CENTER FOR DRUG EVALUATION AND
`
`- RESEARCH
`
`APPLICA TION NUMBER:
`
`2 2 - l 92
`
`PHARMACOLOGY REVIEW
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY REVIEW AND EVALUATION
`
`NDA NUMBER/ SERIAL NUMBER:
`
`22-192 / N-0000
`
`DATE RECEIVED BY CENTER:
`
`9/27/2007
`
`PRODUCT:
`
`Iloperidone
`
`INTENDED CLINICAL POPULATION:
`SPONSOR:
`
`Adults with schizophrenia
`Vanda Pharmaceuticals
`
`DOCUMENTS REVIEWED:
`
`REVIEW DIVISION:
`
`PHARM/I‘OX REVIEWER:
`
`PHARM/TOX SUPERVISOR:
`DIVISION DIRECTOR:
`PROJECT MANAGER:
`
`'
`
`Division of Psychiatry Drug Products (HEB-130)
`
`Sonia Tabacova, Ph.D.
`
`Barry Rosloff, Ph.D.
`Thomas Laughren, M.D.
`Kimberly Updegraff, R.Ph.
`
`Date of review submission to Division File System (DFS): 6/30/2008
`
`

`

`TABLE OF CONTENTS
`
`EHCUTIVE SUD/[MARY
`
`................................. 3
`
`2.6 PHARMACOLOGY/'1‘OXICOLOGY REVIEW ................................................. 11
`
`2.6.]
`
`INTRODUCTION AND DRUG HISTORY................................................................. 11
`
`2.6.2 PHARMACOLOGY....................................................................................................... 13
`2.6.2.1
`Brief summary ...................................................................................................................... l3
`26.2.2
`Primary pharmacodynamics ................................................................................................. 15
`2.6.2.3
`Secondary pharmacodynamics ............................................................................................. 26
`2.6.2.4
`Safety pharmacology .......................................................
`
`................................................... 36
`2.6.2.5
`Pharmacodynamic drug interactions .............................
`
`2.6.3 PHARMACOLOGY TABITLATED SUMMARY....................................................... 40
`
`.................. 44
`2.6.4 PHARMACOKINETICS/TOXICOKINETICS
`2.6.4.1
`Brief summary ...................................................................................................................... 44
`
`2.6.4.2
`Methods of Analysis .......
`2.6.4.3
`Absorption ............................................................................................................................ 47
`2.6.4.4
`Distribution ........................................................................................................................... 51
`
`Metabolism ........................................................................................................................ 54
`2.6.4.5
`2.6.4.6
`Excretion............................................................................................................................... 62
`2.6.4.7
`Pharmacokinetic drug interactions........................................................................................ 64
`2.6.4.8
`Other Pharmacokinetic Studies ........................................................ 64
`2.6.4.9
`Discussion and Conclusions ................................................................................................. 64
`2.6.4.10
`Tables and figures to include comparative TK summary ................................................. 66
`
`2.6.5 PHARMACOKINETICS TABULATED SUMNIARY ............................................... 66
`
`2.6.6 TOXICOLOGY............................................................................................................... 67
`2.6.6.1
`Overall toxicology summary ................................................................................................ 67
`Single-dose toxicity ........................................................................................................... 75
`2.6.6.2
`
`Repeat-dose toxicity ......................................................................................................... 77
`2.6.6.3
`
`2.6.6.4
`Genetic toxicology .......................
`2.6.6.5
`Carcinogenicity................................................................................................................... 136
`2.6.6.6
`Reproductive and developmental toxicology ...................................................................... 167
`2.6.6.7
`Local tolerance ................................................................................................................... 213
`2.6.6.8
`Special toxicology studies .................................................................................................. 216
`2.6.6.9
`Discussion and Conclusions
`
`Tables and Figures .......................................................................................................... 217
`2.6.6.10
`
`2.6.7 TOXICOLOGY TABULATED SUMMARY ............................................................ 217
`
`OVERALL CONCLUSIONS AND RECOMMENDATIONS ............................................. 218
`
`APPENDIX/ATTACHJVIENTS ............................................................................................... 222
`
`

