2.6.6.6 Reproductive and developmental toxicology
`
`Study title: Segment I Study in Rats
`
`Fertility and early embryonic development
`
`Key study findings: This 2-generation study evaluated the effect of iloperidone on male
`and female gonadal function, mating behavior and fertility, as well as on the prenatal and
`postnatal growth and development of offspring. Oral (gavage) administration at doses of
`0, 4, 12, 36 mg/kg/day to Sprague Dawley male and female rats (32/sex/group) for a
`period starting 10 weeks prior to mating (males) or 2 weeks prior to mating (females) and
`continuing through mating, gestation, parturition‘and lactation, resulted in the following
`drug-related effects: Clinical signs (hypoactivity, ptosis and lacrimation at MD and HD;
`ptosis at LD), significant decreases in mean body weight of F0 males and females at MD
`and HD during pre-mating and mating periods, as well as throughout gestation and
`lactation [e.g., the corrected maternal weight at term (terminal body weight minus gravid
`uterine weight) was significantly lower at HD and MD by 13% and 7%, respectively],
`female estrous cycle disturbances (all doses, dose-dependently) and reduction in male
`reproductive organs’ weight (mean absolute prostate weight decreased in all dosed
`groups; mean absolute and relative testis and epididymis weights decreased at HD).
`Lower female fertility indices,
`i.e. 72% and 88% were registered at HD and MD,
`respectively, vs. 100% in control (statistically significant at HD). A significant negative
`_ trend was noted for male fertility, without significant differences between control and any
`of the treated groups. The pregnancy rate was lower in MD and HD groups (86%, and
`60%, respectively, vs. 100% in control), statistically significant at HD. The duration of
`pregnancy was increased (mean duration of 22, 22.5, and 22.6 days at LD, MD, and HD
`vs. 21.7 days in control group, statistically significant at MD and HD). Mean numbers of
`corpora lutea and implantation sites were significantly lower at HD in comparison to
`control; the reduced implantations were secondary to the reduction of corpora lutea and
`not due to an increased pre—implantation embryonic lethality since preimplantation loss
`was not significantly different from control in any of the treated groups. Embryofetal
`growth was retarded at HD, as indicated by a significantly lower mean fetal weight at
`term vs. control values. No external or Visceral malformations were observed in the
`
`treated groups, but visceral variation rates (dilatation of lateral and third brain ventricles,
`dilatation of heart ventricles) were increased in HD group. There was an increased
`prenatal and neonatal mortality in F1 generation, as demonstrated by decreased livebirth
`index (89% and 83% at MD, and HD vs. 99% in control group, statistically significant),
`increase in stillborn pup number (18 and 17 at MD and HD vs. 2 in control group,
`statistically significant) and increase in neonatal deaths (mean viability indices, i.e. N
`alive on postnatal Day 4/ N liveborn = 80% and 24% at MD, and HD vs. 98% in control
`group, statistically significant). There was no pup lethality after the neonatal period (pups
`surviving to weaning/pups alive on day 4 post-cull) or after weaning. Mean pup weight
`was lower in MD and HD groups vs. control, statistically significant at postnatal day 14.
`There were no differences,
`in developmental
`landmarks or
`in neurobehavioral
`development of F1 generation as assessed by activity and learning tests. However, very
`few HD litters were available for growth and behavioral evaluations because of the low
`pregnancy rate and neonatal deaths.
`F1 post~weaning growth and development were
`
`167
`
`

