6.3 59.7 1.006 0 0 132.5 4 5.4 111.9 1.014 19.5
10.7 1090.7 5 5.7 82.3 1.012 18.2 10.5 750 FF 1 5.6 82.0 1.011 19.5
11.2 740.4 4 5.1 208.5 1.018 19.3 21.9 508.3 5 4.9 212.2 1.022 29.2
25.6 663.3 GG 1 6.7 139.5 1.012 7.5 7.9 408.0 4 5.2 18.2* 1.008
74.2 31.6 77.2 5 4.7 26.0 1.009 71.0 30.3 89.2 HH 1 6.8 267.2 1.017
28.7 37.6 2418.1 4 5.9 33.0 1.004 11.2 3.1 221.1 5 5.7 43.8 1.006
10.4 5.9 406.5 II 1 5.6 20.7 1.003 5.5 0 118.0 4 6.5 116.6 1.011 0
0 455.5 5 6.3 183.6 1.014 9.4 11.6 698.4 JJ 1 7.0 101.6 1.013 0 0
454.8 4 7.4 101.2 1.009 0 0 145.0 5 5.4 131.2 1.008 8.3 0 257.9 KK
1 6.1 158.2 1.010 0 0 324.2 4 5.5 209.4 1.019 30.3 5.6 1467.6 5 5.7
176.9 1.019 27.1 12.1 1446.5 *Measurement is below limits for
specimen validity parameter; specimen still valid.
.sup..dagger.Invalid sample.
TABLE-US-00010 TABLE 10 Sample Validity and Urine Results Summary
at 10 mg/day Abilify .RTM. Creatinine Specific Aripi- Dehydro- pH
(mg/dL) Gravity prazole aripiprazole OPC3373 avg 6.27 126.71 1.01
11.67 6.27 718.43 std 0.94 78.55 0.01 17.32 11.13 770.47 dev n 111
Max 9.3 378.9 1.029 102.7 64.8 4601.6 Min 4.7 9.3 0.999 0 0 0
Example 7
[0042] The urine of 25 patients who were prescribed 5 mg of
Abilify.RTM. (aripiprazole) was tested for compliance over 5 days
(Table 11). The data in Table 12 demonstrate the "normal" nature of
the sample validity criteria (i.e., pH, specific gravity, and
creatinine). The preponderance of OPC3373 in the urine as the major
metabolic urine compound is clearly demonstrated in Table 11.
Assuming 75 opportunities to determine the patient to be either
positive or negative for Abilify.RTM. dosing, the use of OPC3373
resulted in 99% correct identification of those taking the
prescribed medicine. Without OPC3373, only 47% were determined to
be positive with patients just being below the reporting cutoffs
for both aripiprazole and dehydroaripiprazole. Thus, use of OPC3373
as a urine biomarker at this lower dose adds a great deal of value
to compliance monitoring for Abilify.RTM..