`

`EXECUTIVE SUMMARY
`
`1.
`
`Recommendations
`
`A. Recommendation on approvability: Approvable
`
`B. Recommendation for nonclinical studies: Adequate
`
`C. Recommendations on labeling: Changes recommended
`
`H.
`
`Summary of noncliniCal findings
`
`A. Brief overview of nonclinical findings
`Pharmacology: Iloperidone has high affinity for serotonin 5-HT2A, adrenergic 011,
`adrenergic (12, .D2, D3, and 5-HT1A receptors in humans, and acts as an antagonist at
`selected dopaminergic, serotonergic, and noradrenergic receptor subtypes. Affinity was
`highest for 5-HT2 and adrenergic (11 receptors, and lower for dopamine D2, which is a
`profile of an atypical antipsychotic. Iloperidone metabolites P88 and P89 have a profile
`similar to that of iloperidone in receptor-binding studies, with potential to exert CNS
`effects mediated by dopaminergic, serotonergic, and noradrenergic antagonism. P95
`exhibits a similar affinity to iloperidone for human 5-HT2A and adrenergic receptor
`subtypes, while exhibiting a substantially lower affinity for D1, D2, and D3' receptor
`subtypes compared with iloperidone. P95 is less likely to exert CNS effects since, as
`shown by whole-body autoradiography,
`it apparently does not cross the blood-brain
`barrier. The high affinities of iloperidone and its metabolites for al- adrenergic receptors
`in peripheral vascular tissues indicate that iloperidone and its metabolites P88, P89, and
`P95 are likely to exert cardiovascular effects, such as postural hypotension.
`In vitro evaluation of iloperidone effects in isolated dog Purkinje fibers and in
`mammalian cells expressing the cloned hERG showed that iloperidone has the capacity to
`prolong action potential duration and to block hERG currents;
`this indicates that
`iloperidone has the capacity to prolong QTc interval. Iloperidone metabolite P88, but not
`P95, also exhibited this potential. In hemodynamic evaluations conducted in rats and
`ddgs, iloperidone was found to dose-dependently decrease blood pressure and to induce
`transient increases in heart rate; however, cardiac output and ECG parameters were not
`affected. Neither iloperidone nor its metabolite P95 was associated with any adverse
`respiratory effects as evaluated1n rats.
`Pharmacokinetics:
`Iloperidone was rapidly absorbed in all animal species tested
`following oral and iv. administrations, but its bioavailability was very low due to a
`significant first-pass effect. Oral bioavailability was <1% in rat, 5% in mouse, 19% in
`both rabbit and dog, and approximately 36% in humans. The absorption profiles of
`metabolites P88 and P95 were similar to the parent compound; their absorption was
`rapid after either oral or i.v. administration. At equal oral doses, bioavailability of P95
`(18%) was significantly higher than P88 (5%) in mice.
`levels generally increased dose—
`Iloperidone plasma exposure (Cmax and AUC)
`proportionally in the tested animal species, except for the rat in which exposure increased
`over—proportionally possibly due to inhibitory activity of iloperidone to CYP enzymes.
`
`