`

`similar in dosed and control groups. Reproductive performance of F1 animals and F2
`generation in utero growth and survival were apparently not affected by treatment.
`In conclusion, based on the results of this study, a NOEL was not identified, since dose-
`related estrous cycle disturbances and a decrease in prostate weight of F0 were induced at
`all dose levels, including the low dose. These effects are not unexpected and are most
`likely secondary to the pharmacological action of the drug. However, at the low dose (4
`mg/kg/day) these effects did not interfere with F0 reproductive capacity, prenatal and
`postnatal survival, growth and development of F1 generation, or with F1 reproductive
`capacity and the prenatal growth and survival of the next, F2 generation. Therefore,
`iloperidone oral dose of 4 mg/kg/day is identified as the NOAEL in the Segment I rat
`fertility study.
`
`
`.
`Study 110.:
`Volume # and page #: N.A.
`Conducting laboratory and location:
`
`e——-—-—"‘~
`
`
`
`Date of sturdy initiation: June 21, 1993
`GLP compliance: yes
`QA reports: yes
`Lot numbers and potency: Batch RC5634 /Purity 99.8% (HPLC)
`Vehicle: 2% potato starch in water
`Methods
`
`Doses: 0, 4, 12, 36 mg/kg/day
`Species/strain: Rat/ —- CD® BR (Sprague—Dawley)
`Number/sex/group: 32
`
`Route formulation volume: Oral gavage, suspension in 2% water solution of
`potato starch, dosing volume 10, 5, 7.5 and 10 kag for control, LD, MD and HD
`groups, respectively.
`Satellite groups used for toxicokinetics: None
`Study design: Males were dosed for 10 weeks prior to mating through
`termination; females were dosed for 2 weeks prior to mating through termination. Of the
`32 females per group, 20 were assigned'to C section, and 12 to natural delivery. The
`group assignments were as follows:
`
`
`E
`.
`ultra
`S W W deliver.
`
`1 (Control)
`2 (L0!)
`3 (Kid)
`4 H1
`
`0
`4
`12
`36
`
`'
`
`32
`32
`32
`32
`
`32
`32
`32
`32
`
`19
`18
`15
`16
`
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`
`13
`14
`14
`16
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`
`During the mating period, one male was cohabited with one female from the same group
`up to a maximum of 21 days or until mating was confirmed. The day of observation of
`presence of sperm in vaginal lavagelwas designated as Day .1 of gestation. Pregnant
`
`168
`
`

`

`females were randomly selected for dose group assignment. On gestation day 20, the F0
`females scheduled for C-section were sacrificed; fetuses were weighed, sacrificed, and
`evaluated. for external and visceral abnormalities. The F0 females selected for natural
`delivery were allowed to litter and raise their pups (F 1 generation) to weaning (Day 21
`post partum). Litters were observed daily for clinical signs, growth and development.
`Following weaning, selected Fl males and females were allowed to undergo a 7—week.
`growth phase, during which behavioral development was monitored in selected animals.
`Upon maturation, the F1 animals were mated and allowed to naturally deliver the F2
`generation which was terminated on Day 1 postpartum.
`In addition, HD F0 males were mated with na‘1’ve (untreated) females until mating was
`confirmed; the pregnant females were sacrificed on gestation day 14 and the numbers of
`corpora lutea, live and dead fetuses were determined.
`Parameters and endpoints evaluated:
`.
`F0 Parental Generation: Mortality and Clinical signs (twice daily); Estrous cycle (all
`females, daily vaginal lavage, beginning 2 weeks prior to mating through mating or end
`of breeding); Body weight (weekly for males and non-pregnant females, on gestation
`days 0, 7, 14 and 20, and on lactation days 0, 4, 7, and 21); Food consumption (weekly
`for males and females prior to breeding; for delivering females— on lactation days 0-4, 4- '
`7, 7— 10, and 10-14; not measured during mating or gestation); Necropsy: F0 males and
`females were examined grossly; male reproductive organs were weighed and abnormal
`viscera and reproductive tract organs were preserved1n 10% formalin.
`F1 fetuses: On gestation day 20, the F0 females scheduled for C-section were sacrificed;
`numbers of corpora lutea, implantations, resorptions, live and dead fetuses were recorded;
`fetuses were weighed, examined for external abnormalities and about 50% of fetuses
`were preserved in Bouin’s for visceral examination.
`Fl pups: Upon natural delivery, pup weight and viability were recorded on postnatal
`(lactation) days 0, 4, 7,
`l4 and 21. Litters were culled to 8 pups on p.n. day 4.
`Developmental and behavioral evaluations were conducted as listed in the following
`sponsor’s table. The evaluations were performed on all pups beginning on the days listed
`and continuing until the developmental landmark was positive for the entire litter, or until
`weaning.
`
`F1 pups — physical and neurobehavioral developmental endpoints
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`In addition, behavioral evaluations of motor activity (open field on postnatal days 22 and
`60) and learning capacity (water maze, 3 weeks after weaning), as well as of sexual
`maturation were performed on selected pups (l/sex/litter).
`Fl Parental and F2 Observations: Following weaning, the F1 pups selected as parental
`offspring were observed daily for mortality and morbidity; body weight was recorded
`weekly. Food consumption was not measured. After a 7—week post-weaning growth
`
`169
`
`

