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

Carcinogenicity

Description of key information

The results of two-year mouse and rat carcinogenicity studies were taken to the Carcinogenicity Assessment Committee - Executive Committee (CAC-EC) on April 28, 1998. The report of that meeting is not yet available. It was agreed that both studies were adequate and that there were dose-related increases in female mice in pituitary gland adenomas and carcinomas and mammary gland adenocarcinomas. The doses at which these tumors occurred were equal to or greater than the maximum recommended human dose of 200 mg/day on a surface area basis. A no-effect dose was not established. There was no increase in tumors in male mice or either sex of rat. Tumors of the mammary and pituitary glands (and also of the endocrine pancreas, not increased in these studies with ziprasidone) have been increased in studies with other drugs of this class and are thought to be mediated by chronic exposure to elevated prolactin levels in rodents. The relevance to humans is unknown.

Overall, available data are inconclusive for the classification of the substance.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

carcinogenicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

other information

Justification for type of information:

1. HYPOTHESIS FOR THE ANALOGUE APPROACH

Ziprasidone and ziprasidone hydrochloride monohydrate have the same common functional groups, breakdown products and common mechanism of action.
The only structural difference is that the source molecule is the salified monohydrate form of ziprasidone.
In dilute aqueous conditions of defined pH a salt will behave no differently to the parent acid, at identical concentration of the particular speciated form present and will be fully dissociated.


2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)

The purity of the chemical source substance i.e. ziprasidone hydrochloride monohydrate is not well specified in the reference document (secondary literature). However, the source of the data is the FDA Pharmacology review with application number 20-825, so, since this is a review of a substance used as an active pharmaceutical ingredient we can be assumed that impurity relevant for the hazard profile of the substance are not present in the test material.

For the chemical target, there are no relevant (for the hazard assessment of the substance) impurities, as reported by the Company.


3. ANALOGUE APPROACH JUSTIFICATION

As a results of the bibliographic search performed for ziprasidone is well clear that toxicological information on the ziprasidone hydrochloride monohydrate may be used to assess adverse health effects arising from exposure to ziprasidone - with the application of a molecular weight correction, if relevant -, if for this latter no data are available.

While the structure and the molecular weight of the two substance (i.e. source and target) are very similar, and the mechanism of action is common, the salts form i.e. the source substance is more soluble in water, so it is foreseeable that its bioavailability is greater and the read-across represents, in this case, a conservative approach to assess the heath adverse effects of ziprasidone.

Value of solubility :
Ziprasidone about 0.5 μg/mL
Ziprasidone hydrochloride about 210 μg/mL


4. DATA MATRIX

Analogue approach has been applied for the hazard assessment of the following endpoint of ziprasidone:
- Acute oral toxicity
- Acute dermal toxicity
- Skin corrosion/irritation
- Eye Irritation/corrosion
- Repeated dose toxicity
- Carcinogenicity
- Mutagenicity
- Toxicity to reproduction

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

The results of two-year mouse and rat carcinogenicity studies were taken to the Carcinogenicity Assessment Committee - Executive Committee (CAC-EC) on April 28, 1998. The report of that meeting is not yet available. It was agreed that both studies were adequate and that there were dose-related increases in female mice in pituitary gland adenomas and carcinomas and mammary gland adenocarcinomas. The doses at which these tumors occurred were equal to or greater than the maximum recommended human dose of 200 mg/day on a surface area basis. A no-effect dose was not established. There was no increase in tumors in male mice or either sex of rat. Tumors of the mammary and pituitary glands (and also of the endocrine pancreas, not increased in these studies with ziprasidone) have been increased in studies with other drugs of this class and are thought to be mediated by chronic exposure to elevated prolactin levels in rodents. The relevance to humans is unknown.

Conclusions:

The results of two-year mouse and rat carcinogenicity studies were taken to the Carcinogenicity Assessment Committee - Executive Committee (CAC-EC) on April 28, 1998. The report of that meeting is not yet available. It was agreed that both studies were adequate and that there were dose-related increases in female mice in pituitary gland adenomas and carcinomas and mammary gland adenocarcinomas. The doses at which these tumors occurred were equal to or greater than the maximum recommended human dose of 200 mg/day on a surface area basis. A no-effect dose was not established. There was no increase in tumors in male mice or either sex of rat. Tumors of the mammary and pituitary glands (and also of the endocrine pancreas, not increased in these studies with ziprasidone) have been increased in studies with other drugs of this class and are thought to be mediated by chronic exposure to elevated prolactin levels in rodents. The relevance to humans is unknown.
Overall, available data are inconclusive for the classification of the substance.

Reference 2

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Species:

mouse

Strain:

Swiss

Details on species / strain selection:

Swiss mice

Sex:

male/female

Route of administration:

oral: feed

Duration of treatment / exposure:

Dosing was continuous for 720-724 days.