`

`Gender differencesin exposure were present in the rat the mean AUC in female rats
`being significantly greater than that1n males.
`Distribution of iloperidone and its metabolites after oral administration was rapid; the
`highest drug concentrations were observed in the liver, kidney, gastrointestinal system,
`and secretory glandular tissues; placental transfer was limited; and drug concentration in
`the brain was very low. P95 metabolite did not pass the blood-brain barrier in the rat
`(whole-body autoradiography). After oral administration to lactating rats, iloperidone was
`excreted in milk; Cmax was attained 4 hours post dosing when iloperidone concentration
`was approximately 10 times higher in milk than in plasma.
`Iloperidone metabolic profiles show differences across species. The most abundant
`metabolites in humans (P95 and P88) are found in the species used in toxicology studies.
`However, in rodents, P95 and P88 are only minor circulating metabolites, in contrast to
`humans. Plasma exposure to the main active metabolite P88 in rodents and dogs is lower
`than that of iloperidone, while in humans, P88 exposure is greater than that of the parent
`compound. For P95, the differences between humans and animals are even greater than
`for P88. Results of pharmacology and pharmacokinetic studies that have bearing on the
`potential toxicological characteristics of metabolite P95, include the following:
`. - While P95 is the predominant circulating metabolite of iloperidone in humans,
`comprising 25% to 54% of its total metabolism, in rodents it represents only 3.9%
`to 5.7% of the total measurable exposure to iloperidone and its metabolites.
`- Although P95 did not appear to cross the blood-brain barrier as assessed in the
`whole-body autoradiography study in rats, in general toxicity studies in rodents
`and dogs with direct oral administration of P95, it induced CNS clinical signs
`similar to those induced by iloperidone, which suggests that the blood—brain
`barrier is not impenetrable to P95.
`P95 is rapidly eliminated in rodents; thehalf—life of P95 is 45 min in mice, 40 'min
`in Sprague—Dawley rats and 100 min in Wistar rats, as compared to a half-life of
`23-26 hours for P95 in humans. _
`
`-
`
`In vitro metabolic studies showed that iloperidone has stronger inhibitory activity to
`CYP2D6 and CYP3A4/3A5 compared with either P88 or P95; neither iloperidone nor its
`metabolites had potential to induce cytochrome P450 enzymes.
`Excretion profiles of iloperidone, P85 and P99 were similar. They are mainly eliminated
`through the feces,
`in contrast
`to humans in which urinary excretion is the major
`elimination pathway.
`Toxicology: Repeat-dose studies of general toxicity and corresponding toxicokinetic
`parameters were conducted with iloperidone in mice,
`rats,
`rabbits, and dogs.
`Additionally, toxicology studies were performed in rats and mice with the predominant
`circulating metabolite of iloperidone in humans, P95, to better characterize its safety and
`toxicity profiles in view of the lower exposure to this metabolite following iloperidone
`administration in animal species vs. humans.
`General toxicology: Among all the repeat-dose general toxicology studies on iloperidone
`and its P95 metabolite, pivotal studies of the longest duration and therefore most relevant
`to safety evaluation, are the 6—month rat study and the 12-month dog study conducted
`with iloperidone, and the 6-month rat study conducted with P95 metabolite. These studies
`are the subject of the present review.
`
`