TABLE-US-00011 TABLE 11 Test Results from Patients Prescribed 5
mg/day Abilify .RTM. Creatinine Specific Dehydro- Sub Day pH
(mg/dL) Gravity Aripiprazole aripiprazole OPC3373 A 1 5.3 45.2
1.006 5.4 0 80.0 4 7.6 147.5 1.010 11.8 0 363.1 5 8.7 204.2
1.001.sup..dagger. 31.6 15.1 1053.3 B 1 5.2 84.1 1.010 10.1 6.6
139.6 4 4.9 103.5 1.010 21.5 10.2 130.4 5 5.1 99.2 1.009 10.2 5.7
152.7 C 1 7.2 94.9 1.013 0 0 148.7 4 5.6 166.2 1.020 11.3 0 377.0 5
8.3 121.2 1.006 5.1 0 531.4 D 1 5.4 203.4 1.016 9 0 972.3 4 5.4
129.1 1.014 6.6 0 520.3 5 5.2 155.4 1.017 7.3 0 233.0 E 1 7.0 12.9*
1.003 0 0 32.8 4 6.7 15.8* 1.003 0.0 0 39.6 5 6.8 23.1 1.004 0 0
59.1 F 1 6.6 61.0 1.006 0 0 355.1 4 6.0 63.4 1.005 5.2 0 695.3 5
6.9 43.0 1.004 0 0 218.3 G 1 6.8 26.8 1.005 0 0 75.0 4 6.8 30.2
1.004 0 0 107.5 5 6.4 36.4 1.005 0 0 92.1 H 1 7.6 149.5 1.008 0 0
179.9 4 7.8 137.1 1.007 0 0 333.6 5 8.9 151.3 1.000* 14.9 5.2 438.5
I 1 4.9 57.8 1.005 7.5 0 69.8 4 7.3 129.7 1.004 0 0 347.1 5 7.5
104.7 1.005 0 0 208.0 J 1 7.3 244.5 1.012 0 0 1123.5 4 7.8 283.3
1.011 0 0 673.9 5 7.0 205.3 1.013 0 0 422.2 K 1 7.0 55.5 1.004 0 0
36.1 4 7.1 39.8 1.003 0 0 18.1 5 6.9 29.6 1.002 0.0 0 29.1 L 1 5.5
88.1 1.014 5.0 0 250.5 4 5.3 163.5 1.014 32.4 17.1 643.5 5 6.0
165.2 1.012 5.3 5.5 528.1 M 1 5.9 64.3 1.008 0 0 211.7 4 5.6 106.6
1.014 0.0 0 293.9 5 7.4 22.3 1.002* 0 0 31.8 N 1 5.6 226.8 1.030
9.7 0 1277.8 4 8.3 83.6 1.016 13.1 0 359.8 5 5.9 126.4 1.023 0 0
492.7 O 1 6.1 45.4 1.010 8.5 0 197.2 4 5.1 79.4 1.013 15.6 8.0
306.3 5 6.3 46.7 1.008 0 0 169.9 P 1 6.5 135.1 1.011 8.8 5.1 941.3
4 6.6 153.9 1.011 6.5 0 1125.4 5 7.2 130.5 1.010 0 0 816.9 Q 1 5.2
138.9 1.015 8.4 7.4 194.7 4 6.5 50.5 1.008 0 0 32.8 5 6.5 41.1
1.007 0 0 28.5 R 1 5.6 15.3* 1.001.sup..dagger. 0 0 65.2 4 5.9 41.6
1.003 0 0 150.5 5 5.1 58.2 1.005 0 0 214.5 S 1 5.2 75.2 1.008 13.1
0 200.2 4 5.4 42.9 1.007 10.3 0 148.4 5 5.5 65.4 1.009 10.1 0 214.5
T 1 5.4 307.9 1.017 6.4 5.3 1015.6 4 7.3 266.3 1.013 7.5 7.5 329.5
5 9.1* 269.1 1.028 0 15.8 538.0 U 1 6.0 139.6 1.016 0 0 174.2 4 5.3
179.2 1.016 6.6 7.4 162.5 5 6.1 146.0 1.014 0 0 272.3 V 1 8.4 80.3
1.003 0 0 112.3 4 7.8 23.1 1.003 0 0 29.7 5 9.0 40.5
0.999.sup..dagger. 0 0 121.7 W 1 6.0 121.0 1.009 0 0 130.8 4 5.5
155.1 1.010 5.5 8.4 253.1 5 5.9 289.5 1.017 12.7 8.2 496.9 X 1 4.9
163.6 1.016 38.4 8.7 476.5 4 4.9 39.2 1.003 9.5 0 57.2 5 5.6 162.0
1.013 9.7 0 385.0 Y 1 5.0 110.8 1.008 0 0 61.0 4 5.2 82.9 1.005 0 0
31.0 5 5.0 139.3 1.010 0 0 57.4 *Measurement is below limits for
specimen validity parameter; specimen still valid.
