1. 9th Euro-Global Summit on Toxicology and Applied Pharmacology
Paris. France June
Comparative repeated toxicity study in rats: enoxaparin biosimilar product versus reference product.
Zina Kobbi
Pharm D. PhD
Faculty of Pharmacy of Monastir. university of Monastir. Tunisia
Principal consultant of “AREMA”

2. 1- Introduction: Tunisian context/ Biosimilars
Content
1- Introduction: Tunisian context/ Biosimilars
2- Method
2-1-Products: Enoxaparine (biosimilar vs reference)
2-2-Lab Animal: Wistar Rats
2-3-Strategy: repeated toxicity
2-4-Tests: comparative assays
3- Results
4- conclusion and perspectives

3. 1- Introduction
Tunisia is amoung first African countries to developp active pharmaceutical industries.
Since 1990/ 36 units (human).
Two pharma industries developping biological products and have arround 10 products under developpment.

4. 1- Introduction Expiry of many patents of biologicals
Explosion of biosimilars/ biosimilar pharmaceutical industries.
Requirements and approval of biosimilars by the competent authorities not yet harmonized : a real dilemma.
« enoxaparin » Europe (EMA) and USA (FDA) : different requirements.

5. Big challenge! 1- Introduction
Our study : set up the first preclinical study in Tunisia according international standards. part of enoxaparin biosimilar evaluation
Big challenge!
Comparative repeated toxicity study in rats of Enoxaprine (biosimilar versus innovator).
Preparation (3 years): setting up protocol , order of materials and reagents, animals selection and preparation, pilot studies …

6. 2- Method
2-1-Products
Enoxparin test drug product. a similar biological medicinal drug products, at 4000 IU anti-Xa/0.4 ml : Enoxa; manufactured by les Laboratoires Médis (Tunisia).
Enoxparin reference drug product, at 4000 IU anti-Xa/0.4 ml: Lovenox;  manufactured by Sanofi-Aventis (France).
Control product: sodium chloride solution at 0.9 %.

7. 2- Method
2-2-Animals
White Wistar rats, Forty (40) rats of each sex, six to seven-week-old
14 days quarantine/acclimation period
Randomly assigned
One (1) control group
Two (2) treatment groups

8. Animals and facilities :
2- Method
2-3-Strategy
Animals and facilities :
Pasteur institute of Tunis ( different services)
National veterinary university of Sidi Thabet (Tunis) 
Laboratory of biochimestry at Child hospital of Tunis
Biosimilar (Enoxa) was subject to a comparative 2 and 4 weeks repeated toxicity study in vivo with reference product (Lovenox)
To detect differences in toxicological response
To assess similarity in the safety profile

9. 2- Method
2-3-Strategy

10. 2- Method 2-4-Tests Animal observation: Hematology: Biochemistry:
Once daily for morbidity and twice daily for mortality (Montgomery )/ Body weight
Hematology:
On day 14 and day 28
Parameters measured by MINDRAY, auto Hematology analyzer, BC-2800Vet
Biochemistry:
On day 14 and day 28
Parameters measured by roche cobas 6000

11. Organ-to-body weight ratios
2- Method
2-4-Tests
Terminal procedure. organ weight:
Necropsy (all rats)
Organs trimmed and weighed: the liver, brain, lung, kidney and heart.
Organ-to-body weight ratios
Anatomo-histopathology :
The organs from all groups
Fixed in 10 % formalin solution, embedded in paraffin, sliced (2 to 4 µm) and stained with hematoxylin-eosin for microscopic analysis

12. 2- Method Statistical analysis
On: body weight, hematology and biochemistry parameters, organ-to-body weight ratios.
Method: XLSTAT, Kruskal-Wallis test and bonferroni correction.

13. 3- results Food consumption and body weight: Clinical observation:
No major effect of the drug product or drug dosage
Body weight depends mainly on animal sex/ fairly constant in female rats and increased in male rats.
Clinical observation:
At dose of 100 mg/kg/jour
Mortality 25 % (4) rats under biosimilar/ reference (3 days)

14. 3- results Clinical observation: At dose of 100 mg/kg/jour
Severe toxic effects (fig):
fig a and b  nodule/ hemorrhagic cyst ; fig c and d: hematoma/ bluish coloration ; fig e genital swelling ; fig f : diarrhea

