4-(1,2-benzothiazol-3-yl)-1-[2-(6-chloro-2-oxo-2,3-dihydro-1H-indol-5-yl)ethyl]piperazin-1-ium (7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonate

Toxicity to reproduction

Administrative data

Endpoint:

reproductive toxicity, other

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Data source

Reference

Reference Type:

secondary source

Title:

APPROVAL PACKAGE FOR: APPLICATION NUMBER 20-825. Pharmacology Review(s).

Bibliographic source:

Food and Drug Administration - Center for Drug Evaluation and research.

Report date:

2000

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

5-[2-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]ethyl]-6-chloro-1,3-dihydroindol-2-one;hydrate;hydrochloride

Cas Number:

138982-67-9

Molecular formula:

C21H24Cl2N4O2S

IUPAC Name:

5-[2-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]ethyl]-6-chloro-1,3-dihydroindol-2-one;hydrate;hydrochloride

Test material form:

solid

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

not specified

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

10 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

40 mg/kg bw/day (nominal)

Doses / concentrations 4

Dose / conc.:

160 mg/kg bw/day (nominal)

No. of animals per sex per dose:

20/grp

Results and discussion

Any other information on results incl. tables

There were no unscheduled deaths during the study. Clinical signs, consisting of ptosis, prostration, piloerection, and dyspnea were observed in all MD and HD animals. Body weight was reduced throughout the dosing period at all doses (3, 7, and 10% in LDF, MDF, and HDF, compared to CF).

There were no apparent gross pathology findings in the dams. In terms of litter parameters, there were no drug-related effects on no. of corpora lutea, implantation sites, viable fetuses, dead implants, or male/female ratio. Fetal body wt was lower in all dosed grps (male and female); however, the effect was statistically significant at the MD and HD in males, and at the HD in females.

There were no clear drug-related extemal fmdings; flexed paws were detected in 1 LD fetus and 4 HD fetuses (1 litter). Hematomas were observed in 2-4 fetuses in each grps, including controls. There were also no drug-related visceral findings. The sponsor provided summaries only of selected skeletal findings, i. e., variations in ribs and degree of ossification of selected bones.  

PK data were collected in satellite animals (5/grp) on Day 17 (the last day of dosing). The concentration of ziprasidone in maternal plasma, amniotic fluid, and fetal homogenates were quantitated. Mean levels (± SD) were 3.66 ± 1.31 (1-hr value), 0.41 ± 0.15, and 1.31 ± 0.08 microg/mL or g wet wt, respectively.

Applicant's summary and conclusion

Conclusions:

There were no unscheduled deaths. Clinical signs (prostration, piloerection, dyspnea) were observed in all MD and HD animals. Body weight was reduced throughout the dosing period in MDF and HDF (7 and 10% compared to CF). There were no drug-related effects on the number of viable fetuses, dead implants, or the male/female ratio. Fetal body weight was reduced (compared to CF) at all doses, although differences were statistically significant only at the MD and HD. There were no external or visceral findings in fetuses, however, delays in ossification of certain skeletal components were noted at all doses.

In the separate maternal toxicity drug-related clinical signs (prostration, piloerection) were evident at all doses, with hunched posture and lacrimation observed in all MD and HD animals. Body weight loss was observed in MD and HDF and body weight gain was reduced in LDF during the first few days of dosing (i.e., Days 6-9 of gestation). Body weight gain was reduced in MDF and HDF during the rest of the dosing period, whereas in LDF, body wt gain tended to normalize. Catch-up growth occurred after the end of dosing in HDF. Even though clinical signs and body weight effects were consistent with maternal toxicity, none of the reproductive parameters measured (including viable litters, no. of fetuses, embryomortality rate, fetal body wt) was affected.

Executive summary:

In the Segment II study in rats, ziprasidone was administered at doses of 0, 10, 40, and 160 mg/kg from Day 6 through Day 17 of gestation. There were no unscheduled deaths. Clinical signs (prostration, piloerection, dyspnea) were observed in all MD and HD animals. Body weight was reduced throughout the dosing period in MDF and HDF (7 and 10% compared to CF). There were no drug-related effects on the number of viable fetuses, dead implants, or the male/female ratio. Fetal body weight was reduced (compared to CF) at all doses, although differences were statistically significant only at the MD and HD. There were no external or visceral findings in fetuses, however, delays in ossification of certain skeletal components were noted at all doses. In a separate maternal toxicity, ziprasidone was administered to Sprague-Dawley rats at doses of 0, 10, 40, and 160 mg/kg from Day 6 to Day 15 of gestation.

Drug-related clinical signs (prostration, piloerection) were evident at all doses, with hunched posture and lacrimation observed in all MD and HD animals. Body weight loss was observed in MD and HDF and body weight gain was reduced in LDF during the first few days of dosing (i.e., Days 6-9 of gestation). Body weight gain was reduced in MDF and HDF during the rest of the dosing period, whereas in LDF, body wt gain tended to normalize. Catch-up growth occurred after the end of dosing in HDF. Even though clinical signs and body weight effects were consistent with maternal toxicity, none of the reproductive parameters measured (including viable litters, no. of fetuses, embryomortality rate, fetal body wt) was affected.