Frequency of treatment:

daily

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

50 mg/kg bw/day (nominal)

Dose / conc.:

100 mg/kg bw/day (nominal)

Dose / conc.:

200 mg/kg bw/day (nominal)

No. of animals per sex per dose:

50/sex/grp except 100/sex/grp for C grps.

Control animals:

yes

Mortality: there were no significant differences in mortality among grps in either males or females.

Clinical signs: the data were not summarized. According to the sponsor, there were no drug-related findings.

Body weight: body weight was reduced compared to C grps in both males and females. At 200 mg/kg, body weight was 8 and 10% lower in HDM and HDF, respectively, than in combined C grps. Body weight gain was reduced by 8, 19, and 34% in LDM, MDM, and HDM, respectively, and by 10, 33, and 31% in LDF, MDF, and HDF, respectively, at the end of the dosing period. In females, body weight was increased (compared to CF) at the LD up to Day 512 and sporadically at the MD up to Day 337. Body weight was significantly reduced in MDF (compared to CF) only at the last measurement time (i.e., Day 715). At the HD, body weight was reduced (compared to CF) only from Day 617 on.

Food consumption: food consumption was reduced at all doses in males and females throughout the dosing period. By the end of the study, food consumption was reduced by 10, 13, and 13% at the LD, MD, and HD, respectively, in males and by 6, 8, and 5% at the LD, MD, and HD, respectively, (significantly only at the MD) in females.

Water consumption: in males, water consumption was reduced throughout the measurement period at all doses; by the end of the study, water intake was 14, 19, and 25% lower in LDM, MDM, and HDM, respectively, compared to CM. In females, water consumption was affected sporadically throughout the measurement period; however, the changes were not necessarily dose-related; by the end of the study, water intake in LDF, MDF, and HDF were 20, 7, and 28%, respectively, lower than in CF.

Ophthalmology: there were no apparent drug-related ophthalmology findings upon examination of the anterior segment of the eye.

Terminal studies

Gross pathology: no summary table was provided for gross pathology findings.

Organ/tissue wts: there were no drug-related findings in females. In males, significant decreases in the absolute wt of brain (LD, HD), heart (LD, HD), kidney (all doses), and liver (HD) were noted. Relative wts of all of these but brain were also reduced (heart: 6% at HD; kidney: 8 and 10% at LD and HD; liver: 4% at HD).

Histopathology: pituitary adenomas in 10/10 HDF examined were prolactin-positive. In comparison, the sponsor noted that in pituitary adenomas examined in 3/3 CF in a previous study were not prolactin-positive.

Conclusions:

The adequacy of the doses was based solely on the drug-related effects on body weight in HDM and HDF (8 and 10%, respectively). In this reviewer's opinion, it is unfortunate when body weight effects alone define an MTD, since the primary reason for maintaining body wt is to avoid presumed protective effects of reduced body wt gain (i.e., a decrease in the spontaneous rate of tumors). There is also the possibility that, without associated toxicities, the reductions in body wt may reflect only unpalatability of the diet (no
gavage dosing studies were available for comparison). This is particularly relevant for male mice, in which no other drug-related toxicities were observed. Neoplastic findings (pituitary adenoma, adenoma/carcinoma combined; mammary gland adenocarcinoma) were observed in females at all doses. The microscopic changes in ovary, pituitary, and mammary gland are consistent with elevations in prolactin.

Drug-effects on serum prolactin were not tested in the 2-yr carcinogenicity; however, a special study was conducted after completion of the 2-yr study to assess drug-related changes in serum prolactin. In this special 1-mo dietary study in CD-1 mice, ziprasidone was reported to increase serum prolactin levels in females, but not males, at all doses tested (50, 100, and 200 mg/kg). Only the effects at the MD and HD were statistically significant, and increases were not dose-proportional (approx. 4-fold increases at both doses). [In general, there was marked interanimal variability in serum prolactin levels.]
It should be noted, however, that drug-related effects were, in general, greater in the 1-mo study than in the 2-yr carcinogenicity study. For example, there were 3 drug-related deaths in HDF and clinical signs (decreased activity) at all doses; no drug-related mortality or clinical signs were observed in the 2-yr study at the same doses. [It is possible that the dose-escalation procedure in the 2-yr study (i.e., increases in dose from 50 mg/kg to final MD and HD over 15-29 days) prevented mortality, but this would not explain the drug-related decreases in activity observed at the LD in the 1-mo study. According to the sponsor, doses were gradually increased in the dose-selection and 2-yr studies to "... attenuate the expected initial decrease in body weight ..." No mention was made of more serious toxicities.] In addition, body wt effects were similar in the 1-mo and 2-yr studies. It is unfortunate that TK data were not available for either study.