`

`phase, the F1 males and females were mated within each group (mating confirmed by
`vaginal lavage), and pregnant F1 females were weighed on gestation days 0, 7, 14, 20 and
`on lactation day 0. Upon spontaneous delivery,
`the F2 pups were weighed, sexed,
`observed for external abnormalities, terminated and preserved in 10% buffered formalin.
`F1 parental males and females were sacrificed, gross pathology assessment was
`performed, and abnormal viscera and reproductive organs were preserved in 10%
`buffered formalin.
`
`For maternal reproductive and fetal parameters, the litter was selected as the independent
`sampling unit.
`
`Results
`
`-
`
`1 MD and 6 HD females were sacrificed following total litter death (no
`Mortalifl:
`notable clinical observations were recorded). There was no spontaneous mortality.
`Clinical signs: Pre-mating and mating, males and females: Hypoactivity, ptosis and
`lacrimation at MD and HD; ptosis at LD. During gestation, clinical signs were present in
`all dosed groups.
`Body weight:
`- Body weights ofF0 males and females duringpre-mating and mating periods:
`Prior to dose administration, the mean body weights were similar between the control and
`treated groups. Mean body weight and body weight gain was significantly lower vs.
`control in HD and MD males throughout the study; in females, after an initial increase, a
`significant decrease in mean body weight vs. control was registered at HD and MD (see
`sponsor’s tables below and on the next page).
`
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`170
`
`

`

`n I
`
`Mean bod wei_hts F0 Males)- Continued ,
`
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`Body weights of F0 Dams during gestation and lactation
`Mean-body weights and body weight gain values of pregnant and lactating females are
`presented in the sponsor’s tables on the next page. Significantly lower mean body
`weights in comparison to control were registered at MD and HD throughout gestation (on
`gestation days 7, 14, and 20) and lactation (as measured on postnatal days 0, 4, 7 and 14;
`on day 21, the changes were not statistically significant).
`Mean body weight of pregnant females at term (gestation day 20, at Caesarean section)
`was significantly lower at HD and MD vs. control by 16% and 9%, respectively; the
`
`171
`
`

`

`corrected maternal weight (terminal body weight minus gravid uterine weight) was
`significantly lower by 13% and 7%, respectively. Maternal weight gain throughout
`pregnancy (gestation days 0 through 20) was lower by 49% and 26% at HD and MD,
`respectively vs. control. For those females that were allowed to deliver spontaneously,
`the mean body weight after delivery (Lactation Day 0) was significantly lower at HD and
`MD vs. control by 11% and 7%, respectively; similar differences in maternal body
`weight vs. control were registered on Lactation Day 4 through 14, but by weaning
`(Lactation day 21) the mean maternal weight has normalized and the differences fiom
`control (—4% and -5% at MD and HD) were no longer statistically significant. At LD,
`there were no notable differences in mean maternal weight or weight gain in comparison
`to control during gestation or lactation.
`
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`Food consumption: In males, significantly decreased mean food consumption vs. control
`were noted at HD (weeks 3 through 9) and MD (weeks 7-10); at LD, the mean food
`consumption was significantly increased. In females during ,pre—mating and mating
`periods, food consumption was significantly increased at all dose levels at weeks 8-9, and
`at I-lD additionally at weeks 9-10. During lactation, mean maternal food consumption
`was significantly decreased vs. control at MD (during the first 2 weeks post partum) and
`HD (at all intervals).
`F0 reproductive performance:
`Disturbances in estrous cycle were induced at all dose levels in a dose-dependent manner.
`Prolonged periods of diestrous stage (25 days) were observed during the pre-mating (in
`18, 22, and 28 females at LD, MD and HD, respectively), as well as during the mating
`period (in 7, 15 and 25 animals at LD, MD and HD, respectively, vs. 2 in control). This
`resulted in lower female fertility indices, i.e. 72%, 88% and 97% at HD, MD and LD,
`respectively, vs. 100% in control (a significant negative trend, as well as statistically
`significant at HD). The pregnancy rate was lower in MD and HD groups. A significant
`negative trend was noted for male fertility, without significant differences between
`.control and any of the treated groups. The mean absolute and relative testis and
`epididymis weights and absolute weights of seminal vesicles were lower in the HD group
`vs. control; the mean absolute prostate weight was decreased in all dosed groups vs.
`control (see sponsor’s table below). Mean body weight was significantly reduced in
`HDM and MDM.
`
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`SEIIMI. fiSlOlES
`
`173
`
`

