Study title: Twelve-month oral toxicity study of iloperidone in dogs (Study 0992-
`0220)
`
`'
`
`Key study findings:
`Iloperidone was administered orally to beagle dogs (4/sex/dose) at 6, l2, and 24 mg/kg/d
`for 12 months. There was no drug-related mortality. Drug-related clinical signs were
`noted at all dosages and included decreased spontaneous activity,
`tremors, bizarre
`behaviors, labored breathing, scleral infection, ptosis; slow response times and/or lack of
`pupillary reflex were revealed at neurological examination. Most of the clinical signs
`were noted in all
`treated animals and showed little dose dependence. Drug-related
`findings in the mid- and high—dose groups that were not seen in the low dose group
`included ataxia, loss of righting and toe pinch reflex (in single animals), emaciation.
`Body weight losses occurred in LD and HD groups; mean body weight decreases of 7.3%
`and 9.2% vs. control were registered over the treatment period at LD and HD,
`respectively. Hematology and clinical chemistry changes were induced at MD and HD,
`i.e., dose—dependent decreases in mean erythrocyte count and in hemoglobin and
`, hematocrit levels in males and females; lower cholesterol and triglyceride levels in the
`females throughout the dosing period, and increase in alanin aminotransferase in HD
`males. No abnormalities were found in any dose group on ECG and auditory
`examination.
`
`Drug-related gross and microscopic pathology changes were not found in LD and MD
`groups;
`in' the HD group, higher mean absolute and relative liver weights and
`hepatocellular hypertrophy resulting fiom proliferation of the endoplasmic reticulum
`were found in the males, probably secondary to liver enzyme induction .
`_
`The toxicokinetic analysis showed that mean plasma concentrations of iloperidone at
`week 49 were 5.0, 4.3, and 29.7 ng/ml for males, and BLQ, 29.7 ng/ml, and 119.8 lng/ml
`for females, at 6, 12 and 24 mg/kg/d, respectively, pointing to an over dose-proportional
`increase in plasma concentrations in the females. The principal metabolite was P89 9430,
`which was detected at higher levels than iloperidone, while P89 9124 and P88 899] were
`below the limits of quantification.
`The MTD in this study is 6 mg/kg/d in view of severe clinical signs and emaciation
`induced. at and above the next higher dose of 12 mg/kg/d.
`A NOAEL was not reached in this study as the lowest dose induced decreased body
`weight and neurological clinical signs.
`
`Study no: 0992-0220
`Volume # and page #: N.A. (electronic submission)
`Conducting laboratory and location: Drug Safety, Hoechst-Roussel Pharmaceuticals
`Inc, Somerville, NJ
`'
`Date of study initiation: June 16, 1992
`GLP compliance: Yes
`QA report: yes
`Drug, lot #, radiolabel, and % purity: Batch/Lot RC 4840, Purity 99.8%;
`Batch RC 5634, Purity>99.1 %
`
`Formulation/vehicle: gelatin capsules
`
`89
`
`