`

`Iloperidone 6-month oral administration to rats.(Sprague-Dawley) at doses of 0,
`12, 24, and 48 mg/kg/d induced dose-related clinical signs indicative of CNS depression
`(ptosis, decreased motor activity, relaxation of the scrotum, anus, vaginal opening) and
`decrease of mean body weight at all dose levels; hematological changes (lower total
`leukocyte and lymphocyte counts at LD, MD and HD and lower platelet counts at MD
`and HD); dose-related decrease in serum triglycerides and glucose levels in females at all
`doses and in MD and HD males. Prolactin was not determined. Increased incidence and
`severity of vacuolization of glandular epithelium in the mammary glands of males and
`females was seen in all dose groups, mammary hypertrophy/hyperplasia in females at
`MD and HD, testicular degeneration and atrophy at MD and HD, and fatty infiltration in
`bone marrow sections in HD group. During the 5-week recovery period, an incomplete
`reversibility was seen for decreased body weight, hematology and mammary glandular
`epithelium changes. The MTD was 12 mg/kg/d, based on a marked body weight decrease
`(18-22% vs. control) at the next higher dose tested (24 mg/kg/d). An NOAEL was not
`reached in this study, as the lowest tested dose (12 mg/kg/d) induced a decrease in body
`and organ weights, hematological and clinical chemistry changes, and histopathology
`changes in the mammary glands of males and females. This dose is about 5 times the
`human dose at MRHD (24 mg/day) on an mg/m2 basis.
`Iloperidone 1-year oral administration to beagle dogs at 6, 12, and 24 mg/kg/d .
`induced drug-related clinical signs at all dosages (decreased spontaneous activity,
`tremors, bizarre behaviors, labored breathing, ptosis, slow response times and/or lack of
`pupillary reflex); the mid- and high-dose induced ataxia, loss of righting and toe pinch
`reflex (in single animals), emaciation. 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 dose-dependently at MD and
`HD, i.e., decreases in mean erythrocyte count and in hemoglobin and hematocrit levels in
`males and females; lower cholesterol and triglyceride levels in females, and increase in
`alanin aminotransferase in HD males. No abnormalities were found in any dose group on
`ECG and auditory examination. Higher mean absolute and relative liver weights and
`hepatocellular hypertrophy resulting from proliferation of the endoplasmic reticulum
`were found in males in the HD group, probably secondary to liver enzyme induction. The
`MTD was 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. NOAEL was not reached in this study as the
`lowest tested dose (6 mg/kg/d) induced decreased body weight and neurological clinical
`signs. This dose is 8 times the human dose at MRHD (24 mg/day) on an mg/m2 basis.
`Iloperidone metabolite P95 six-month administration to rats (Wistar) at oral doses
`of 50 and 500 mg/kg/day (yielding P95 plasma exposures of about 2 to 3x and 150 to
`400x, respectively, the human P95 plasma exposure at iloperidone MRHD of 24 mg/d),
`induced dose-dependent CNS clinical signs at both dose levels throughout the entire
`treatment period, similar to those induced by iloperidone (ptosis, decreased motor
`activity, relaxation of the scrotum, anus, vaginal opening) that are attributable to
`pharmacological effect. Body weight and weight gain decreases were induced at HD
`only. There were no drug-related abnormal findings in hematology, clinical chemistry
`(including prolactin plasma levels), or urine analysis. Functional and morphologic
`reproductive system changes were induced in both genders. 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 males,
`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 HD.
`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, non-reversible after the
`recovery period. Drug—related proliferative 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). 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. An NOAEL was not reached in either male or female rats since
`pathomorphological proliferative changes in multiple organs/tissues were present at the
`lowest tested dose of 50 mg/kg/day, corresponding to plasma exposure (AUC 0-24)
`approximately 2 to 3x the human P95 plasma exposure at MRI-1D of 24 mg
`iloperidone/day.
`Genetic toxicology: Iloperidone Was clastogenic in one in vitro test (chromosomal
`aberration assay in Chinese Hamster Ovary (CHO) cells). It is likely that the positive
`results obtained in the chromosomal aberration assay in vitro are of little biological
`relevance, having in mind the negative results obtained in the in vivo micronucleus
`assays in rat hepatocytes and mouse bone marrow. Iloperidone metabolite P95 was
`negative for potential genotoxicity in a battery of 3 tests: an Ames, a chromosomal
`aberration test
`in CHO cells, and a bone marrow micronucleus test
`in rats. For
`iloperidone genotoxic and potentially genotoxic impurities ;.,;______’—-——
`
`the acceptance criteria are set at the level ova—— each, so that the
`overall daily exposure from the sum of these - mpurities is f ----—_ g/day.
`Carcinogenicity: Two—year carcinogenicity studies of iloperidone were conducted in mice '
`and rats of both genders.
`Iloperidone administration tc «TD-l (ICR) 'BR mice ‘at oral doses of 2.5, 5, and 10
`mg/kg/d (causing an increased mortality in males at HD and in females at all dose levels),
`did not exert carcinogenic effect
`in males. In females,
`the incidence of malignant
`mammary tumors was significantly increased above the concurrent and historical control
`range in the low dose group only. On an mg/m2 basis, there is no safety margin between
`the low dose employed in the study (2.5 mg/kg/day) and the maximal recommended dose
`in humans (24 mg/day). However, mammary tumor incidences were not increased in the
`mid— and high—dose groups, although the duration of treatment was the same in the mid—
`dose and low dose groups. It is not clear why similar increases in mammary tumor
`incidences were not seen at the higher doses employed in this study. Drugs which elevate
`plasma prolactin typically cause mammary tumors in rodents.
`Iloperidone administration to ww- 3D(SD)BR rats at oral doses of 4, 8, and 16 mg/kg/d
`for 24 months (inducing a dose—related, significant decrease in mean body weights of
`
`N4)
`
`[1(4)
`
`

