Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: (as the data is used in a read-across approach, a maximal reliability score of 2 was attributed).

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2008
Report Date:
2010

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Preliminar pharmacokinetic study.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Name: LAB 3822
Batch Number: FAL 07/25
Galenic form: Slightly yellowish liquid
Molecular weight (base form): about 426 g/mol
Expiry date: March 2010
Intended use: Chemicals
Storage conditions: Immediately upon receipt, the test item was registered, then stored at ambient temperature in accordance with the Sponsor's instructions.
Handling instructions of LAB 3822: General safety procedures as appropriate for handling of chemicals of unknown hazard potential were applied.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Choice of species: The rat was chosen because of its acceptance as a predictor of toxic effects of drugs in man and the recognition by regularity authorities that this species is suitable for toxicity studies.
Sex: Male and female. Females were nulliparous and non gravid.
Origin: Charles River Laboratoires France - Domaine des Oncins - 69592 L0Arbresle Cedex - France.
Identification: Animals were identified individually, by marking the tail with a felt-tip marker.
Age: 6 to 10 weeks on the day of randomisation.
Weight: Between 150.6 g and 311.4 g with a maximum range of 36.3 g for each sex on the day of randomisation.
Acclimatisation: A minimum of five days in the laboratory animal house where the experiment took place.
Housing: Observations were performed at the time of delivery of the animals and daily during the
period of acclimatisation. Animals were housed in cages of standard dimensions with sawdust bedding
(SAFE, Reference B8/20). Cages were cleaned according to CERB0s internal SOPs. The animals were
placed in an air-conditioned (20-24°C) animal house kept at relative humidity between 45% and 65%
(except during the cleaning slot) in which non-recycled filtered air was changed 10-15 times per hour.
Any deviations outside of the temperature and hygrometry ranges were stated by the Study Director
according to the SOP 5.36. These parameters were continuously recorded using a computerised acquisition
system. The artificial day/night cycle involved 12 hours light and 12 hours darkness with light on
at 7.30 a.m.
Feeding: RM1 (E)-SQC SDS/DIETEX feed (quality controlled/irradiation sterilised) was available
ad libitum except during the fasting experimental period. The criteria for acceptable levels of contaminants in the
feed supply were within the limits of the analytical specifications established by the diet manufacturer.
Drinking water: Drinking water was available ad libitum in polycarbonate bottles with a stainless
steel nipple. A specimen of water is obtained every 6 months and sent to the LAEASE Région Sud
Est -5, avenue Achille Maureau -B.P. 95 - 84703 Sorgues Cedex - France, for analysis. The criteria for acceptable levels of contaminants in
the water supplied were within the limits of the analytical specifications.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Duration and frequency of treatment / exposure:
single oral administration
Doses / concentrations
Remarks:
Doses / Concentrations:
Study design
Group Number of animals and sex Matrix Treatment dose Doses (g of LAB 3822/kg)
1 12 M + 12 F plasma 0.5 g of DEI/kg 0.575
2 12 M + 12 F plasma 1 g of DEI/kg 1.15
3 12 M + 12 F plasma 2 g of DEI/kg 2.3
4 12 M + 12 F plasma ISOSORBIDE 2 g/kg -
5 3 M + 3 F urine 0.5 g of DEI/kg 0.575
6 3 M + 3 F urine 1 g of DEI/kg 1.15
7 3 M + 3 F urine 2 g of DEI/kg 2.3
8 3 M + 3 F urine ISOSORBIDE 2 g/kg -
No. of animals per sex per dose:
The study involved 4 groups of 12 males and 12 females for plasma and 4 groups of 4 males and 4 females for urine SPF Sprague-Dawley rats.
Control animals:
no
Positive control:
Name: ISOSORBIDE
Batch Number: E1040
Galenic form: white crystals
Molecular weight (base form): 146 g/mol
Purity: 99.8%
Weighing correction factor: 1.002
Expiry date: 24 March 2010
Details on study design:
Choice of doses: Proposed doses were selected in agreement with the Sponsor on the basis of current knowledge of the test item.
Dose adjustment: Water content: about 0.1% (according to the certificate of analysis).
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).
Quantity of reference item was expressed in mL/kg and was adjusted on the basis of the most recent body weight.
For the reference item, a correction factor of 1.002 was taken into account for calculation
Details on dosing and sampling:
Tissues and body fluids sampled : urine



Results and discussion

Preliminary studies:
The study no.20080304TRCB is a preliminary study; it stated that animals dosed with LAB 3822 at the doses of 0.5, 1 and 2g of DEI/kg were exposed to LAB 3822.