15. 3- results Clinical observation: At dose of 40 mg/kg/jour
One rat died under biosimilar
At dose of 20 mg/kg/jour
Adverse effects/ Bluish coloration

16. Product (dose mg/kg/j) No significant statistical difference
3- results
Hematology:
14 days (male group):
Parameter
(units of measure)
Product (dose mg/kg/j)
Control
Reference 3.5
Test 3.5
Reference 20
Test 20
WBC (109 /L)
15.4 ±3.54
14.9 ±2.76
11.72 ±3.53
12.97 ±4.75
± 1.24
Lymphocytes (109/L)
9.2 ± 2
8.32 ± 2.35
7.07 ± 2.02
8.1 ± 2.86
Lymphocytes (%)
59.60±2.92
55.25±6.70
60.28±1.13
62.45±3.54
Monocyte (109 /L)
0.53±0.19
0.60±0.20
0.40±0.14
0.45±0.19
Monocyte (%)
3.65±0.41
3.88±0.55
3.68±0.22
3.53±0.34
Granylocytes (109/L)
5.68±1.45
5.98±0.66
4.25±1.38
4.43±1.80
Granylocytes (%)
36.75±3.27
40.88±6.91
36.05±1.01
34.03±3.47
RBC (1012 /L)
10.21±0.43
9.67±0.39
9.66±0.56
9.19±0.85
9.78±0.59
Hemoglobin (g/dL)
16.75±0.70
16.08±0.50
15.38±1.05
15.53±1.14
Hematocrit (%)
65.25±2.47
62.35±2.18
62.20±4.15
62.13±5.19
65.43±0.95
MCV ( fL)
64.00±0.83
64.60±3.11
64.43±0.98
67.70±0.85
67.15±4.31
MCH (pg)
16.38±0.13
16.60±0.57
15.88±0.46
16.85±0.34
16.60±0.94
MCHC (g/dL)
25.60±0.36
25.73±0.43
24.68±0.46
24.93±0.30
24.80±0.36
RDW (%)
11.43±0.45
11.63±1.73
11.65±0.91
11.73±0.87
13.20±1.06
PLT (109 /L)
846.75±23.3
808.67±82.6
755.00±37
760.00±38.3
875.67±76.04
MPV (fL)
6.23±0.13
6.58±0.26
6.43±0.05
6.68±0.38
6.60±0.22
PDW
14.88±0.10
15.25±0.44
15.05±0.13
15.38±0.19
15.30±0.14
pct (%)
0.53±0.01
0.56±0.09
0.48±0.02
0.53±0.08
0.58±0.04
* Significant difference when test or reference compared with control.
** Significant difference when test compared with reference.
No significant statistical difference

17. Product (dose mg/kg/j) No significant statistical difference
3- results
Hematology:
14 days (female group):
Parameter
(units of measure)
Product (dose mg/kg/j)
Control
Reference 3.5
Test 3.5
Reference 20
Test 20
WBC (109 /L)
12.67 ± 2.1
9.47 ± 1.2
9.82 ± 2.45
8.77 ± 2.23
9 ± 1.12
Lymphocytes (109/L)
7.35 ± 2.1
4.85 ± 0.75
5.15 ± 1.4
5.25 ± 1.43
4.72± 0.95
Lymphocytes (%)
58.00±4.48
51.08±4.20
52.03±7.42
59.45±2.57
52.20±5.67
Monocyte (109 /L)
0.38±0.05
0.40±0.00
0.28±0.05
0.30±0.00
Monocyte (%)
3.35±0.40
4.25±0.62
4.10±0.42
3.68±0.44
3.60±0.34
Granylocytes (109/L)
4.95±1.23
4.23±0.68
4.30±1.42
3.25±0.81
3.98±0.56
Granylocytes (%)
38.65±4.48
44.68±4.25
43.88±7.70
36.88±2.29
44.20±5.43
RBC (1012 /L)
9.59±0.74
8.62±0.67
9.11±0.31
8.51±0.86
9.08±0.38
Hemoglobin (g/dL)
16.15±0.89
15.08±1.35
15.55±0.71
14.60±1.92
15.45±0.10
Hematocrit (%)
64.63±3.56
58.03±5.02
62.98±2.98
59.58±7.94
61.30±0.84
MCV ( fL)
67.50±1.63
67.38±1.86
69.23±3.83
69.88±3.37
67.65±2.81
MCH (pg)
16.80±0.40
17.45±0.59
17.05±0.90
17.08±0.78
16.98±0.75
MCHC (g/dL)
24.95±0.13
25.93±0.19
24.68±0.21
24.45±0.17
25.15±0.24
RDW (%)
9.60±0.33
11.00±2.62
11.98±2.17
11.78±1.91
13.20±1.06
PLT (109 /L)
800.25±65
811.67±56.8
768.33±27.7
779.0±161.2
950.67±50.65
MPV (fL)
6.35±0.21
6.40±0.22
6.25±0.06
6.18±0.31
6.40±0.14
PDW
15.13±0.13
15.23±0.17
15.13±0.10
15.10±0.26
15.28±0.13
pct (%)
0.51±0.05
0.56±0.10
0.50±0.10
0.62±0.03
* Significant difference when test or reference compared with control.
** Significant difference when test compared with reference.
No significant statistical difference