Executive summary:

Dose-selection for the definitive studies were based on 1- and 3-mo dietary studies in mice, the strain used in the 2-yr study.

The substance was administered orally in the diet to 50/sex/grp at doses of 0, 0, 50, 100, and 200 mg/kg. Dosing was initiated at 50 mg/kg for the 3 drug-treated grps, and increased after 14 days to 100 mg/kg in the MD and HD grps, then to 200 mg/kg in the HD on Day 29. Dosing was continuous for 720-724 days.

The adequacy of the doses was based solely on the drug-related effects on body weight in HDM and HDF (8 and 10%, respectively). In this reviewer's opinion, it is unfortunate when body weight effects alone define an MTD, since the primary reason for maintaining body wt is to avoid presumed protective effects of reduced body wt gain (i.e., a decrease in the spontaneous rate of tumors). There is also the possibility that, without associated toxicities, the reductions in body wt may reflect only unpalatability of the diet (no

gavage dosing studies were available for comparison). This is particularly relevant for male mice, in which no other drug-related toxicities were observed. Neoplastic findings (pituitary adenoma, adenoma/carcinoma combined; mammary gland adenocarcinoma) were observed in females at all doses. The microscopic changes in ovary, pituitary, and mammary gland are consistent with elevations in prolactin.

Drug-effects on serum prolactin were not tested in the 2-yr carcinogenicity; however, a special study was conducted after completion of the 2-yr study to assess drug-related changes in serum prolactin. In this special 1-mo dietary study in CD-1 mice, ziprasidone was reported to increase serum prolactin levels in females, but not males, at all doses tested (50, 100, and 200 mg/kg). Only the effects at the MD and HD were statistically significant, and increases were not dose-proportional (approx. 4-fold increases at both doses). [In general, there was marked interanimal variability in serum prolactin levels.]

It should be noted, however, that drug-related effects were, in general, greater in the 1-mo study than in the 2-yr carcinogenicity study. For example, there were 3 drug-related deaths in HDF and clinical signs (decreased activity) at all doses; no drug-related mortality or clinical signs were observed in the 2-yr study at the same doses. [It is possible that the dose-escalation procedure in the 2-yr study (i.e., increases in dose from 50 mg/kg to final MD and HD over 15-29 days) prevented mortality, but this would not explain the drug-related decreases in activity observed at the LD in the 1-mo study. According to the sponsor, doses were gradually increased in the dose-selection and 2-yr studies to "... attenuate the expected initial decrease in body weight ..." No mention was made of more serious toxicities.] In addition, body wt effects were similar in the 1-mo and 2-yr studies. It is unfortunate that TK data were not available for either study.

Reference 3

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Species:

rat

Strain:

Long-Evans

Sex:

male/female

Route of administration:

oral: feed

Duration of treatment / exposure:

2 years

Frequency of treatment:

daily

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

2 mg/kg bw/day (nominal)

Dose / conc.:

6 mg/kg bw/day (nominal)

Dose / conc.:

12 mg/kg bw/day (nominal)

No. of animals per sex per dose:

50/sex/grp + 16/sex/grp (LD, MD, HD grps only) for TK analysis.

Control animals:

yes

Mortality: there were no drug-related increases in mortality. There was a tendency for survival rate to be higher in HD grps (25-30% vs 14-23% in C grps).

Clinical] signs: according to the sponsor, there were no drug-related clinical signs.

Ophthalmology: there were no apparent drug-related findings (C and HD groups only were examined, 25/sex/grp).

Body weight: in males, body weight was reduced (compared to CM) at the MD and HD (maximum of 5 and 9-10%, respectively) from Day 113-176 and Day 57-568, respectively. However, by the end of the dosing period, body weights were fairly similar among grps, due, in part, to mean body weight loss in the reference C grp (designated C1). Overall mean body weight gain was similar among grps.

In females, body weight was lower (compared to CF) in dose grps throughout the dosing period. Up to Day 372, however, the effect ranged from 4-7% and was not dose-related and not always statistically significant. By Day 400, body weight in HDF was significantly lower than in CF and remained so throughout the rest of the dosing period (maximum effect, 19% on Day 680). During this period, body weight tended to be lower in LDF and MDF as well, achieving statistical significance at the LD (maximum effect, 15% on Day 680). Overall mean body-weight gain was significantly reduced only at the HD (22%).

Food consumption: in males, food consumption was lower throughout most of the dosing period at the HD and during portions of the dosing period (particularly during Days 148-344)-at the MD. From Day 596 on, food consumption was slightly elevated in HDM (<= 22%) when compared to the reference CM (but fairly similar to the second CM grp).

In females, food consumption was lower at the HD throughout the dosing period, and during the first 78 days of dosing at the lower doses.