`

`over 10% in all treated groups), did not exert carcinogenic effect in male rats. In females,
`the combined incidences for pancreatic islet cell adenomas and islet cell carcinomas were
`increased at HD (2, 2, 0, 3, and 7 for the two controls, LD, MD and HD, respectively).
`The incidence value at HD was within historical control range for this species and strain;
`the dose—response trend analysis showed a p-value of 0.0051 that approached but did not
`reach the level of statistical significance required for common tumors (alpha=0.005).
`Having in mind that the incidences of pancreatic islet cell tumors in this study were
`within the reported historical control range for this species and strain and that there was
`no other evidence indicating a treatment-related effect (such as multiplicity of tumors,
`increased incidence of pre—neoplastic findings), it is concluded there was no carcinogenic
`effect in the female rats attributable to the test article.
`
`Reproductive and developmental toxicifl was assessed in a Fertility (Segment 1) study in
`rats; Embryofetal 'deVelopment (Segment 11) Study in rats and rabbits; and in a Pre- and
`postnatal deVelopment (Segment III) study in rats.
`Segment I rat fertilifl study: Iloperidone oral administration at doses of 0, 4, 12,
`36 mg/kg/day to Sprague 'Daney male and female rats
`for a period starting 10 weeks
`prior to mating (males) or 2 weeks prior to mating (females) and continuingthrough
`mating, gestation and lactation,
`resulted in the following drug-related effects:
`pharmacological clinical signs at all doses, significant decreases in body weight of both
`males and females at MD and HD, female estrous cycle disturbances (all doses, dose-
`dependently) and reduction in male reproductive organs’ weight
`(prostate weight
`decreased in all dosed groups; testis and epididymis weights decreased at HD), lower
`fertility indices (72% and 88% at HD and MD, respectively, vs. 100% in control), lower
`pregnancy rates at MD and HD groups (86%, and 60%, respectively, vs. 100% in
`control), reduction of corpora lutea count at HD in comparison to control; increased
`duration of pregnancy at MD and HD; increased stillbirth rates and neonatal'deaths at
`MD and HD. At HD, embryofetal growth was retarded, and visceral variation rates
`(dilatation of lateral and third brain ventricles, dilatation of heart ventricles) were
`increased, but no external malformations Were observed in the treated groups. There were
`no differences in developmental landmarks or in neurobehavioral' development of the
`surviving Fl pups (however, insufficient number of HD litters were available for growth
`and behavioral evaluations because of the low pregnancy rate and neonatal deaths).
`Reproductive performance of F1 generation was apparently not affected. The NOAEL
`‘ was 4 mg/kg/day (1.6 times the human dose at MRHD (24 mg/day) on an mg/m2 basis).
`Although this dose induced estrous cycle disturbances and a decrease in prostate weight,
`it did not affect parental fertility or the prenatal and postnatal survival, development and
`reproductive capacity of the progeny.
`Segr_nent II Prenatal developmental toxicig studies in rats:
`Iloperidone administration to pregnant Wistar‘ rats at oral doses of 0, 4, 16, and 64
`mg/kg/day during the period of major organogenesis (Gestation Days 7 through 18)
`induced developmental toxicity (expressed as embryofetal lethality, retarded intrauterine
`development and minor skeletal abnormalities) at oral doses above 16 mg/kg/day. Signs
`of maternal toxicity (reduced weight and weight gain, reduced placental weight) were
`present at and above 16 mg/kg/day. The NOAEL for developmental toxicity was 16
`mg/kg/day (6 times the human dose at MRHD of 24 mg/day on an mg/m2 basis).
`
`

`

`The predominant circulating iloperidone metabolite in humans (P95) administered to
`pregnant rats at oral doses of 20, 80 and 200 mg/kg/day (Gestation Days 7 through 17),
`produced dose-dependent maternal pharmacological effect (signs of sedation) at all dose
`levels, but no maternal toxicity. Maternal plasma exposure (AUC) at the high dose was
`approximately 4 times the mean. human plasma AUC of metabolite P95 when the parent
`compound (iloperidone) was administered at the MRHD of 24 mg/day. The treatment did
`not induce embryo/fetal mortality or congenital malformations but produced a dose-
`dependent increase in the incidence of retarded skeletal ossification vs. the concurrent
`control at all tested dose levels, ranging from 8% (LD) to 14% (HD). These values,
`however, were within the historical control range for the tested species and strain.
`Segment II_Prenata_l developmental toxicity studyin rabbits:
`Iloperidone adminiStration at oral (gavage) doses ‘of 0, 4, 10 and 25 mg/kg/day to
`‘ pregnant rabbits from gestation day 6 through 18 caused maternal mortality (1/15) and
`decreased maternal body weight at the HD and dose-dependent drug-related clinical signs
`(sedation) at all dose levels. Maternal food intake was reduced at MD and HD. The high
`dose induced increase in embryo/fetal
`intrauterine lethality and a decrease in fetal
`viability at term. No embryo/fetal toxicity or teratogenicity were observed at LD and
`MD. Based on these results, the NOAEL for embryo/fetal toxicity is 10 mg/kg/day (8x
`the human dose at MRHD of 24 mg/day on an mg/m2 basis).
`Segment III Prenatal and postnatal developmental toxicity-study in rats
`Iloperidone oral administration to pregnant CD rats from gestation day 17 through
`weaning (postnatal day 21) at doses of 4, l6 and 48/36 mg/kg/day, caused maternal
`toxicity statistically significant at HD and MD (maternal mortality at HD and dose—
`dependent decrease in maternal body weight at HD, MD and LD), significantly prolonged
`gestation and parturition, high perinatal- and postnatal mortality (stillbirths and neonatal
`deaths) in F1 generation at HD and MD, and some increase in stillbirth rate at LD (mean
`stillbirth rate per litter 0.6 vs. 0.04 in control). The growth of the surviving F1 offspring
`was impaired at MD and HD, as demonstrated by the reduced pup weight at birth and
`weight gain through weaning. However, there was no apparent adverse effect on F1
`development, including behavior, sexual maturation and reproductive capacity, at any of
`the administered dose levels. The NOAEL was 4 mg/kg/day (1.6 times the human dose at
`MRHD of 24 mg/day on an mg/m2 basis).
`B. Pharmacologic activity
`The pharmacological profile of iloperidone is consistent with that of an atypical
`antipsychotic with a reduced potential for extrapyramidal side effects and therapeutic
`potential with regard to positive, negative, and social withdrawal symptoms of
`schizophrenia. Iloperidone has the potential to induce hypotensive effects and to prolong
`QTc interval duration
`
`C. Nonclinical safety issues relevant to clinical use
`
`- The high affinity for (11- adrenergic receptors in peripheral vascular tissues,
`indicate that iloperidone and its metabolites P88, P89, and P95 are likely to exert
`cardiovascular effects, such as postural hypotension.
`Iloperidone prolongs action potential duration and block hERG currents in vitro;
`indicating a capacity to prolong QTc interval.
`In vivo,
`iloperidone dose-
`
`-
`
`