18. Product (dose mg/kg/j)
3- results
Hematology:
28 days (male group):
Parameter
(units of measure)
Product (dose mg/kg/j)
Control
Reference 3.5
Test 3.5
Reference 20
Test 20
WBC (109 /L)
11.42± 1.92
10.85± 1.55
12.95± 3.44
10.125± 1.33
17.55± 7
Lymphocytes (109/L)
7.42 ± 1.36
6.5 ± 0.9
7.12 ± 0.97
5.9 ± 0.92
11.5 ± 5.24
Lymphocytes (%)
65.15±6.49
59.90±4.14
56.30±7.30
58.35±1.81
64.75±4.03
Monocyte (109 /L)
0.35±0.06
0.68±0.10
0.88±0.36
0.80±0.22
0.75±0.35
Monocyte (%)
3.10±0.47
6.50±0.39*
6.83±1.32 *
7.58±1.62 *
4.05±0.49
Granylocytes (109/L)
3.65±1.05
3.68±0.78
4.95±2.21
3.43±0.33
5.30±1.41
Granylocytes (%)
31.75±6.08
33.60±4.34
36.88±6.67
34.08±1.96
31.20±4.53
RBC (1012 /L)
9.93±0.70
8.51±0.54
9.08±0.33
9.16±0.34
8.71±1.35
Hemoglobin (g/dL)
16.53±1.11
14.30±0.88
15.73±0.49
15.40±0.63
14.83±2.10
Hematocrit (%)
64.35±4.05
38.68±2.88
43.00±1.53
42.20±1.88
57.97±8.28
MCV ( fL)
64.93±1.67
45.50±0.48
47.40±0.49
46.13±0.82
66.73±1.43
MCH (pg)
16.63±0.46
16.75±0.13
17.28±0.22
16.78±0.13
17.03±0.32
MCHC (g/dL)
25.63±0.15
36.95±0.54
36.53±0.21
36.45±0.70
25.53±0.06
RDW (%)
11.65±1.19
10.70±0.74
12.75±2.04
10.90±0.58
12.83±2.59
PLT (109 /L)
831.25±64.2
397.50±39.9
412.50±39.3
450.50±51.9
539.50±84.15
MPV (fL)
6.10±0.14
5.33±0.22
5.45±0.13
5.33±0.19
6.57±0.40
PDW
14.90±0.08
14.35±0.19
14.48±0.17
14.38±0.17
15.33±0.25
pct (%)
0.51±0.05
0.21±0.03
0.22±0.02
0.24±0.04
0.64±0.03
* Significant difference when test or reference compared with control.
** Significant difference when test compared with reference.
Monocyte decreased for rats receiving test and reference drug products when compared to control

