Registration Dossier

Toxicological information

Basic toxicokinetics

Currently viewing:

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
2010
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
Non-GLP (Winonlin software was not validated), guideline study, available as unpublished report, minor restrictions in design and/or reporting but otherwise adequate for assessment

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2010
Report Date:
2010

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
according to
Guideline:
other: OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
no
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratoires France, Domaine des Oncins, 69592 L’Arbresle Cedex, France
- Age at study initiation: 6 to 10 weeks
- Weight at study initiation: males 237.1 - 273.8 g, females 142.9 - 182.0 g
- Housing: Animals were housed in groups (separated by sex) in cages of standard dimensions with sawdust bedding (or equivalent).
- Diet: RM1 (E)-SQC SDS/DIETEX feed (quality controlled/irridiation sterilised) was available ad libitum except during fasting experimental periods.
- Water: Drinking water was available ad libitum in polycarbonate feeder bottles with a stainless steel nipple.
- Acclimation period: minimum of 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 – 24
- Humidity (%): 45 – 65
- Air changes (per hr): 10

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Doses of test item were expressed in g/kg of DEI (Di-ester-isosorbide) and were adjusted on the basis of the most recent body weight. A correction factor of 1.15 was used (1 g of LAB 3822 contains 87 % of DEI).

Animals received the following volumes:
- group 1 (0 g/kg bw of DEI): 2.35 mL/kg bw
- group 2 (0.5 g/kg bw of DEI): 0.59 mL/kg bw
- group 3 (1 g/kg bw of DEI): 1.17 mL/kg bw
- group 4 (2 g/kg bw of DEI): 2.35 mL/kg bw
Duration and frequency of treatment / exposure:
daily for 91 consecutive days
Doses / concentrationsopen allclose all
Dose / conc.:
575 mg/kg bw (total dose)
Remarks:
test substance dissolved in water
Dose / conc.:
1 150 mg/kg bw (total dose)
Remarks:
tets substance dissolved in water
Dose / conc.:
2 300 mg/kg bw (total dose)
Remarks:
test substance dissolved in water
Dose / conc.:
500 mg/kg bw (total dose)
Remarks:
mg/kg bw of the active ingredient (DEI)
Dose / conc.:
1 000 mg/kg bw (total dose)
Remarks:
mg/kg bw of the active ingredient (DEI)
Dose / conc.:
2 000 mg/kg bw (total dose)
Remarks:
mg/kg bw of the active ingredient (DEI)
No. of animals per sex per dose:
- Control group: 3
- Test groups: 9
Control animals:
yes
Details on study design:
- Dose selection rationale: Proposed doses selected are based on previous studies (Repeated dose 28-day toxicity study in the rat by the oral route followed by a 14-day drug withdrawal period, CERB REPORT No. 20070263TRB) and on the presumed effective pharmacological dose. The highest dose should reveal signs of toxicity and the lowest dose should represent a no-observed-adverse effect level (NOAEL).
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: blood
- Time and frequency of sampling - test groups: D1 (before dosing and at 30 min, 1 h, 2 h, 4 h and 8 h post-dose) on D28 at pre-dose and on D91 (before dosing and at 30 min, 1 h, 2 h, 4 h and 8 h post-dose)
- Time and frequency of sampling - control group: D1 (before dosing and at 2 hours post-dose) on D28 at pre-dose and on D91 (before dosing and at 2 hours post-dose).
- After oral administration, the hypothesis is made that the DEI is hydrolysed by the pancreatic's lipase. This hydrolysis split DEI into Isosorbide and free fatty acids. Consequently, the assay of Isosorbide in plasma could be used as a marker of the exposure to the LAB 3822.
- Other: Three males and three females were sampled per time point.
Statistics:
Toxicokinetic parameters were evaluated by non compartmental modeling from mean plasma concentrations of the test substance achieved after dosing by the oral route at each dose level, using Winonlin software.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Toxicokinetic parameters
Key result
Test no.:
#1
Toxicokinetic parameters:
half-life 1st: 2.09 to 4.56 h

Metabolite characterisation studies

Metabolites identified:
no

Bioaccessibility

Bioaccessibility testing results:
The half-life was found between 2.09 to 4.65 hours. Comparison of exposure (AUClast) in males and females suggested that the males were slightly more exposed than the females (ratio between 1.14 at 1 g of DEI/kg on D91 to 1.55 at 1 g of DEI/kg on D1). Furthermore, AUClast increased with the dose level and were comparable between D1 and D91 (ratio AUClast D91/D1 between 0.76 and 1.08). There was a good linearity between exposure or Cmax and the dose levels.

Any other information on results incl. tables

Dosing

Sex

Day

T1/2 (h)

Tmax (h)

Cmax (µg/mL)

Cmax/dose (kg*µg/mL/g)

AUClast (h*µg/mL)

AUClast/dose (kg*h*µg/mL/g)

0.5 g of DEI/kg

M

1

3.99

1

204.96

409.920

937.33

1874.66

0.5 g of DEI/kg

F

1

2.25

1

211.34

422.680

687.15

1374.29

0.5 g of DEI/kg

M

91

2.76

1

206.80

413.600

924.99

1849.97

0.5 g of DEI/kg

F

91

2.30

1

200.51

401.020

743.77

1487.53

1 g of DEI/kg

M

1

3.27

1

368.08

368.080

1870.48

1870.48

1 g of DEI/kg

F

1

2.09

1

367.97

367.970

1208.38

1208.38

1 g of DEI/kg

M

91

3.16

2

322.18

322.180

1427.30

1427.30

1 g of DEI/kg

F

91

4.65

1

325.51

325.510

1255.79

1255.79

2 g of DEI/kg

M

1

3.31

2

654.61

327.305

3089.45

1544.73

2 g of DEI/kg

F

1

2.35

2

542.13

271.065

2304.52

1152.26

2 g of DEI/kg

M

91

3.40

2

498.96

249.480

2879.04

1439.52

2 g of DEI/kg

F

91

2.48

2

507.94

253.970

2061.12

1030.56

Applicant's summary and conclusion