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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2011
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2011
Report Date:
2011

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
Oral (BID Gavage) Pre- and
Postnatal Development Study in Sprague Dawley Rats
GLP compliance:
yes (incl. certificate)

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: Solid, powder

Test animals

Species:
rat
Strain:
Crj: CD(SD)

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: Hypromellose
Duration of treatment / exposure:
From gestation day 6 through lactation day 20 for a total of 36-38 days of dose administration
Frequency of treatment:
Twice daily in equally divided doses (approximately 10 hours apart)
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day
Dose / conc.:
50 mg/kg bw/day
Dose / conc.:
100 mg/kg bw/day
Dose / conc.:
200 mg/kg bw/day
No. of animals per sex per dose:
25
Control animals:
yes

Examinations

Maternal examinations:
In the 200 mg/kg/day group, 2 females were euthanized in extremis on gestation days 10 and
23 and 1 female was found dead on lactation day 8. In addition, 8 females in this group had
total litter loss during lactation days 0-5. Relevant clinical findings observed for these
females prior to death/euthanasia at approximately 1 hour following each daily dose. These findings consisted primarily of
behavior-related findings (prostration, hunched posture, hindlimbs splayed, rocking, lurching,
or swaying while ambulating, impaired use of hindlimbs, and body drags [abdomen touches
surface]) and body pale, body cool to touch, and red and/or clear material around the nose
and/or mouth and were noted 4-17 days prior to death/euthanasia/total litter loss. Due to
mortality observed in the 200 mg/kg/day group animals assigned to the pre- and postnatal
phase, 7 dams and their litters in the 200 mg/kg/day group previously assigned to the
toxicokinetic phase were transferred to the main study phase on lactation day 8 or 9. With the
exception of 1, 2, and 2 females in the control, 50, and 200 mg/kg/day groups, respectively,
that failed to deliver, all other females survived to lactation day 21.
Test item-related excreta-related findings of light brown and yellow feces and/or decreased
defecation were observed for females that were found dead, euthanized in extremis, with total
litter loss, failed to deliver, or that survived to the scheduled necropsy in the 50, 100, and
200 mg/kg/day groups at the daily examinations beginning as early as gestation day 7 and
generally continuing through lactation day 7; the decreased defecation correlated with the
reduced body weight gains and food consumption noted for these females. Test item-related
clinical findings, including behavior-related findings (prostration, rocking, lurching, or
swaying while ambulating, hunched posture, hindlimbs splayed, body drags [abdomen makes
contact with surface], impaired use of hindlimbs), body cool to touch, body pale, red and/or
clear material around the nose and/or mouth, dilated pupils were observed in the
200 mg/kg/day group approximately 1 hour following each daily dose administration
generally during gestation day 6 through lactation day 20.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Mean body weight losses and lower mean body weight gains
and food consumption at 100 and 200 mg/kg/day
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Immunological findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
no effects observed

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
ca. 50 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
body weight and weight gain

Results (fetuses)

Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
no effects observed

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
>= 200 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: decreased learning

Overall developmental toxicity

Key result
Developmental effects observed:
no
Lowest effective dose / conc.:
200 mg/kg bw/day
Treatment related:
yes

Applicant's summary and conclusion

Conclusions:
Three groups of bred female Crl:CD(SD) rats were administered the test item, lacosamide
(SPM 927), twice daily (bid) in 2 equally divided doses given approximately 10 hours apart,
by oral gavage.
Based on F0 clinical findings, mean body weight losses and lower mean body weight gains
and food consumption at 100 and 200 mg/kg/day and increased F0 mortality/moribundity at
200 mg/kg/day, the no-observed-adverse-effect level (NOAEL) for F0 maternal systemic
effects was considered to be 50 mg/kg/day of lacosamide (SPM 927). Based on lower F1
postnatal survival (including total litter loss) and lower birth weights for the 200 mg/kg/day
F1 males and females, the dosage level of 100 mg/kg/day was considered to be the NOAEL
for F1 developmental/neonatal toxicity. Decreased learning performance was noted only for
females in the 200 mg/kg/day group during PND 22 Biel maze testing and there was no effect
noted for females or for males in this group or in any groups during the PND 62 assessment.
Although based on a transient effect in 1 sex, 100 mg/kg/day was considered to be the
NOAEL for F1 neurobehavioral assessment. There were no test item-related macroscopic or
microscopic changes in the F1 animals, including no changes assessed in brain structure as
investigated by sensitive techniques (brain weights and macroscopic and microscopic
evaluations). Based on lower body weights in the 200 mg/kg group F1 males and females, a
dosage level of 100 mg/kg/day was considered to be the NOAEL for F1 male and female
systemic toxicity. Due to the absence of effects on reproductive performance at any dosage
level, a dosage of 200 mg/kg/day was considered to be the NOAEL for F1 reproductive
toxicity and F2 development.
The 50, 100, and 200 mg/kg/day dosage levels correspond to lacosamide AUC0-24 values on
lactation day 10 of 151, 277, and 517 μg*h/mL, respectively.
Executive summary:

In the 200 mg/kg/day group, 2 females were euthanized in extremis on gestation days 10 and

23, 8 females had total litter loss during lactation days 0-5, and 1 female was found dead on

lactation day 8. It was therefore decided to transfer 7 dams and their litters that were

originally assigned to the toxicokinetic phase to the main study phase, in order to retain

enough animals in the high-dose group. The transfer was done on lactation day 8 or 9. Test

item-related clinical findings were observed for females in the 200 mg/kg/day group that were

found dead, euthanized in extremis, with total litter loss, failed to deliver, or that survived to

the scheduled necropsy. These findings included behavior-related findings (prostration,

rocking, lurching, or swaying while ambulating, hunched posture, hindlimbs splayed, body

drags, impaired use of hindlimbs), body cool to touch, body pale, red and/or clear material

around the nose and/or mouth, and dilated pupils were noted approximately 1 hour following

each daily dose administration generally throughout the treatment period. In addition, test

item-related, non-adverse excreta-related findings (light brown and/or yellow feces and

decreased defecation) were observed in the 50, 100, and 200 mg/kg/day groups at the daily

examinations generally throughout the gestation treatment period until lactation day 7.

The pregnancy rates in the control, 50, 100, and 200 mg/kg/day groups were unaffected by

test item administration.

In the 100 and 200 mg/kg/day F0 groups, mean body weight losses (4 g and 16 g, respectively,

during gestation days 6-9), lower mean body weight gains (13.3% and 41.6%, respectively,

during gestation days 6-20), lower mean body weights on gestation day 20 (5.0% and 12.6%,

respectively), and lower mean food consumption (13.0% and 34.8% during gestation

days 6-20) were measured over the gestation period compared to the control group. The

decrements in mean body weights generally continued through lactation day 4 in the

200 mg/kg/day group F0 females (up to 8.4%); mean body weights in the 100 mg/kg/day

group F0 females were similar to the control group during lactation. No effects on mean food

consumption were noted in the 100 and 200 mg/kg/day groups during lactation. In the

50 mg/kg/day group, test item-related, lower mean maternal body weight gain (80%) with

corresponding reduced mean food consumption (23.8%) were only noted during the first

3 days of test item administration (gestation days 6-9). This transient decrement in food

consumption early in gestation was sufficient to result in lower mean food consumption in the

50 mg/kg/day group when the entire gestation treatment period was evaluated. However,

mean body weight and body weight gain and food consumption in this group was similar to

the control group for the remainder of the gestation (gestation day 9 onwards) and lactation

treatment periods; therefore, the initial decrement in mean body weight gain and food

consumption noted in the 50 mg/kg/day group was considered to be test item-related but not

adverse.

Mean F0 gestation lengths and the process or parturition were not affected by test item

administration at any dosage level. No test item-related macroscopic findings were noted at

the F0 necropsy; mean numbers of implantation sites and unaccounted-for sites in the 50, 100,

and 200 mg/kg/day groups were similar to the control group.