.sup..dagger.Invalid sample.
TABLE-US-00012 TABLE 12 Sample Validity and Urine Results Summary
at 5 mg/day Abilify .RTM. Creatinine Specific Aripi- Dehydro- pH
(mg/dL) Gravity prazole aripiprazole OPC3373 Avg 6.37 111.16 1.01
5.34 1.96 318.10 Std 1.13 72.96 0.01 7.87 4.05 305.90 Dev n 75 Max
9.1 307.9 1.03 38.4 17.1 1277.8 Min 4.9 12.9 0.999 0 0 18.1
TABLE-US-00013 TABLE 13 Urine drug/metabolite concentrations on
Days 1, 4 and 5 at 5 mg/day Abilify .RTM. Dehydro- Aripiprazole
aripiprazole OPC3373 Day N (%) Positive 4 (80%) 2 (40%) 4 (80%) 1
Mean +/- SD 12.4 +/- 8.8 2.3 +/- 3.2 375.7 +/- 493.1 Median 11.1 0
175 Extremes 0-22.3 0-6.5 0-1214 Day N (%) Positive 2 (40%) 1 (20%)
4 (80%) 4 Mean +/- SD 5.8 +/- 8.0 1.2 +/- 2/7 245.3 +/- 16.5 Median
0 0 228.2 Extremes 0-16.3 0-6.1 0-571.4 Day N (%) Positive 2 (40%)
1 (20%) 4 (80%) 5 Mean +/- SD 6.1 +/- 9.2 1.6 +/- 3/7 216.8 +/-
92.9 Median 0 0 182.4 Extremes 0-18.3 0-8.2 0-493.9
Example 8
[0043] The urine of 15 patients who were prescribed 2 mg of
Abilify.RTM. (aripiprazole) was tested for compliance over 5 days
(Table 14). The data in Table 14 demonstrate the "normal" nature of
the sample validity criteria (i.e., pH, specific gravity, and
creatinine). The preponderance of OPC3373 in the urine as the major
metabolic urine compound is clearly demonstrated in Table 14.
Assuming 45 opportunities to determine the patient to be either
positive or negative for Abilify.RTM. dosing, the use of OPC3373
resulted in 87% correct identification of those taking the
prescribed medicine. Without OPC3373, only 24% were determined to
be positive with patients just being below the reporting cutoffs
for both aripiprazole and dehydroaripiprazole. Thus, use of OPC3373
as a urine biomarker at this lower dose makes compliance monitoring
for Abilify.RTM. possible. Two patients in Table 14 demonstrated
very low levels of creatinine and as is well known in the industry
may have been severely diluted such that in one subject (subject
K), the aripiprazole metabolite, OPC3373, was below levels of
quantitation for all samples collected. However, OPC3373 in subject
M confirmed the subject's adherence to aripirazole therapy despite
the low observed creatinine level.