`

`The following sponsor’s tables summarize the reproductive performance results.
`
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`Maternal and embryofetal parameters at Caesarean section: Corrected maternal weight
`(terminal body weight minus gravid uterine weight) and net body weight gain were
`significantly lower at MD and HD in comparison to control; gravid uterine weight was
`decreased dose-dependently at MD and HD, statistically significant at the HD.
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`Mean number of corpora lutea and implantation sites were significantly lower at the HD
`in comparison to control; the reduced implantations were secondary to the reduction of
`corpora lutea and not due to an increased pre-implantation embryonic lethality since the
`mean per cent of preimplantation loss was not significantly different from control in any
`
`174
`
`

`

`of the treated groups (see sponsor’s table on the next page). There were no significant
`differences in the rate of resorptions; however, two dams (one from MD and one from
`HD group) had no viable fetuses at term.
`
`SIGNIFIMU mm mm mm: ’ I ”0.05: “‘ - "0.01.
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`Embryofetal' growth was retarded in HD group, as indicated by a significantly lower fetal
`weight vs. control values.
`No external or visceral malformations were observed in the treated groups, but visceral
`variation rate was increased in the HD group (see sponsor’s table on the next page).
`
`175
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`Significant positive trends and significantly higher fetal incidence values in HD group vs.
`control were found for the dilatation of lateral and third brain ventricles, dilatation of
`heart ventricles and total soft tissue variations.
`
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`The following dose-dependent effects were registered: lower pregnancy rates (93%, 86%,
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`increased duration of pregnancy (mean duration of 22, 22.5, and 22.6 days at LD, MD,
`and HD vs. 21.7 days in control group, statistically significant at MD and HD), increased
`pre—, perinatal and neonatal mortality, as demonstrated by decreased livebirth index
`(95%, 89% and 83% at LD, MD, and HD vs. 99% in control group, statistically
`significant at MD and HD), increase in stillborn pup number (8, 18 and 17 at LD, MD,
`and HD vs. 2 in control group, statistically significant at MD and HD) and increase in
`neonatal deaths (mean viability indices, i.e. N alive on postnatal Day 4/ N livebom =
`96%, 80% and 24% at LD, MD, and HD vs. 98% in control group, statistically significant
`at MD and HD). Total litter deaths occurred within the first 4 postnatal days in 1 and 6
`litters fi'om MD and HD groups, respectively. There was no pup lethality after the
`neonatal period (pups surviving to weaning/pups alive on day 4 post-cull) or after
`weaning up to assignment to the behavioral or maturation phase of F1 generation.
`
`176
`
`

`

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`onward, statistically significant at postnatal day 14 (see sponsor’s table on the next page).
`
`177
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`

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`in neurobehavioral
`landmarks or
`in developmental
`There were no differences
`development of F1 generation as assessed by activity and learning tests. However, very
`few HD litters were available for growth and behavioral evaluations because of the low
`pregnancy rate and neonatal deaths.
`Fl post-weaning growth and development were
`similar in dosed and Control groups. Reproductive performance of F1 animals and F2
`generation in utero growth and survival were apparently not affected by treatment.
`
`Conclusion. Based on the results of this study, a NOEL was not identified, since dose-
`related estrous cycle disturbances and a decrease'1n prostate weight of F0 were induced at
`all dose levels, including the low dose. These effects are not unexpected and are most
`likely secondary to the pharmacological action of the drug. However, at the low dose (4
`mg/kg/day) these effects did not interfere with F0 reproductive capacity, prenatal and
`postnatal survival, growth and development of F1 generation, or with F1 reproductive
`capacity and prenatal growth and survival of the next, F2 generation. Therefore,
`iloperidone oral dose of 4 mg/kg/day‘ is identified as the NOAEL in the Segment I rat
`fertility study. The higher doses employed in this study induced dose-dependent
`decreased parental F0 fertility (male and female), prolonged gestation, increased prenatal
`and neonatal
`lethality of F1 progeny, and reduced F 1 pre- and postnatal growth (as
`indicated by lower body weight at term and postnatally).
`
`178
`
`

