2H-Indol-2-one, 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-

Toxicity to reproduction

Administrative data

Endpoint:

reproductive toxicity, other

Remarks:

mating and fertility

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

Principles of method if other than guideline:

Assessment of mating and fertility parameters.

GLP compliance:

not specified

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

Results and discussion

Any other information on results incl. tables

There were no drug-related deaths during the study. Clinical signs consisted primarily of sedation (dose-dependent), which was noted throughout the dosing period, and chromodacryorrhea (MDM, HD animals). Body weigbt was reduced in a dose-related manner in males, with the effect being significant only at the MD and HD (10-18%). In females, body weight during gestation was significantly lower (as compared to CF) at the HD (maximum of 9% on Day 20 of gestation).

Body weight gain was reduced primarily at the HD and primarily during the first wk of gestation (36% vs 23 and 16% at Wk 2 and Wk 3, respectively). During Wk 2, body wt gain was significantly reduced at all doses (11, 13, and 23% in LDF, MDF, and HDF, respectively); however, mean body wts on Day 14 were within 0-2% of CF at the LD and MD (327.8 ± 17.6, 326.6 ± 23.4, 322.1 ± 20.4 in CF, LDF, and MDF, respectively). (It should be noted that the sponsor'& summaries or the body wt data (tables, figs) during gestation included only those dams with viable pupa and not all pregnant dams. It should also be noted that there was a discrepancy between the no. or dams per grp listed in the summary table and the no. or pregnant dama with viable pups listed in the individual data tables.

According to the individuai tables, there were 33, 36, 35, and 33 CF, LDF, MDF, and HDF, respectlvely, whereas the summary table listed "n" as 32, 31, 34, and 32, respectively.

Even with missing body wt data taken into account, the "n's" do not agree.]

Body wt was reduced by 7-10% at the HD (compared to CF) throughout the lactation period; however, the differences between these two grps achieved statisticaliy significant only

sporadically.

Body wt gain during lactation was fairly similar among grps and was significantly higher in HDF during the last wk of lactation (-8.5 ± 11.5, -13.5 ± 14.5, -7.7 ± 18.3, and 2.1 ± 14.5 g in CF, LDF, MDF, and HDF, respectively).

In males, food intake was reduced at all doses during the premating period (8-17%). In females, food intake was reduced only in HDF and only during Wks l and 2. During lactation, food intake was reduced by 11-19% in HDF. On fertility parameters (taking all dams into account), the following effects were observed: (1) an increase in the cohabitation interval (i.e., time to sperm-positive vaginal smear). The median time was 3, 4, 3-4, and 5-7 for CF, LDF, MDF, and HDF, respectively. The sponsor considered only HDF affected. The median interval was 1-4 in CF, LDF, and MDF, and 5-7 days in HDF; at the HD, a sperm-positive vaginal smear was not obtained in 10 females until >=Day 10. The number of females with sperm-positive vaginal smears at Day 10 or later was 3, 3, 6, and 10 CF, LDF, MDF, and HDF, respectively. (2) an increase in the no. of days during the premating period with no sign of estrus in all dose grps (1/40 CF, 7/40 LDF, 12/40 MDF, and 13/40 HDF). [The sponsor noted that "... days on which estrus was observed were recorded ... "; however, There was a large individuai variation between animals within each dose group and because all stages of the estrous cycle were not recorded, clear pattens did not emerge after one week of examination." No drug-related effects were noted on the number of sperm-positive vaginal smears, pregnant females, total copulation rate (98-100%), or total pregnancy rate (85-90%).

The only significant drug-related finding was a decrease in mean fetal (M/F) body wt in MDF (7%) and HDF (9%); the 4% decrease in mean fetal body wt for LDF was not statistically significant. Although not statistically significant, the following were also noted: (1) the no. of corpora lutea, implantation sites, and of viable fetuses were slightly reduced at the HD (4-11 %), (2) the no. of resorptions was increased (45%) at the MD and HD, and (3) the ratio of M/F pups was lower (20%) at the HD.

Examination of fetuses indicated no apparent drug-related extemal or visceral findings. The sponsor provided a summary of selected skeletal findings and expressed the summary data in terms of an "ossification index" (mean ± SD) or number of affected fetuses. The data expressed as "ossification index" could not be compared to the individuai data. In addition, the sponsor stated that "Only fetuses without skeletal variations in bones listed ... were included in the ossification index".

There were no apparent drug-related effects on the length of gestation. However, decreases in implantation sites were noted in HDF and the number of live pups (per litter) was reduced at both the MD and HD. The majority of pups in one MD litter were stillborn which did contribute to the overall higher percentage of dead pups at the MD. However, the percentage dead in the affected MD litter was 59% (i.e., 10/17), not greater than 60%". In addition, the no. of litters in which at least one pup was stillborn was increased at the MD and HD (3/17, 3/20, 7/17, and 10/18 affected litters in CF, LDF, MDF, and HDF, respectively). There was also a decrease in survival rate on bay 4 at the HD, although the effect was not statistically significant. Individuai survival data were not provided.)