19. Product (dose mg/kg/j)
3- results
Hematology:
28 days (female group):
Parameter
(units of measure)
Product (dose mg/kg/j)
Control
Reference 3.5
Test 3.5
Reference 20
Test 20
WBC (109 /L)
10.15 ± 0.61
9.02 ± 1.86
9.15 ± 2.55
9.52 ± 1.66
10.65 ± 1.91
Lymphocytes (109/L)
6.45± 0.38
4.55 ± 1.12
5.47 ± 1.14
4.97 ± 0.92
6.02± 1.24
Lymphocytes (%)
63.18±1.58
50.03±5.40
60.20±4.34
52.58±7.74
56.60±4.45
Monocyte (109 /L)
0.28±0.05
0.53±0.15
0.58±0.22
0.65±0.25
0.55±0.21
Monocyte (%)
3.35±0.42
5.93±1.21
6.40±0.67
6.88±1.89
5.05±1.35
Granylocytes (109/L)
3.43±0.30
3.95±0.86
3.10±1.22
3.90±1.14
4.08±0.72
Granylocytes (%)
33.48±1.96
44.05±6.56
33.40±3.86
40.55±6.80
38.35±3.16
RBC (1012 /L)
8.92±0.21
8.81±0.10
8.64±0.37
8.32±0.63
8.56±0.55
Hemoglobin (g/dL)
14.88±0.41
15.23±0.31
15.25±0.82
14.18±1.46
15.33±0.81
Hematocrit (%)
58.85±1.64
41.60±0.79
41.95±2.11
38.78±4.04
51.70±9.46
MCV ( fL)
66.03±0.61
47.30±0.68
48.63±1.03
46.60±1.48
60.73±12.08
MCH (pg)
16.60±0.08
17.20±0.23
17.58±0.40
16.98±0.54
17.88±0.46
MCHC (g/dL)
25.23±0.21
36.55±0.58
36.33±0.15
36.50±0.26
30.40±6.18
RDW (%)
9.55±0.34
10.38±0.59
10.45±0.41
10.38±0.29
12.63±2.08
PLT (109 /L)
934±78.97
365±32.28*
380±83.54
417.5±63.94
691.75±31.94
MPV (fL)
6.33±0.13
5.33±0.13
5.43±0.34
5.45±0.21
5.73±0.43
PDW
15.13±0.10
14.43±0.10
14.53±0.32
14.48±0.29
14.75±0.31
pct (%)
0.59±0.06
0.19±0.01
0.20±0.04
0.23±0.04
0.41±0.21
* Significant difference when test or reference compared with control.
** Significant difference when test compared with reference.
Platelet decreased for rats receiving test and reference drug products when compared to control.

20. Changes only in Platelet and monocytes.
3- results
Hematology:
Changes only in Platelet and monocytes.
Changes only between test and reference drug products when compared to control.
No statistically significant differences in all parameters between rats of both sexes treated with test and reference products.

21. Product (dose mg/kg/j) No significant statistical difference
3- results
Biochemistry:
14 days (male group):
Parameter
(units of measure)
Product (dose mg/kg/j)
Control
Reference 3.5
Test 3.5
Reference 20
Test 20
ALP (U/L)
104.25±17.06
128.75±19.29
105.00±17.61
143.50±39.82
131.75±30.54
ALT (U/L)
62.05±6.96
62.18±22.01
67.55±12.82
73.73±13.04
62.40±13.90
AST (U/L)
178.98±15.75
141.25±23.46
137.25±26.82
138.13±31.54
154.53±34.90
BUN (mg/dL)
7.43±0.96
6.83±1.72
7.73±1.06
7.00±0.74
6.98±0.53
Triglyceride (mg/dL)
1.96±0.52
1.40±0.22
1.37±0.60
0.59±0.16
0.90±0.53
total protein (/dL)
72.23±1.36
72.90±6.01
67.40±6.00
77.55±12.85
69.83±6.21
Creatinine (mg/dL)
0.26±0.02
0.29±0.06
0.23±0.06
0.20±0.13
Total cholesterol (mmol/L)
1.45±0.13
1.11±0.53
1.21±0.22
1.61±0.13
1.33±0.21
Total bilirubin (U/L)
0.89±0.41
0.99±0.08
0.70±0.21
0.67±0.19
* Significant difference when test or reference compared with control.
** Significant difference when test compared with reference.
No significant statistical difference

22. Product (dose mg/kg/j) No significant statistical difference
3- results
Biochemistry:
14 days (female group):
Parameter
(units of measure)
Product (dose mg/kg/j)
Control
Reference 3.5
Test 3.5
Reference 20
Test 20
ALP (U/L)
61.33±24.85
55.75±13.96
75.25±14.24
46.50±25.25
54.25±17.61
ALT (U/L)
62.97±1.25
43.50±6.93
54.18±10.89
51.33±12.01
62.70±17.84
AST (U/L)
158.30±22.63
151.18±42.87
106.95±13.21
276.85±29.11
133.20±30.17
BUN (mg/dL)
8.73±2.75
6.35±0.67
6.95±1.99
9.90±1.99
6.83±1.24
Triglyceride (mg/dL)
1.08±0.40
0.91±0.24
0.59±0.22
1.12±0.21
0.50±0.12
total protein (/dL)
75.17±1.86
73.15±2.79
71.60±1.62
66.88±5.46
78.38±3.69
Creatinine (mg/dL)
0.22±0.15
0.36±0.04
0.27±0.03
0.45±0.09
0.28±0.03
Total cholesterol (mmol/L)
1.25±0.11
1.01±0.27
1.12±0.51
1.61±0.46
1.29±0.19
Total bilirubin (U/L)
1.05±0.45
0.85±0.34
0.69±0.21
0.98±0.47
0.80±0.47
* Significant difference when test or reference compared with control.
** Significant difference when test compared with reference.
No significant statistical difference

