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

Repeated dose toxicity: oral

Administrative data

Endpoint:

repeated dose toxicity: oral, other

Remarks:

6-mo study

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

GLP compliance:

yes

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

Duration of treatment / exposure:

6 month

Frequency of treatment:

daily

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.:

200 mg/kg bw/day (nominal)

No. of animals per sex per dose:

15/sex/grp

Control animals:

yes

Results and discussion

Any other information on results incl. tables

There were 11 unscheduled deaths. Of these, 8 were attributed to trauma during dosing or upon recapture (i.e., handling error). The cause of death in 1 CM, 1 LDF, and 1 HDM could not be determined. The primary drug-related clinical sign was sedation (to the point of unconsciousness) which was noted at all doses. One sign noted only at the HD was described as a peculiar tail reflex consisting of arching of the tail over the back. Difficulty in handling and food wastage also were limited to the HD grps. Body weight was affected in both males and females. In males, body weight loss was noted during the first wk of dosing (-5.4 gm vs. +47.0 gm in CM). Final mean body weight was reduced (compared to CM) at all doses in males (approx. 17, 31, and 35% in LDM, MDM, and HDM, respectively). In females, final mean body weight (compared to CF) was slightly elevated at the LD (3.5%), but reduced at the MD and HD (6 and 9%, respectively). Food consumption could not be accurately assessed at the HD due to instances of food wastage. In the lower dose grps, food consumption was reduced in males, but not females. There were no drug-related findings on ophthalmology (3, 6-mo); however, repeated orbital sinus bleeding may have compromised the evaluation. On hematology parameters, decreases were noted in wbc ct at the HD (37-20%), with the differential analysis indicating an increase in neutrophils (approx. 70%) and a decrease in lymphocytes (10-12%). The only notable findings in clinical chemistry parameters were increases in ALT (55-60% at Day 194), AST (81 and 45% at Day 194), and 5'-nucleotidase (36% at Day 194 in males only) at the HD. No drug-related findings were noted on urinalysis parameters. A complete battery of organ/tissue weights were not performed; only kidneys, liver, and testes were weighed. Changes in kidney and liver wt reflected decreases in body weight. Absolute testis wt, however, was similar among grps, reflecting either sparing of testis from body weight-induced changes or an increase in wt masked by reduced body weight gain.

According to the sponsor, there were no gross findings at necropsy (no summary or line listings were provided for survivors). The primary histopathology findings were as follows: (1) lung changes consisting of pleuritis (a few HD animals) and multifocal granulomatous pneumonia (all grps, but an increase in incidence and severity in 1 MDF and HD animals). This finding was characterized as aggregates of foamy macrophages and was attributed to aspiration of drug during dosing, (2) adrenal gland changes consisting of multifocal cystic degeneration and multifocal telangiectasia (i.e., dilation of small or terminal vessels) in MD and HD females (telangiectasia was also detected in 1 LDF), focal fibrosis in 1 HDF, and diffuse hypertrophy (characterized by increased cytoplasmic mass in cells of the zona fasciculata in MDF, and HD animals, (3) multifocal, suppurative prostatitis in MD and HD males. In terms of the adrenal changes, the sponsor suggested that adrenal cortical telangiectasia and cystic degeneration may "...represent different stages of the same degenerative process ... Cystic degeneration is .... believed to occur secondary to lesions in the cortical capillaries." Both findings were detected together in 1 MDF and 3 HDF; however, in 1 MDM, 3 MDF, 1 HDM, and 3 HDF only one or the other was found.

Applicant's summary and conclusion

Conclusions:

Sedation was the primary drug-related clinical sign and was observed at all doses, with severity being dose-related. Body weight was affected in both males and females; however, males were more markedly affected than females. Final body weights were reduced (compared to CM) by 17, 31, and 35% in LDM, MDM, and HDM. In females, final mean body weights (compared to CF) were slightly elevated in LDF, but reduced at the MD and HD (6 and 9%, respectively). No marked drug-related effects were observed on ophthalmology, hematology, clinical, chemistry, or urinalysis parameters. There were small changes in wbc ct and LFTs at the HD; however, the effects were small (LFT increased by <2-fold). A complete-battery of organ weights were not obtained; only kidney, liver, and testes were weighed. Changes in the weight of these organs were consistent with those in body weight.