`

`Methods: Iloperidone was administered orally in gelatin capsules to male and female
`beagle dogs at 6, 12, and 24 mg/kg/d (4/sex/dose) for 12 months. A control group
`received capsules containing microcrystalline cellulose.
`Dosing:
`Species/strain: Dog/Beagle
`#/sex/group or time point (main study): 4
`Satellite groups used for toxicokinetics or recovery: TK analysis performed on all
`main study dogs; recovery not studied.
`Age: 13—36 months
`Weight:
`Doses in administered units: 6, 12, and 24 mg/kg/d ~
`Route, form, volume, and infusion rate: orally in gelatin capsules
`Observations and times:
`.
`Parameters evaluated for adverse effects included mortality, general condition and
`clinical signs, body weight, food consumption, neurological (righting reflex, placing
`reflex
`and
`pinch
`toe
`reflex),
`auditory
`and
`ophthalmoscopic
`examination,
`electrocardiography (ECG tracings of Lead II in conscious dogs from all groups recorded
`at baseline and at weeks 13, 26, and 53) , hematology, serum chemistry, urinalysis, organ
`weights, gross and microscopic pathology, and electron microscopic examination of
`livers (high dose group only). TK analysis was performed on blood samples collected
`from all dogs at 4 hours post-dose on the first day of dosing and again during the last
`month of dosing (Week 49).
`
`Results: No spontaneous mortality occurred in this study.
`Clinical signs: Drug-related clinical signs noted at all dosages included decreased
`spontaneous activity and/or crouching posture, intermittent tremors, starting during the lSt
`month of treatment, with a dose-related incidence, highest at HD, bizarre behaviors
`(sniffing, chewing, pawing, nose—jamming, circling, jumping at cage walls, jerking head
`about, aggressive barking when disturbed, stereotypy) in 2, 2 and 6 animals at LD, MD
`and HD, respectively; labored breathing (in 2, 2, and 4 animals at LD, MD and HD,
`respectively), scleral
`infection, eyelid ptosis (all dose groups), prolapsed nictitating
`membranes, and glassy eyes. Most of these signs were noted in all treated animals and
`showed little dose dependence. Drug—related findings in the mid- and high-dose groups
`that were not seen in the low dose group included ataxia and or lethargy (1 MDF, 1 HDM
`and l HDF), loss ofrighting and toe pinch reflex (in single MD and HD animals)
`Body weights: Body weight losses occurred primarily during the latter half of the
`study (weeks 28 through 39) in LD and HD groups; mean body weight decreases of 7.3%
`and 9.2% in males vs. control were registered at LD and HD, respectively (see sponsor’s
`table on the next page). Emaciation was noted after the 2nd month of dosing in 2 MD
`animals (1M, 1 F) and in 4 HD animals (3M, 1F).
`Food consumption: The relative mean food consumption (as shown in sponsor’s
`table following the body weight table) was decreased in LD (males) at weeks 4 and 29;
`and in HD (females) at weeks 0 through 6. During the rest of the study,
`the food
`consumption values were comparable to control.
`'
`
`90
`
`