`

`dependently decreases blood pressure and induces transient increases in heart rate
`in rats and dogs; however, ECG parameters were not affected.
`the
`Iloperidone has the potential
`to inhibit CYP2D6 and CYP3A4/5 at
`recommended therapeutic dose in humans (12 mg BID); its metabolites P88 and
`P95 have a weaker inhibitory activity on CYP2D6 and CYP3A4/5.
`Chronic oral administration of iloperidone to rats (6'months) and dogs (1 year)
`and of iloperidone P95 metabolite to rats (6 months) induced general toxicity in
`all tested species. An NOAEL was not reached in either of these studies. The
`lowest tested dose of iloperidone in the 6-month rat study (12 mg/kg/d, about 5
`times the human dose at MRHD (24 mg/day) on an mg/m2 basis) induced a
`decrease in body and organ weights, hematological and clinical chemistry
`changes, and histopathology changes in the mammary glands of males and
`females. The lowest tested dose of iloperidone in the 1-year dog study (6 mg/kg/d,
`8 times the human dose at MRHD on an mg/m2 basis) induced decreased body
`weight and neurological clinical signs. The lowest tested dose of P95 in the 6-
`month rat study (50 mg/kg/day, corresponding to plasma exposure (AUC 0-24)
`approximately 2 to 3x the human exposure at MRHD) induced proliferative
`pathomorphological changes in multiple organs/tissues,
`i.e., endocrine glands
`(pituitary, thyroid, and pancreas), mammary gland (both genders) and ovary.
`Iloperidone was clastogenic in one in vitro test (chromosomal aberration assay in
`Chinese Hamster Ovary (CHO) cells) but was not clastogenic1n the in vivo
`micronucleus assays in rat hepatocytes and mouse bone marrow. The positive
`results obtained in chromosomal aberration assay in CHO cells in vitro are of
`little biological relevance, having in mind the negative results obtained in vivo.
`Iloperidone
`genotoxic
`and potentially genotoxic
`impurities e—x
`________,__,__———-—- do not constitute a genetic toxicity risk for humans
`
`since the. acceptance criteria for each of these impurities are set at the level of
`ppm, so that the overall daily exposure from the sum of these -— mpurities is
`rig/day
`in mice
`.-Iloperidone administration for 2 years was not carcinogenic to rats;
`(female) administered oral doses of 2.5, 5 and 10 mg/kg/day for 2 years the
`incidence of malignant mammary tumors was significantly increased above the
`concurrent and historical control range in the low dose group only. On an mg/m2
`basis, there is no safety margin between the low dose employed in the study (2.5
`mg/kg/day) and the maximal
`recommended dose in humans (24 mg/day).
`However, mammary tumor incidences were not increased in the mid— and high-
`dose groups, although the duration of treatment was the same. It is not clear why
`similar increases in mammary tumor incidences were not seen at higher doses.
`In view of the proliferative effects seen with iloperidone metabolite P95 in the 6-
`month rat study, the Division required a 2-year carcinogenicity study with P95 in
`he rat which is ongoing (CAC meeting of March 25, 2008).
`Iloperidone induces decreased fertility, prolonged gestation, increased prenatal
`and neonatal mortality, and retarded growth of the progeny upon oral
`administration to male and female rats for a period starting 10 weeks prior to
`mating (males) or 2 weeks prior to mating (females) and continuing through
`
`[3(4)
`
`