TABLE-US-00014 TABLE 14 Test Results from Patients Prescribed 2
mg/day Abilify .RTM. Creatinine Specific Dehydro- Sub Day pH
(mg/dL) Gravity Aripiprazole aripiprazole OPC3373 A 1 6.7 175.7
1.025 0 0 196.1 4 8.0 260.4 1.028 0.0 0 451.1 5 5.8 314.4 1.029 0 0
478.7 B 1 5.3 180.5 1.023 9.0 0 174.1 4 5.7 108.9 1.010 0 0 76.5 5
8.9 159.8 1.024 10.5 0 243.0 C 1 6.6 61.2 1.008 0 0 159.2 4 5.9
48.4 1.005 0 0 113.0 5 6.3 39.4 1.003 0 0 85.4 D 1 5.2 170.5 1.022
7.9 0 166.8 4 6.9 53.1 1.016 0 0 194.9 5 8.6 107.8 1.004 30.9 10.7
715.8 E 1 7.0 31.2 1.007 0 0 0 4 6.8 22.2 1.005 0 0 0 5 7.9 25.1
1.003 0 0 0 F 1 5.4 112.0 1.015 0 0 57.0 4 7.0 195.2 1.014 0 0
226.2 5 5.6 182.8 1.017 0 0 257.1 G 1 6.7 49.7 1.005 0 0 37.7 4 8.6
41.2 0.998 0 0 84.8 5 8.8 48.4 0.997 0 0 109.7 H 1 6.3 80.6 1.014 0
0 156.3 4 5.8 84.5 1.007 0 0 211.1 5 6.0 174.6 1.019 6.1 0.0 372.3
I 1 6.2 42.0 1.006 0 0 40.4 4 5.4 116.2 1.011 0 0 250.8 5 6.5 275.5
1.017 0 0 460.4 J 1 5.5 228.6 1.014 0 0 132.3 4 5.2 152.9 1.011 0 0
40.5 5 5.1 153.4 1.014 6.0 0 47.0 K 1 6.2 22.4 1.003 0 0 0.0 4 7.0
17.6* 1.004 0 0 0 5 5.7 27.0 1.005 0 0 0 L 1 5.2 169.4 1.015 0 0
103.1 4 5.3 78.3 1.010 0 0 54.9 5 6.0 286.7 1.014 0 0 328.2 M 1 5.9
41.9 1.006 0 0 43.0 4 6.8 17.9* 1.002* 0 0 31.0 5 5.8 96.8 1.012
11.2 0 198.2 N 1 5.4 172.2 1.018 0 0 240.4 4 7 63.6 1.010 0 0 79.7
5 6.1 140.9 1.011 0 0 144.7 O 1 5.3 77.6 1.008 0 0 104.9 4 4.7 42.1
1.005 0 0 49.4 5 6.5 117.7 1.013 0 0 176.0 *Measurement is below
limits for specimen validity parameter; specimen still valid.
TABLE-US-00015 TABLE 15 Sample Validity and Urine Results Summary
at 2 mg/day Abilify .RTM. Creatinine Specific Aripi- Dehydro- pH
(mg/dL) Gravity prazole aripiprazole OPC3373 Avg 6.32 112.63 1.01
1.81 0.24 157.59 Std 1.05 79.79 0.01 5.35 1.60 151.65 Dev n 45 Max
8.9 314.4 1.029 30.9 10.7 715.8 Min 4.7 17.6 0.997 0 0 0
TABLE-US-00016 TABLE 16 Urine drug/metabolite concentrations on
Days 1, 4 and 5 at 2 mg/day Abilify .RTM. Dehydro- Aripiprazole
aripiprazole OPC3373 Day 1 N (%) Positive 8 (53%) 1 (7%) 15 (100%)
Mean +/- SD 5.1 +/- 5.7 0.5 +/- 1.9 186.1 +/- 183.8 Median 5.8 0
122.2 Extremes 0-17.4 0-7.4 63.6-649.8 Day 4 N (%) Positive 8 (53%)
0 (0%) 15 (100%) Mean +/- SD 5.0 +/- 5.9 0 +/- 0 248.6 +/- 195.1
Median 5.8 0 197.1 Extremes 0-18.3 0-0 55-820.5 Day 5 N (%)
Positive 7 (47%) 0 (0%) 14 (93%) Mean +/- SD 4.1 +/- 4.9 0 +/- 0
194.9 +/- 235.2 Median 0 0 182.4 Extremes 0-12.8 0-0 0-493.9
[0044] Thus, in separate populations (e.g., different dose groups),
the use of OPC3373 to monitor patient adherence is more sensitive
than using the more commonly available and predicted compounds
aripiprazole and dehydroaripiprazole. Indeed, without using
OPC3373, 5 out of 22 patients in the first study and 1 out of 6
patients in the second study would have been incorrectly identified
as "negative" while at a dosage of 2 mg/day, only 24% of the
patients would be correctly identified as taking their
medicine.
* * * * *