`

`Mean body weights (kg)
`mmmmmcmmwwmmmas
`
`mm-mamzms INC. 31W “LOW—020
`
`'-
`
`-.
`
`-
`
`.
`
`'
`
`.
`
`.
`
`TEST
`MES: DAILY IDSE nu m
`MALES: DAILY DOSE II 16/!!!
`
`
`HEEK
`0
`6
`12
`24
`24
`6
`0
`12
`m:
`11.0
`9.2
`9.3
`9.9
`11.3
`10.9
`14.0
`10.7
`0
`10.8
`9.0
`9.0
`9.5
`10.9
`10.5
`13.7
`10.4
`1
`10.7
`8.7
`8.9
`9.1
`10.5
`10.4
`13.5 1*
`10.2
`2
`11.0
`9.0
`9.2
`9.3
`10.7
`10.6
`13.7 1'
`10.2
`3
`10.9
`8.9
`0.8
`9.0
`10.4
`10.4
`13.4 t
`9.9
`4
`10.9
`9.1
`8.8
`9.2
`10.4
`10.7
`13.1
`10.1
`5
`11.0 '
`9.1
`- 9.0
`9.2
`10.6
`10.9
`13.4
`10.1 ‘
`0
`11.1
`9.2
`. 9.1
`9.1
`4.10.7
`10.9
`13.3
`10.2
`7
`11.2
`. 9.4
`9.4
`9.4
`10.9
`11.1
`13.6
`10.5
`B
`11.4
`9.5
`9.5
`‘ 9.4
`‘ 10.9
`11.2
`13.7
`10.7
`9
`11.3
`. 9.4
`9.3
`. 9.4
`11.1
`11.2
`13.7
`10.7
`10
`11.4
`9.5
`. 9.4
`9.0
`10.9
`11.5
`- 13.4
`10.7
`11
`11.4
`9.7
`9.4
`9.3
`.. 11.0.
`11.4
`13.5
`10.0
`12 '
`11.6 ‘
`10.0
`9.0 ‘
`9.7
`_ 11.2
`11.6
`13.0
`10.0
`13
`11.6
`9.7 '
`9.4
`9.6
`11.0
`11.4
`- 13.4
`10.7
`14
`11.6
`» 9.6.
`' 9.4
`9.3
`11.0
`11.3
`13.6
`510.7
`15
`11.4
`9.5
`. 9.2
`9.7 .
`10.9
`10.9
`13.2
`10.0
`10
`11.3 '
`9.7
`9.5
`, 9.9
`11.0 .
`11.2
`.13.;
`10.0“
`17
`11.3
`~9.5
`"9.5
`9.7'
`11.0
`11.1
`' 13.0
`‘ 10.0
`18
`11.6
`9.6
`9.7
`.10.1
`11.0
`11.3
`13.6
`. 10.8
`19
`11.4
`9.0
`9.0
`10.0
`10.7
`11.2
`1.3.5
`10.9
`20
`11.4
`9.7
`9.7
`10.0
`10.0
`11.3
`13.5
`10.0
`21
`11.4
`9.7
`9.6
`9.9
`10.7 '
`11.2
`13.7
`10.9
`22
`11.6
`9.7
`9.7
`10.0
`10.9
`11.5
`13.6
`11.0
`23 '
`11.6
`10.0
`9.8
`10.0
`10.0
`11.5
`13.7
`11.0
`24
`11.6
`9.7
`9.6
`10.0
`10.0
`11.7
`13.0
`11.0
`25
`11.0
`9.8
`9.7
`10.0
`10.0
`11.5
`13.7
`11.1
`20
`11.7
`9.7
`9.0
`9.9
`10.7
`11.3
`13.0
`11.1
`91
`11.0
`9.8
`9.6
`9.8
`10.4
`11.:
`1.9.4
`10.7
`28
`11.0
`9.9
`9.9
`9.9
`10.2
`11.6
`13.6
`10.9
`29
`11.5
`9.6
`9.9
`9.8
`10.3
`11.4
`13.1
`10.7
`30
`11.6
`9.0
`10.0
`10.1
`10.6
`11.4
`13.1
`10.8
`31
`11.5
`9.7 .
`9.6
`9.7
`10.2
`11.3
`13.1
`10.8
`32
`11.4
`9.0
`9.7
`9.6
`10.4
`11.3
`13.2
`10.9
`33
`11.0
`9.7
`9.0
`9.0
`10.0
`11.0
`13.1
`10.6
`34
`11.0
`9.5
`9.3
`9.0
`10.4
`11.5
`13.2
`10.5
`35
`11.5
`9.6
`9.0
`9.6
`10.4
`11.4
`13.2
`10.3
`36
`11.6
`. 9.6
`0.9
`9.3
`10.3
`11.6
`13.5
`10.6
`37
`11.9
`9.6
`9.3
`9.4
`10.0
`11.5
`13.1
`10.5
`38
`11.8
`9.5
`9.3
`9.7
`10.0
`11.4
`13.1
`10.6
`39
`11.0
`9.5
`9.0
`9.4
`9.5
`11.5
`13.0
`10.0
`40 .
`‘ 12.0
`9.6
`9.1
`9.4
`9.7
`11.7
`13.3
`10.0
`41
`12.1
`9.3
`9.0
`9.4
`9.7
`11.7
`13.3
`10.0
`42
`12.3
`9.0
`9.0
`9.4
`9.6
`11.8
`13.1
`10.7
`43
`12.5
`9.9
`9.1
`9.3
`9.7
`12.1
`13.5
`10.7
`44
`12.3
`9.0
`9.3
`9.6
`9.6
`12.0
`13.0
`10.9
`45
`12.4
`9.6
`9.5
`9.4
`9.7
`12.1
`13.4
`10.9
`46 '
`12.3
`9.9
`9.0
`9.9
`9.6
`12.1
`13.5
`11.2
`47
`12.2
`9.0
`9.5
`9.0
`9.0
`12.1
`13.2
`10.9
`48
`12.4
`10.0
`9.6
`9.5
`10.1
`12.0
`13.4
`11.1
`49
`12.0
`10.2
`9.5
`9.5
`9.9
`12.2
`12.0
`10.6
`50
`12.0
`12.9
`10.7
`10.0
`12.4
`10.1
`9.1
`9.3
`51
`10.9
`9.9
`12.5
`10.1
`9.0
`9.6
`12.1
`13.2
`
`._ “_
`_§2
`10.7
`9.9
`_1_2.6
`10.0
`9.3
`9.6
`_11.9
`12.3-
`Il-4VALIES DRLES PEIFEANAS IDICATEIN‘MEIJDMWALDATA
`' - SIWIFICANTLY DIFFERB" FEM 000m. 0741.05)
`
`‘
`
`,
`
`,_
`
`‘
`
`.
`
`.
`
`
`
`Weight Changes (kg)
`
`
`
`WIGIT ONES
`CHEERS)
`
`MALE: DAILY DOSE Ill W
`59013: DAILY RISE 19 16/3
`
`0
`6
`12
`24
`0
`6
`12
`
`24
`
`0 - 26
`
`0 — 52
`
`0.8
`1.4
`
`—0.1
`-1.0
`
`0.7
`0.3
`
`-0.2
`-1.0
`
`0.9
`1.0
`
`0.7
`1.0
`
`0.4
`0.8
` um.
`0.3
`0.1
`
`91
`
`