`

`gestation, parturition and lactation. The NOAEL is 4 mg/kg/day (1.6 times the
`human dose at MRI-ID (24 mg/day) on an mg/m2 basis).
`Iloperidone oral administration to pregnant rats and rabbits during the period of
`major organogenesis induces developmental
`toxicity (embryofetal
`lethality in
`both species, retarded intrauterine development and minor skeletal abnormalities
`in the rat) at doses that are maternally toxic The NOAEL for developmental
`toxicity is 16 mg/kg/day in rats and 10 mg/kg/day in rabbits (6- and 8 times,
`respectively, the human dose at MRI-ID of 24 mg/day on an mg/m2 basis).
`Iloperidone perinatal and postnatal administration to rats (Gestation day 17
`through postnatal day 21) produced, at maternally toxic doses, prolonged
`gestation and parturition, increased incidence of stillbirths, neonatal mortality, and
`retarded growth of progeny up to weaning, but did not affect neurobehavioral and
`'reprOductive development ofthesurViving pups.TheNOAEL1's 4mg/kg/day (1 6
`times the human dose at MRHD (24 mg/day)on anmg/m2 basis).
`
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`APPEARS THIS WAY ON ORIGINAL
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`2. 6 PHARMA COLOGY/TOXICOLOGY RE VIEW
`
`2.6.1
`
`INTRODUCTION AND DRUG HISTORY
`
`NDA number: 22—192
`Review number:
`1
`
`Sequence number/date/type of submission: N-0000
`Information to sponsor: No (x)
`Sponsor and/or agent: Vanda Pharmaceuticals
`Manufacturer for drug substance: Vanda Pharmaceuticals
`
`Reviewer name: Sonia Tabacova
`
`Division name: Psychiatry Drug Products
`HFD #: 130
`
`Review completion date:
`
`June 2008
`
`Drug:
`
`Trade name: None provided
`Generic name: Iloperidone
`Code name: 1L0522 (Novartis); ILOSZZ—NXA (Novartis); VYV-683 (Vanda)
`Chemical name: 1 —[4-[3-[4-(6-Fluorobenzo[d] isoxazol—3-yl)—1 -
`pz’peridinyUpropoxy}3-methoxyphenyl] ethanone .
`Chemical Abstract Service_(CAS) Number: 133454-47—4
`Mole file number:
`
`Molecular formula/molecular weight: C24H27N204F / 426.5 '
`Structure:
`
`(r3113
`
`Relevant INDs/NDAs/DMFS: IND 36827
`
`Drug class: Antipsychotic
`Intended clinical population: Adults with schizophrenia
`Clinical formulation: Tablets
`Route of administration: oral
`
`Disclaimer: Tabular and graphical information is from sponsor’s submission unless
`stated otherwise.
`
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`Studies reviewed within this submission: All submitted studies, except for the non-
`pivotal iloperidone repeat—dose general toxicology studies
`
`Studies M reviewed within this submission: Non-pivotal
`general toxicology studies
`
`iloperidone repeat-dose
`
`APPEARS THlS WAY ON ORIGINAL
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`2.6.2 PHARMACOLOGY
`
`.
`2.6.2.1 Brief summary
`Iloperidone has an in vitro and/or ex vivo binding profile consistent with an atypical
`antipsychotic, displaying affinity for human dopamine (D), serotonergic (S—HT), a-
`noradrenergic, and sigma receptors, and no affinity for glycine-binding site, N-methyl-D
`aspartate (NMDA) receptor channel, or muscarinic receptors. Affinity of iloperidone was
`found to be highest for human S-HTlA, 5-HT2A, D2, D3, adrenergic a1 and a2
`receptors, and lower for D1, D5, and other serotonergic receptors. Iloperidone has no
`agonist activity at any receptors evaluated (rat or human), but was found to have
`significant in vitro and in vivo