`

`Embryofetal development (Segment ID
`
`Three Segment II studies were performed:
`— Oral embryotoxicity study of iloperidone in rats
`- Oral embryotoxicity study of iloperidone metabolite P95 12113 in rats
`- Oral embryotoxicity study of iloperidone in rabbits
`
`Study title: Oral Embflotoxicity Study of Iloperidone (HP 873) in Wistar Rats
`Key study findings:
`Iloperidone administration to pregnant Wistar rats at doses of 0
`(vehicle control), 4, 16, and 64 mg/kg/day by oral gavage on Gestation Days 7 through 18
`induced at HD and MD a significant dose-dependent reduction in maternal weight (by
`18% and 6%, respectively, vs. control at term) and in maternal weight gain (by up to 92%
`and 34% of control values, respectively). Maternal food consumption was decreased at
`HD by up to 11% vs. control. Placental weights were statistically significantly lower at
`HD (by 17% vs. control) and MD (by 7% vs. control). Clinical signs associated with
`pharmacological action of the test agent (sedation, ptosis) were present in all dosed
`groups, dose—dependently. The high dose induced a marked (over 5-fold) increase in
`post—implantation embryonic lethality. Early post-implantation death of all conceptuses
`occurred in two thirds of the treated HD dams. The surviving HD fetuses exhibited
`growth retardation (as expressed by significantly decreased fetal weight and crown/rump
`length at term by 12% and 7%, respectively as compared to control, and retarded skeletal
`ossification). An increased incidence of minor skeletal abnormalities (fragmented and/or
`displastic thoracic vertebral centra) and skeletal variations (supemumerary thoracic rib)
`was registered in the HD group. No increase in external or visceral abnormalities was
`registered in any of the dosed groups. Intrauterine development was not adversely
`affected at MD and LD. The embryo/fetal lethality and mean fetal body weight and
`length in these groups did not differ appreciably from control.
`Based on the study findings, iloperidone induces 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) are induced at and above 16
`mg/kg/day. The NOAEL for developmental toxicity in this study is 16 mg/kg/day (6
`times the MRHD of 24 mg/da'y on an mg/m2 basis).
`
`Study no.: 92.0011; Report No. 94.0623
`Volume # and page #: N.A.
`Conducting laboratory and location: Pharma Development Corporate Toxicology,
`Hoechst Actiengesellshafi, Frankfurt/Main
`Date of study initiation: 11 May 1993
`GLP compliance: yes.
`QA reports: yes
`Lot numbers and potency: RC 5634; purity 99.1% (HPLC)
`Vehicle: Starch mucilage (20 g/l)
`
`Methods
`
`Doses: 4, 16, 64 mg/kg/day
`Species/strain: Rat, Wistar
`Number/sex/gxoup: 22-24 mated females
`
`179
`
`

`

`
`Route formulation volume: Oral gavage, suspension in 2% aqueous starch,
`dosing volume 5 ml/kg (all groups)
`Satellite groups used for toxicokinetics: None
`(22-24/group) were
`Study design:
`Mated female Sprague-Dawley rats
`administered iloperidone at doses of 0 (vehicle control), 4, 16, and 64 mg/kg/day by oral
`gavage on Gestation Days 7 through 18 (day of sperm detection defined as Gestation Day
`1). Cesarean section was performed on Gestation Day 21 for evaluation of maternal
`reproductive parameters, pre- and postimplantation embryofetal lethality, fetal viability,
`weight, gender, and morphology.
`Parameters and endpoints evaluated:
`Maternal: survival and clinical signs (daily), body weight and food consumption
`(weekly), reproductive parameters (number of corpora lutea in ovaries, number of
`implantations
`(uterine staining by ammonium sulfide),
`resorptions
`(number and
`diameter), placental weights, live and dead fetuses).
`Fetal: viability, gender, individual weight, crown-rump length, external, visceral (Bouin’s
`fixative) and skeletal (alizarin staining) anomalies.
`The findings obtained at the autopsy and at fetal examination were statistically evaluated
`separately for the fetuses and for the litters.
`
`Results
`Mortality (dams 1: One HD dam was killed moribund after 9 treatments. There were no
`spontaneous deaths in any of the groups.
`Clinical signs (dams): Sedation and ptosis occurred in all dosed groups in a dose-related
`manner.
`
`Body weight (dams): Mean maternal body weights were dose-dependently decreased at
`HD and MD, by 18% and 6%, respectively, vs. control at~ term; the decrease was
`statistically significant from gestation day 14 onward. Mean body weight gains were
`markedly reduced during the treatment period by up to 92% and 34% of control values at
`HD and MD, respectively. There were no changes in mean body weight or weight gain at
`LD.
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`
`

`

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`The results are presented in the sponsor’s tables reproduced below and on the next page.
`
`181
`
`

`

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`

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`Segment II Study in Rats - Skeletal defects
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