23. Product (dose mg/kg/j) No significant statistical difference
3- results
Biochemistry:
28 days (male group):
Parameter
(units of measure)
Product (dose mg/kg/j)
Control
Reference 3.5
Test 3.5
Reference 20
Test 20
ALP (U/L)
129.00±2.83
122.00±10.80
168.25±42.74
170.00±51.08
194.67±45.08
ALT (U/L)
64.08±45.76
47.65±8.38
64.93±8.05
71.38±7.42
82.57±17.05
AST (U/L)
128.90±67.61
98.53±14.43
120.95±41.18
145.60±69.45
132.90±49.36
BUN (mg/dL)
6.98±1.33
5.53±0.63
6.40±0.88
6.05±0.79
7.43±0.83
Triglyceride (mg/dL)
2.51±1.97
1.78±1.13
3.80±1.23
0.90±0.19
1.15±0.27
total protein (/dL)
79.05±2.71
75.18±8.21
82.60±6.83
86.18±3.81
82.53±9.79
Creatinine (mg/dL)
0.25±0.05
0.22±0.02
0.25±0.03
0.21±0.03
0.15±0.11
Total cholesterol (mmol/L)
1.90±0.28
1.62±0.38
1.98±0.25
2.24±0.75
1.97±0.47
Total bilirubin (U/L)
0.74±0.17
0.77±0.47
0.89±0.17
0.59±0.37
0.97±0.17
* Significant difference when test or reference compared with control.
** Significant difference when test compared with reference.
No significant statistical difference

24. Product (dose mg/kg/j) No significant statistical difference
3- results
Biochemistry:
28 days (Female group):
Parameter
(units of measure)
Product (dose mg/kg/j)
Control
Reference 3.5
Test 3.5
Reference 20
Test 20
ALP (U/L)
79.33±17.62
87.75±24.43
71.00±21.37
82.75±11.79
89.25±27.73
ALT (U/L)
71.30±11.75
66.20±6.01
68.73±20.79
82.23±9.68
70.13±18.62
AST (U/L)
114.40±11.53
92.00±10.49
118.03±51.65
108.00±19.88
103.67±13.20
BUN (mg/dL)
7.60±1.25
5.60±0.98
5.80±0.73
6.03±1.39
6.48±0.63
Triglyceride (mg/dL)
2.63±0.68
1.83±0.65
3.02±1.57
0.73±0.13
0.93±0.30
total protein (/dL)
87.87±5.35
82.88±2.13
87.45±5.80
81.28±3.62
78.93±4.18
Creatinine (mg/dL)
0.20±0.13
0.30±0.02
0.29±0.03
0.28±0.02
0.23±0.03
Total cholesterol (mmol/L)
2.06±0.17
1.39±0.24
2.10±0.47
1.55±0.30
1.34±0.27
Total bilirubin (U/L)
0.54±0.26
1.22±0.19
1.20±0.81
1.14±0.25
0.73±0.35
* Significant difference when test or reference compared with control.
** Significant difference when test compared with reference.
No significant statistical difference

25. 3- results Biochemistry:
Alanine aminotransferase increased after 28 days of injections in rats of both test and reference drug products and with doses 20mg/kg/day when compared to control and to doses 3.5 mg/kg/day.
No statistically significant differences were observed in all parameters between rats of both sexes treated with test and reference products.