`

`HEM Fl!" “"9“"!!! VRUIEI - UPTAIECSHIII" HEIEIIHIGIIAIIHAL M‘I
`WELVE-Hlll'l‘ll MAI. 1031611? 9"" IF I" 313 1' ID“
`.....--...-----....—--.-n--.n-..---~.---u--..¢~.-.---n-~.¢—.m------_-.u.-u----nw-mnnum-—u-u--—u----.--u
`9911.1 999: 19 999/99
`99199199:
`1291
`.
`9191.99:
`99119 999: 99 91:19:
`29
`29
`9:99
`9
`9
`92
`9
`9
`12
`21.9
`12.9
`9
`19.9
`19.9
`22.9 9
`29.9
`11.9
`19.9
`22.9
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`9
`29.2
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`29.1
`29.9
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`22.9
`29.9
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`29.9
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`29.9
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`9
`29.9
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`29.9
`21.9
`99.9
`9
`29.2
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`21.1
`99.1
`29.9
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`9
`29.9
`19.9
`99.2
`29.9
`21.1
`29.2
`21.9
`22.9
`1
`29.9
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`29.9
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`9
`29.1
`21.9
`99.9
`21.9
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`29.9
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`29.9
`22.9
`29.9
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`29 .1
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`19
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`29.1
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`21.9
`21.9
`12
`99.9
`29.9
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`19
`29 .9
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`29.9 9
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`19‘
`29.1
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`29.9
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`22.9
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`19
`19.9
`“219.9
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`19.9
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`19
`29.9
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`29.9
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`22.9
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`29.9 ‘
`29.9
`11
`29.9_
`229.1
`'29.9_
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`21.9
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`99
`29.9
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`29
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`19.9
`19.9
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`29.1
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`91
`29.9
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`29.9
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`99.9
`29.1
`29.2
`92
`22.1
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`_21.2
`21.9
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`29.9
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`29.1
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`99.9
`22.9
`29.2
`99
`22.9
`29.1
`99.9 9
`19.1
`29.9
`29.9
`29.9
`29.9
`91
`21.1
`99.2
`99.1
`29.9
`29.9
`29.1
`21.9
`91.2 9
`99
`21.9
`29.1
`29.9 9
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`29.9
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`99
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`22.9
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`11.1
`91.9 9
`29.1
`21.1
`29.9
`21.1
`29.9
`91
`21.1
`29.9
`29.1
`29.9
`29.9
`29.9
`29.9
`21.2
`92
`19.1
`11.9
`29.9
`21.9
`21.9
`99.9
`29.9
`‘ VALUES II LEI! PEI 9299 kl “IRATE! II THE IIIIUIIIMI. DAM
`SIBIIFIBIITU NFFEIEII FRI” EDITRGL (NO-l5!
`Neurology and auditory examination: Pupillary light responses were slow or non-
`apparent in all treated males and females; this finding occurred earlier at HD (month 1 as
`compared to month 3 for LD and MD) and the frequency of occurrence was highest at the
`HD. The righting reflex was slow or absent in single animals from LD and MD groups,
`V and the placement reflex andlthe toe—pinch reflex were absent in single females from MD
`and HD groups. Auditory tests were not remarkable.
`.
`Ophthalmoscopy: On indirect ophthalmoscopy no ocular abnormalities were
`
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`found.
`
`Electrocardiography: Electrocardiographic analysis of ECG tracings by a
`veterinary cardiologist did not show drug-related changes in the parameters evaluated,
`
`92
`
`