Hematology: there were no apparent drug-related changes. Wbc counts were elevated sporadically in both C and HD grps in males.

Clinical chemistry: there were no marked drug-related effects. Total protein was and albumin were reduced at all doses in males on Day 722 (total protein: 7, 9, and

10% at the LD, MD, and HD, respectively; albumin: 10-11%). Sodium was slightly (but significantly) reduced in HDM and HDF (2%) on Day 722.

TK: The sponsor did not provide estimates of variability for the AUC data, nor

individuai AUC data.

Plasma exposure (Cmax , AUC) was approx. 2-fold higher in females than in males at all doses.

Terminal studies

Gross pathology: there were no clear drug-related findings.

Organ/tissue wts: the only effects were decreases in wts of several organs (i.e., liver, heart, and adrenal) in HDF due to decreases in body weight; relative wts of these organs were similar to or slightly higher than in CF.

Histopathology: The only, significant findings were an increase in beta-keratoacanthoma (incidental) in HDM and an increase in mammary gland fibroadenoma in HDF. [According to the sponsor, when adjusted for multiple pair-wise comparisons (using Bonferonni), the finding in HDM was no longer statistically significant.] The finding in females, however, would not be statistically significant using the recommended p-values for common tumors.

The eye mineralization was characterized as "slight to mild focal to multifocal corneal mineralization" by the sponsor, but was not considered a drug-related finding.

Conclusions:

The study in rats was negative, i.e., no drug-related increases in neoplastic findings were observed in either males or females. The adequacy of dosing was demonstrated only by reductions in body weight in HD animals (10 and 19% in HDM and HDF, respectively) as compared to controls. Although this is adequate justification for limiting the high dose (if
not due to unpalatability of the drug-diet admixture), it is unfortunate that other dose limiting toxicities were not observed since the primary reason for limiting body weight effects is to avoid a loss in sensitivity due to the potential protective effects of body weight "restriction" on spontaneous tumor rates. Regarding the palatability issue, it is unlikely that the reduced body wts (compared to C grps) in HD animals was due to unpalatability of the diet. In the chronic (6-mo) study in rats dosing was by gavage and body wts were reduced in males at all doses (17, 31, and 35% at 10, 40, and 200 mg/kg, respectively); in females, however, body wt was slightly elevated at the LD (i.e., 10 mg/kg), but reduced by 6 and 9% at the MD and HD). Although body wt was not as affected in females, it is unlikely that there is a sex difference in palatability. Unfortunately, a different strain of rats was used in the 6-mo study (Sprague-Dawley instead of Long-Evans) and, therefore, the studies may not be entirely comparable.

Executive summary:

The substance was administered orally in the diet to Long-Evans rats at doses of 0, 0, 2, 6, and 12 mg/kg. Doses were titrated to the final levels over the flrst 2-4 wks of the study. Observations consisted of the following: clinical signs, body wt, food consumption, ophthalmology, hematology, clinical chemistry, urinalysis, TK, and terminal studies

[organ/tissue wts (kidney, liver, brain, heart, adrenals, and testes), gross pathology, histopathology]. The control grps were combined for statistical analysis.

The study in rats was negative, i.e., no drug-related increases in neoplastic findings were observed in either males or females. The adequacy of dosing was demonstrated only by reductions in body weight in HD animals (10 and 19% in HDM and HDF, respectively) as compared to controls. Although this is adequate justification for limiting the high dose (if

not due to unpalatability of the drug-diet admixture), it is unfortunate that other dose limiting toxicities were not observed since the primary reason for limiting body weight effects is to avoid a loss in sensitivity due to the potential protective effects of body weight "restriction" on spontaneous tumor rates. Regarding the palatability issue, it is unlikely that the reduced body wts (compared to C grps) in HD animals was due to unpalatability of the diet. In the chronic (6-mo) study in rats dosing was by gavage and body wts were reduced in males at all doses (17, 31, and 35% at 10, 40, and 200 mg/kg, respectively); in females, however, body wt was slightly elevated at the LD (i.e., 10 mg/kg), but reduced by 6 and 9% at the MD and HD). Although body wt was not as affected in females, it is unlikely that there is a sex difference in palatability. Unfortunately, a different strain of rats was used in the 6-mo study (Sprague-Dawley instead of Long-Evans) and, therefore, the studies may not be entirely comparable.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Mode of Action Analysis / Human Relevance Framework

The relevance to humans is unknown.

Justification for classification or non-classification

Tumors of the mammary and pituitary glands (and also of the endocrine pancreas, not increased in these studies with ziprasidone) have been increased in studies with other drugs of this class and are thought to be mediated by chronic exposure to elevated prolactin levels in rodents. The relevance to humans is unknown.

Overall, available data are inconclusive for the classification of the substance.