26. Product (dose mg/kg/j) No significant statistical difference
3- results
Organ weights: 14 days groups
Product (dose mg/kg/j)
Organ (%)
Control
Reference 3.5
Test 3.5
Reference 20
Test 20
Males
Kidney
0.85±0.06
0.53±0.37
0.89±0.11
0.80±0.08
0.78±0.09
Lungs
0.76±0.08
0.91±0.08
0.88±0.12
0.82±0.32
0.68±0.46
Heart
0.32±0.03
0.30±0.20
0.40±0.06
0.32±0.01
0.32±0.04
Brain
0.47±0.10
0.43±0.30
0.63±0.07
0.58±0.04
0.59±0.04
Liver
3.24±0.27
2.40±1.74
3.92±0.59
3.09±0.22
3.02±0.17
Females
0.84±0.04
0.90±0.06
0.85±0.10
0.71±0.47
0.74±0.15
0.60±0.43
0.88±0.15
0.82±0.19
0.57±0.14
0.42±0.06
0.42±0.04
0.41±0.05
0.30±0.21
0.77±0.14
0.93±0.07
0.83±0.06
0.86±0.09
2.94±0.39
3.12±0.75
3.41±0.20
3.43±0.25
3.12±0.09
No significant statistical difference

27. Product (dose mg/kg/j) No significant statistical difference
3- results
Organ wheights: 28 days groups
Product (dose mg/kg/j)
Organ (%)
Control
Reference 3.5
Test 3.5
Reference 20
Test 20
Males
Kidney
0.94±0.10
0.85±0.12
0.79±0.08
0.98±0.05
0.95±0.11
Lungs
0.79±0.10
0.92±0.06
0.80±0.09
0.81±0.09
0.78±0.16
Heart
0.40±0.06
0.38±0.03
0.34±0.03
0.35±0.03
0.36±0.04
Brain
0.57±0.09
0.50±0.07
0.48±0.06
0.55±0.03
0.55±0.06
Liver
4.84±0.47
3.82±0.24
4.86±0.57
5.05±0.52
5.73±0.65
Females
0.99±0.11
0.92±0.04
0.82±0.03
0.96±0.04
0.90±0.05
0.85±0.32
0.50±0.04
0.52±0.05
0.80±0.18
0.70±0.12
0.39±0.06
0.42±0.05
0.39±0.04
0.38±0.02
0.39±0.05
0.66±0.13
0.82±0.05
0.71±0.05
0.74±0.08
0.72±0.04
5.37±0.83
4.47±0.43
3.82±0.19
4.43±0.28
4.59±0.53
No significant statistical difference

28. 3- results Histopathology:
Female rats (28 days). Scalebar:100 mm (40 x magnification). Liver. lung. heart. kidney. and brain from control product (A. D. G. J. and M. respectively); from test product at 20mg/ kg/day (B. E. H. K. and N. respectively). and from reference product at 20 mg/kg/day (C. F. I. L. and O. respectively).
Comparable features
No remarkable changes

29. 3- results Histopathology:
Histopathology of lung from a control rat showing interstitial alveolar hemorrhage. Scale bar: 100 mm (40 x magnification)
Change discarded as observed also in control groups and not due to product but caused by CO2 used in anesthesia.

30. 3- conclusion
Results from different doses and analysis performed on rats of different groups treated with biosimilar and reference (innovator) product are similar.
No adverse effects were observed at doses of 3.5mg/kg/day and doses of 5mg/kg/day and few adverse effects were observed at doses 20 mg/kg/day and mortality at doses 100 mg/kg/day and 40mg/kg/day.

31. 3- conclusion
Taken together, these findings suggest that the similar biological version of enoxaparin drug product “Enoxa” and reference product “Lovenox” have comparable safety profile in rats.
The similar biological product is considered suitable for human trial to continue clinical investigation of biosimilarity, using appropriate clinical studies to confirm its safety and efficacy.

32. Perspectives
Local tunisian /African /middle east countries, could develop complicated biosimilar products. First demonstration of the ability to acess bio-safety of biosimilar products
Assesment of comparative toxicity profile is the starting point and could enable performing additional human trial to confirm safety and efficacy of these products
Harmonization of worldwide biosimilar guidelines could help strategic decision for pharmaceutical companies and commercial facilities that provide animal-testing services.

33. This work was published in the journal:
Regulatory Toxicology and Pharmacology 84 (2017) 9-17
Comparative subcutaneous repeated toxicity study of enoxaparin products in rats
Kobbi Zina. Kraiem Hazar. Benlasfar Zakaria. Marouani Ammar.Massoud Taieb. Boubaker Samir.
Bouhaouala-Zahar Balkiss and Fenina Nadia
(Faculty of pharmacy of Monastir and
Pasteur Institute of Tunis )

34. THANK YOU