`

`i.e., average heart rate, rhythm, P-QRS wave amplitude and duration, P-R interval, Q-T
`interval, ST segment and T-wave.
`'
`.
`Hematology: Mean erythrocyte count, hemoglobin and hematocrit were decreased
`dose-dependently in both genders at MD and HD (significantly different only for
`erythrocyte count in HDM).
`
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`
`Clinical chemistry and Urinalysis:
`Drug-related differences in clinical chemistry (as shown in the sponsor’s table below)
`included cholesterol and triglyceride levels in females, that were lower than control
`values throughout the study (weeks 4, 14, 26, and 52), statistically significant at MD and
`HD. Other differences in serum chemistry included sporadically higher mean alanine
`aminotransferase values in all groups (statistically significant at MD (M and F) at week
`26 and at HD (M) at week 52) and lower alkaline phosphatase values in LD and HD
`males at week 14. These differences were variable, not dose-related and did not have
`histological correlates. Iron values were moderately increased in LDM and HDF at week
`52; no dose-related trends were seen.
`There were no drug-related findings in the urinalysis data.
`
`93
`
`

`

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`Organ weights: No statistically significant differences in mean organ weights
`were registered. Higher mean absolute and relative liver weights were seen in HD males.
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`94
`
`

`

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`Pathomorphological examination: All specified organs and tissues from the
`control and HD groups were stained with H&E and examined microscopically. These
`tissues included:
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`The microscopic examination of H&E stained tissues of LD and MD groups was limited
`to the liver, heart, adrenal glands, bone marrow, and tissues with gross lesions. In
`addition, liver, kidney and spleen sections stained with the periodic acid—Schiff (PAS)
`technique, and liver sections stained with oil-red-O (0R0) were processed and examined
`from all animals in all groups. Electron microscopic evaluation was performed on liver
`samples from the control and HD groups.
`Gross pathology: Compound-related gross alterations were not observed.
`Histopathology: “Minimal to mild” enlargement of hepatocytes was foundin all
`HD males, but the special staining did not demonstrate an increase in neutral fat or
`glycogen. These findings were “consistent with hepatocellular hypertrophy induced1n
`HD males presumably resulting from a proliferation of cellular organelles,
`i.e.,
`the
`endoplasmic reticulum”. This was confirmed by the ultrastructural examination of liver
`which indicated moderate to marked proliferation of the smooth endoplasmic reticulum
`in HD males. The amount of the smooth endoplasmic reticulum in hepatocytes of HD
`males was increased 2-fold vs. controls, and “in many regions it appeared to supplant
`other cellular organelles”. No such changes were observed in the HD females. The
`hepatocellular hypertrophy and smooth endoplasmic reticular proliferation may be an
`indication of metabolic enzyme induction1n the HD males. No neoplastic lesions were
`found.
`
`Toxicokinetics:
`PLASIAA CONCENTRATIONS OF HP 873 AND "’3 METABOLI’I'ES
`
`
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`
`95
`
`