Microscopic findings were detected in lung, adrenal gland, and prostate. Lung changes consisted of pleuritis in a few HD animals and multifocal granulomatous pneumonia. The latter finding was observed in all grps, including controls; however, the incidence and severity of the finding was dose-related. The granulomas were characterized as accumulations of foamy macrophages; the sponsor attributed this finding to "chronic, low level aspiration of the compound during dosing". However, there was no mention of detection of drug-related particles in lung samples. Foamy macrophages can result from drug-related phospholipidosis, as a reaction to inhalation of foreign bodies, or the cause may not be evident. The information provided was not sufficient to determine the possible cause. However, considering the dose-related incidence in males and females, a direct drug-related effect cannot be dismissed. Adrenal gland changes consisted of multifocal cystic degeneration and telangiectasia in MDF and HDF, and diffuse hypertrophy in MDF and HD animals. The diffuse hypertrophy was characterized as increased cytoplasmic mass in cells of the zona fasciculata. The sponsor attributed this finding to stress, and the blood vessel changes and cystic degeneration to age-related degeneration.
However, these explanations are not consistent with the dose-related incidences of these findings. The sponsor attributed the prostatitis to age and/or stress, as well as to
" ... hormones and immunologie factors ... " Again, the dose-related severity and incidence would suggest some drug involvement.

Executive summary:

In rat ziprasidone was administered by gavage at doses of 0, 10, 40, and 200 mg/kg. There were 11 unscheduled deaths, 8 of which were attributed to trauma during dosing or during recapture. (The nature of the injuries attributed to trauma sustained during re-capture suggested the possibility at the personnel responsible for care and for testing of the animals were not sufficiently trained. This issue was referred to DSI, but was not adequately resolved.) The other three deaths were not dose-related. Sedation was the primary drug-related clinical sign and was observed at all doses, with severity being dose-related. Body weight was affected in both males and females; however, males were more markedly affected than females. Final body weights were reduced (compared to CM) by 17, 31, and 35% in LDM, MDM, and HDM. In females, final mean body weights (compared to CF) were slightly elevated in LDF, but reduced at the MD and HD (6 and 9%, respectively). No marked drug-related effects were observed on ophthalmology, hematology, clinical, chemistry, or urinalysis parameters. There were small changes in wbc ct and LFTs at the HD; however, the effects were small (LFT increased by <2-fold). A complete-battery of organ weights were not obtained; only kidney, liver, and testes were weighed. Changes in the weight of these organs were consistent with those in body weight. According to the sponsor, there were no gross findings; however, no summary table(s) or line listings were provided. Microscopic findings were detected in lung, adrenal gland, and prostate. Lung changes consisted of pleuritis in a few HD animals and multifocal granulomatous pneumonia. The latter finding was observed in all grps, including controls; however, the incidence and severity of the finding was dose-related. The granulomas were characterized as accumulations of foamy macrophages; the sponsor attributed this finding to "chronic, low level aspiration of the compound during dosing". However, there was no mention of detection of drug-related particles in lung samples. Foamy macrophages can result from drug-related phospholipidosis, as a reaction to inhalation of foreign bodies, or the cause may not be evident. The information provided was not sufficient to determine the possible cause. However, considering the dose-related incidence in males and females, a direct drug-related effect cannot be dismissed. Adrenal gland changes consisted of multifocal cystic degeneration and telangiectasia in MDF and HDF, and diffuse hypertrophy in MDF and HD animals. The diffuse hypertrophy was characterized as increased cytoplasmic mass in cells of the zona fasciculata. The sponsor attributed this finding to stress, and the blood vessel changes and cystic degeneration to age-related degeneration.

However, these explanations are not consistent with the dose-related incidences of these findings. The sponsor attributed the prostatitis to age and/or stress, as well as to " ... hormones and immunologie factors ... " Again, the dose-related severity and incidence would suggest some drug involvement.