Lower mean live litter size and mean F1 postnatal survival (including total litter loss) was

noted in the 200 mg/kg/day group. Lower mean body weight gains were noted in the

200 mg/kg/day F1 pups through PND 7, resulting in lower (up to 13.8% for males and

13.5% for females) mean body weights throughout the pre-weaning period. No test

item-related effects on the number of F1 pups born, the percentages of males at birth, the

general physical condition of the F1 pups at any dosage level, live litter size, F1 postnatal

survival, body weights, or body weight gains in the 50 and 100 mg/kg/day groups were noted.

No macroscopic findings that could be attributed to F0 maternal test item administration were

noted at any dosage level at the necropsy of F1 pups that were found dead, euthanized

in extremis or due to death of the dam, or at the scheduled necropsy on PND 21.

There were no effects on the ages of attainment of surface righting response, pinnal

detachment, incisor eruption, eye opening, balanopreputial separation, and vaginal patency at

any dosage level. No consistent dose-related trends were noted when detailed clinical

observation data were evaluated for PND 21 and 61.

In the 200 mg/kg/day group, the F1 females only exhibited transient decreased learning

performances in the Path B of the Biel maze assessments on PND 22. This effect was not

observed on PND 62, and it was therefore concluded that there were no persistent effects on

learning ability. There were no effects of F0 maternal test item administration observed on

locomotor activity and auditory startle responsiveness in the 50, 100, and 200 mg/kg/day

males and females, and learning and memory assessments in the F1 males and females in the

50 and 100 mg/kg/day groups and F1 males in the 200 mg/kg/day group.

There were no deaths or clinical findings in the F1 generation following weaning that could be

attributed to administration of the test item to the F0 females. Decrements in mean F1 body

weights noted for the 200 mg/kg/day group during the pre-weaning period continued to the

post-weaning period. Lower mean F1 body weights were noted for the 200 mg/kg/day group

males and females during the entire generation (males) or pre-mating period (females). Mean

body weight gain in the 200 mg/kg/day group males was lower than the control group during

PND 28-35 but was generally similar throughout the remainder of the F1 generation; mean

body weight gain in the 200 mg/kg/day group females was similar to the control group during

the pre-mating period. Mean F1 body weights and body weight gains for the 50 mg/kg/day

males and females and the 100 mg/kg/day group males and females during the post-weaning

period were unaffected by F0 maternal test item administration. Mean F1 gestation and

lactation body weight gains were similar to the control group in all test item-treated group.

However, the decrements in mean body weights continued generally throughout gestation in

the 200 mg/kg/day group and during lactation days 1-4 in the 200 mg/kg/day group. No

effects on mean body weights were noted in the 50 and 100 mg/kg/day group F1 females

during gestation or lactation.

There were no effects of F0 maternal test item administration on F1 reproductive performance,

gestation length, the process of parturition, macroscopic findings, or the mean numbers of

corpora lutea, implantation sites and unaccounted-for sites.

Lower mean final body weights were noted in the 200 mg/kg/day F1 males and females at the

scheduled necropsies on PND 72 and lactation day 10. There were no test item-related

macroscopic or microscopic changes in the central or peripheral nervous system or in the

pituitary (examined in males only), kidney, liver, lung, and heart in the F1 animals that were

exposed to the test item in utero and via maternal milk.

There were no effects of F0 maternal test item administration on the mean number of F2 pups

born, viability on PND 0, percentage of males at birth, postnatal survival, physical condition,

body weights, body weight gains, or necropsy findings of F2 pups that were found dead or

euthanized in extremis.

Control animals were not exposed to SPM 927 or it major metabolite, SPM 12809. Treated

F0 females were continuously exposed to both the parent compound and its major metabolite.

The extent of exposure to the metabolite represented 20% to 35% of the extent of exposure to

the parent compound throughout the study. The test item was rapidly absorbed. The

exposure – dose relationship was approximately proportional. The exposure to the parent

compound was higher at gestation day 18 compared to the first day of dosing and lactation

day 10. The exposure to the major metabolite was lower at the first day of treatment than on

gestation day 18 or lactation day 10. The F1 pups were exposed to lacosamide (SPM 927) and

to its major metabolite (SPM 12809) at all dose levels and the plasma concentrations were

similar in both genders. The exposure of the F1 pups to both parent compound and its

metabolite represented 6% to 8% of the exposure of the lactating F0 females, whatever the

dose.