`

`The TK analysis showed that the mean plasma concentrations of iloperidone at week 49
`were 5.0, 4.3, and 29.7 ng/ml for males, and BLQ, 29.7 ng/ml, and 119.8 ng/ml for
`females, at 6, 12 and 24 mg/kg/d, respectively. Plasma concentrations in the females
`increased over dose-proportionally. The principal metabolite was P89 9430, which was
`detected at higher levels than iloperidone, while P89 9124 and P88 8991 were generally
`below the limits of quantification.
`Conclusion: The MTD in this study is 6 mg/kg/d in view of the severe clinical signs
`(ataxia, emaciation) at the next higher dose of 12 mg/kg/d. NOAEL was not reached as
`the lowest dose induced decreased body weight and neurological clinical signs.
`
`Summary of individual study findings: A summary of the findings ofthis study is
`presented the ,fOIIQWing sponsorfs table. .
`_
`.
`Repeat-dose toxicity (12-month oral study in dogs) (pivotal study)
`
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`PmdnuEnl-aflnNo. Evaluated:
`
`-- No findings ofnote.
`* Significantly different from control (P < 0.05 by Dunnett’s 2-sided multiple comparisons test).
`a No statistically significant differences from control in mean individual organ weights.
`ND = not done; RBC = red blood cell count; Hct = hematocrit; AST = aspartate aminotransferase.
`
`96
`
`

`

`Repeat-dose studies conducted with iloperidone metabolite P95
`Summa_ry: The repeat oral dose toxicity of iloperidone metabolite P95 was evaluated in 4
`studies: a 4-week study in mice (Study 0170087), a 13-week study with 4-week recovery
`(Study 007008) in Wistar rats, a 13-week dose range-finding study in Sprague-Dawley
`(CD) rats, and a 26-week study with 4-week recovery stUdy in Wistar rats (Study
`017013). The design and noteworthy findings of these studies are summarized in the
`sponsor’s table below. Among these studies, the pivotal one is the 26-week study in rats.
`Summary of P95 repeat-dose toxicity studies
`
`:: allFat'lSO, allMat750—>500 '
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`Wthedosn—
`
`97
`
`

`

`Summary of P95 repeat-dose toxicity studies (continued)
`
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`
`
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`
`
`proportionally with dose; no-
`sex-related differences;
`
`expom 1‘ overtime.
`ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN= blood urea nitrogen,
`
`
`
`
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`
`
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`
`
`98
`
`