In F1 pups body wt was reduced throughout the lactation period in HD male and female pups (9-14%) (birth wts, i.e., Day 0; were not provided). After weaning, body wt was still reduced in HD pups during the first wk after weaning; however, over the next 3 wks, body wt tended to normalize (more rapidly in male pups) and by Day 49 postpartum, there were no significant differences among grps.

In terms of developmental milestones, no drug-related effects were noted on pinna detachment, surface righting, eye opening, visual cliff avoidance, or motor activity. Delays (expressed as the % of litters meeting criterion on test days) in the following were noted: (1) negative geotaxis in HDM, (2) eruption of incisors in HDF, (3) grip strength in MDM and HDM, and (4) air righting at all doses in males. By the end of testing, the only effect still evident was a delay in air right in HDM. Postweaning, there were no significant drug-related effects on locomotor activity, vaginal opening, and preputial separation; however, horizontal counts tended to be increased in females in a dose-related manner (2-24%). Reproductive perfonnauce was not adversely affected in F1 animals.

Applicant's summary and conclusion

Conclusions:

In the definitive study, there were no clear drug-related effects on the number of corpora lutea, implantation sites, resorptions, or live fetuses. However, the number of resorptions tended to be higher in MDF and HDF and the no. of live fetuses tended to be lower in HDF. Also, the ratio of males to females was reduced in HDF [None of these differences on reproductive parameters achieved statistical significance]. No extemal or visceral findings were observed, but delayed or absent ossification of certain skeletal components was increased at all doses. Fetal body wt was reduced at the MD and HD in the definitive study. The number of stillborn pups was increased in both studies at doses >5 mg/kg. Pup survival during the first four days of lactation was reduced at the HD (40 mg/kg) in the definitive study, and at all doses in the preliminary study. Pup body wt was reduced the HD in both studies. In the definitive study, this effect was noted throughout the lactation period in HD pups. Also, there were delays in a number of developmental milestones (e.g., negative geotaxis, eruption of incisors, grip strength, air righting) primarily at the HD in the definitive study; however, delays in air righting were noted at all doses in male pups. No effects were noted on the reproductive performance of F1 animals.

Executive summary:

The effect of ziprasidone on mating and fertility was tested in Sprague-Dawley rats in two studies (one preliminary). In the preliminary study, ziprasidone was administered by gavage at doses of 0, 10, 40, and 160 mg/kg; included in this study was a grp in which treated (HD) males were mated with untreated females and a grp in which treated females (HD) were mated with untreated males. Females were dosed from 29 days prior to mating, throughout gestation and lactation. Males were dosed from 4 wks prior to mating through the mating period.

In the definitive study, ziprasidone was administered at doses of 0, 5, 10, and 40 mg/ kg (oral by gavage). In females, dosing was started 15 day prior to mating and continued throughout the lactation period. Males were dosed for 72 days prior to mating and during the mating period. Each male was mated with 2 females. One-half of the dams were delivered by Cesarean section and fetuses were examined. The remaining dams were allowed to deliver naturally and postnatal pup development was assessed.

In treated dams, there were no unscheduled deaths; however, drug-related effects were noted at all doses. Clinical signs consisted of dose-related sedation and chromodacryorrhea (>5 mg/kg). Body wt gain was reduced primarily at doses >= 40 mg/kg during gestation and, in the definitive study, body wt remained 7-10% lower than CF in HDF followed through the lactation period. Mating was delayed at doses >5 mg/kg in both studies. The pregnancy rate, however, was reduced only at 160 mg/kg. Drug-related effects on fertility may be due to effects on the female since the pregnancy rate was not affected when HDM (160 mg/kg) were mated with untreated females. Although estrus cycles were noted in both Segment I studies, the sponsor noted in the report for the definitive study that the data were too variable and no clear pattem could be determined. There was no discussion of the estrus data in the report of the preliminary study). In the definitive study, there were no clear drug-related effects on the number of corpora lutea, implantation sites, resorptions, or live fetuses. However, the number of resorptions tended to be higher in MDF and HDF and the no. of live fetuses tended to be lower in HDF. Also, the ratio of males to females was reduced in HDF [None of these differences on reproductive parameters achieved statistical significance]. No extemal or visceral findings were observed, but delayed or absent ossification of certain skeletal components was increased at all doses. Fetal body wt was reduced at the MD and HD in the definitive study. The number of stillborn pups was increased in both studies at doses >5 mg/kg. Pup survival during the first four days of lactation was reduced at the HD (40 mg/kg) in the definitive study, and at all doses in the preliminary study. Pup body wt was reduced the HD in both studies. In the definitive study, this effect was noted throughout the lactation period in HD pups. Also, there were delays in a number of developmental milestones (e.g., negative geotaxis, eruption of incisors, grip strength, air righting) primarily at the HD in the definitive study; however, delays in air righting were noted at all doses in male pups. No effects were noted on the reproductive performance of F1 animals.