`

`The predominant clinical signs associated with P95 were similar to those seen with
`iloperidone, and included ptosis, relaxed scrotum, relaxed vaginal opening, and decreased
`spontaneous motor activity. An MTD of P95 in the 26-Week study in Wistar rats was not
`reached in females; in males it was less than 500 mg/kg/d (due to body weight loss and
`mortality at 500 mg/kg/d). A NOAEL was not reached, as morphological changes in both
`genders were induced at the lowest P95 dose tested. The target tissue effects were in the
`mammary gland, uterus/vagina, adrenals, and thyroid; some of these effects were likely
`_ to be pharmacologically mediated. Drug-related histopathology changes, demonstrable by
`routine histology and/or immunohistochemical method (BrdU labeling), were induced in
`endocrine glands (pituitary and adrenals in males, thyroid in females, and pancreas in
`both genders), mammary gland (both genders) and reproductive organs (ovary, uterus,
`testes, prostate). Most of these histopathology deviations (with. the exception of the
`pancreatic, adrenal, and testicular pathology) were induced dose-dependently at both '
`tested dose levels of P95, eor're'sponding at LD to plasma exposure (AUG 0-24)
`"
`- approximately 2 to 3x the human exposure at MRI-1D of 12 mg twice dailygIn ‘the"2-6-'
`week P95 study, histOlog'iCal' evidence of hyperplasia'and/or pro1iferation as assessed by '
`BrdU labeling-was found in 5 tissues: mammary gland, pituitary, endocrine pancreas,-
`thyroid,vand ovary. As BrdU'labeling was not performed in any of iloperidone repeat-
`dose toxicity studies, no comparisonof these findings can .be made to iloperidone, The
`morhologic pathology findings for iloperidone (by routine histology) were limited to -
`mammary gland epithelial vacuolization in both genders at all dose levels with dose-
`related incidence and
`severity, dose—related reduced size of testicles and testicular
`degeneration/atrophy (in single animals) and higher incidence of prostate inflammation at
`HD.
`
`.4
`
`,
`
`An additional 13-week study was performed in Sprague-Dawley (CD) rats to assess strain
`differences in preparation for a carcinogenicity study, as all of the general toxicity studies
`in rats with the parent iloperidone were conducted with Sprague-Dawley rats. In this
`study, at all doses, effects on potential pharmacological
`targets (mammary gland,
`reproductive organs, adrenal) were similar to those seen with Wistar rats. However, at the
`top dose of 500 mg/kg/d, mortalities and toxic effects on the biliary system (biliary
`obstruction)
`and the kidney (tubular degeneration) with
`secondary systemic
`mineralization due to electrolyte imbalances were seen. The overall pathogenesis was
`Compatible with incompetent metabolism and excretion of P95 by the hepatobiliary
`system with development of local toxicity, increased renal excretion with toxic effects on
`tubules and other renal components, and systemic deposition of mineral secondary to
`electrolyte imbalances. Sprague—Dawley rats appeared to be more susceptible to these
`effects than Wistar rats, as the exposures achieved in Sprague—Dawley rats at comparable '
`doses were lower, yet associated with a significant increase in toxicity.
`The pivotal 26-week study in Wistar rats was previously reviewed by this reviewer under '
`IND 36827, SN 207 of 8/23/2002, review dated 07/14/2007. Relevant parts of the review
`are reproduced on the next pages.
`
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`Study title: Iloperidone metabolite P95 12113 26-week oral (gavage) toxicity study in
`rats with a 4-week recovery period
`for 6 months to
`Key study findings: Administration of iloperidone metabolite P95
`Wistar rats at oral (gavage) doses of 50 and 500 mg/kg/day (yielding P95 plasma exposures of
`about 2 to 3x and 150 to 400x, respectively, the human P95AUC at iloperidone MRHD of 24
`mgd), induced dose-dependent clinical signs at both dose levels throughout the entire treatment
`period, indicative of CNS depression and relaxation (ptosis, decreased motor activity, relaxation
`of the scrotum, anus, vaginal opening) that are attributable to exaggerated pharmacological effect.
`At HD, there was one possibly treatment-related death (1 HDM) on day 123 (the cause of death
`could not be determined). Body weight and weight gain decrease (not due to reduced food
`intake) was induced at HD in males only (by 1 1% and 26%, respectively vs. control by the end of
`treatment); the decrease was not compensated during the recovery period. There were no drug—
`related abnormal findings in hematology, clinical chemistry (including prolactin plasma levels),
`or urine analysis. Drug-related histopathology changes, demonstrable by routine histology and/or
`immunohistochemical method (BrdU labeling) were induced in endocrine glands (pituitary and
`adrenals in males, thyroid in females, and pancreas in both genders), mammary gland (both
`genders) and reproductive organs (ovary, uterus, testes, prostate). In females, dose—dependent
`cycle prolongation occurred at both LD and HD, consistent with the finding of vaginal epithelium
`mucification and decreased uterine weight in the treated grOUps. In the ovaries, a dose-related
`interstitial cell hyperplasia was observed at LD and HD that was likely‘associated with. the
`reduced estrus cycle activity. After the recovery period the prolongation of estrus cycle did not
`fully normalize, and increased corpora lutea were observed in the ovaries of HDF, concordant
`with increased ovarian weight. In the thyroid, diffuse follicular hyperplasia was induced in both
`LDF and HDF; this finding did not normalize after the recovery period. In males, pituitary
`changes were induced at both tested doses, while adrenal, testicular and secondary sex organ
`pathology was seen at l-ID only. Pituitary histopathology (decreased eosinophilia of the acidophil'
`cells of the distal part of the pituitary) was noted in both LDM and HDM with a dose-related
`incidence. These morphological findings were supported by an increase in the cell proliferation
`index in male pituitary at all time points, consistent with the increased pituitary weight. Adrenal
`morphological changes as well as testicular and secondary sex organ pathology occurred in HD
`males only. In the adrenals, an increased incidence of diffuse cortical hypertrophy and reduced
`cortical cytoplasmic vacuolation was seen in HDM;
`this finding was concordant with the
`increased absolute and relative adrenal weight and was reversible after the recovery period.
`Atrophy of testicular seminiferous tubule epithelium (in 2 animals) and an increased incidence of
`mixed cell inflammation of prostate gland with associated degenerative changes were found at
`I-ID. Prostate changes were reversible after the recovery period.
`In both genders, increased
`cellular proliferation in the mammary gland (alveolar hyperplasia,
`increased secretion and
`dilatation of mammary ducts) occurred with dose-related severity at LD and HD during treatment
`and even after recovery period. Statistically significant,
`treatment-related increase in cell
`proliferation (increased proportion of cells in S phase of the cell cycle, as assessed by BrdU
`labeling) was found in pituitary (LDM and HDM), mammary gland (duct and alveoli) in both
`genders (LDM, HDM, HDF), and the endocrine pancreas in both genders (HDM, HDF). Most of
`these histopathology deviations (with the exception of the adrenal, testicular and secondary sex
`organ pathology in males) were induced in a dose-dependent manner at both tested dose levels,
`corresponding at LD to plasma exposure (AUC 0—24) approximately 2 to 3x the human exposure
`at MRHD of 12 mg twice daily.
`An NOAEL was not reached in either male or female rats in View of the presence of
`pathomorphological changes in multiple organs/tissues at the lowest tested dose of 50 mg/kg/day.
`The MTD was <500 mg/kg/day for males in View of mortality and body weight decrease at 500
`mg/kg/day; for females, an MTD was not reached.
`
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`Study no: 017013
`Conducting laboratory and location: Novartis Pharmaceuticals Corporation, East
`Hanover, NJ
`‘ Date of study initiation: Feb 16, 2001
`GLP compliance: Yes; QA report: yes
`Drug, lot #, radiolabel, and % purity: Iloperidone metabolite P95 12113, batch
`#011983, purity 99.8%
`Formulation/vehicle: 0.5% carboxymethylcellulose
`
`Methods (unique aspects): Immunohistochemical staining for assessment of cell
`proliferation in selected tissues (endocrine pancreas, liver, pituitary, and
`mammary gland)
`Dosing:
`Species/strain: IGS Wistar Hannover rats
`#/sex/group or time point (main study): 40
`Satellite groups used for toxicokinetics or recovery: 10 sex/group
`Age: 9 weeks
`Weight: Males: 247-304 g; Females: 171-201 g.
`Doses in administered units: 0, 50 and 500 mg/kg/day
`Route, form, volume, and infusion rate: oral gavage, suspension in 0.5% carboxy-
`methylcellulose, dosing volume '5 ml/kg
`The dose selection was based upon the results of a 13-week oral (gavage) toxicity study
`in rats with a 4-week recovery period (study 007008) that employed P95 12113 doses of
`50, 200 and 500 mg/kg/day. In the 13-week study, P95 12113 produced “microscopic
`alterations in the mammary gland consistent with induction of secretion in both sexes” at
`doses 2200 mg/kg/day, as well as adrenal cortical hyperthrophy and increase in plasma
`prolactin in males at 500 mg/kg/day (prolactin increase and microscopic changes were
`reversible).
`Observations and times:
`
`- Mortality and clinical signs (twice daily)
`- Body weight and food consumption (weekly during dosing wks 1- 14 and recovery; every 2 wks
`during dosing weeks 16-26)
`- Ophthalmology (pre—test: all groups; Wk 12 and 24: HD and control animals)
`- Clinical chemistry — routi