Toxicokinetic / pharmacokinetic studies

Details on excretion:
Urinary excretion
The maximum observed excretion rate and the AURC all increased with the dose of LAB 3822. The amount of LAB 3822 found in urines was greater in males than in females whatever the dose, probably as a consequence of the greater exposure in males. When compared to LAB 3822 at 2 g of DEI/kg,
values of all urinary parameters of ISOSORBIDE administered at 2 g/kg was twice higher.
Toxicokinetic parametersopen allclose all
Test no.:
#1
Toxicokinetic parameters:
Cmax: 0.5-2 hours post dosing for males
Test no.:
#1
Toxicokinetic parameters:
Cmax: 1 hour post dosing for female
Test no.:
#1
Toxicokinetic parameters:
half-life 1st: 1.9-3.4 hours

Any other information on results incl. tables

There was no mortality during the study period.

Under the experimental conditions adopted, animals dosed with LAB 3822 and ISOSORBIDE did not exhibit any significant clinical signs.

The toxicokinetics (TK) analysis was performed on mean concentrations from three males and three females sampled per time point and per group using a non-compartmental analysis (NCA). The linearity of exposure was evaluated from comparison of the AUC/Dose and Cmax/Dose ratios.

Concentrations found LLD or LLQ at predose were considered as zero for TK calculations.

Since no ISOSORBIDE was detected from 24 hours post-dosing, mean values of plasma concentration was calculated from 0.25 hour to 10 hours post-dosing. There is no more LAB 3822 or ISOSORBIDE from 24 hours post-dosing.

Concentrations of ISOSORBIDE were found LLD/LLQ (Lower than the Limit of Detection / Lower than the Limit of Quantification) in all predose samples.

Results given as indicative values were not taken into consideration for TK parameters calculation. In mean tables and individual tables LLD/LLQ values were considered as concentration zero for the TK parameters calculation.

Toxicokinetics results confirmed that all treated animals were exposed to LAB 3822 for both gender with a moderate inter-individual variability. The peak plasma concentration Cmax was observed between 0.5 and 2 hours post-dosing for males and at 1 hour after dosing for female. The half-live of LAB 3822 was between 1.9 to 3.4 hours.

Comparison of exposure of AUCall of LAB 3822 or ISOSORBIDE in males and females (from 1.43 to 1.75) suggests that males were slightly more exposed to LAB 3822 or ISOSORBIDE than females. Furthermore, AUClast increased with the dose level. There was a good linearity between exposure or Cmax and the dose levels.

Applicant's summary and conclusion

Conclusions:
Animals dosed with LAB 3822 at the doses of 0.5, 1 and 2 g of DEI/kg were exposed to LAB 3822.
Executive summary:

At the request of ROQUETTE FRERES, this study was conducted to determine in the rat, pharmacokinetic parameters and urinary excretion of ISOSORBIDE following single oral administration of LAB 3822.

Indeed the hypothesis is made that after administration, the LAB 3822, constitued of DEI (Di-ester- ISOSORBIDE) is hydrolysed by the pancreastic0s lipase. This hydrolysis split DEI into ISOSORBIDE and free fatty Acids.

The study involved 4 groups of 12 males and 12 females for plasma and 4 groups of 4 males and 4 females for urine SPF Sprague-Dawley rats, 8 weeks old and weighing between 274.5 g and 311.4 g for males and between 150.6 g and 184.3 g for females on the day of randomisation. Animals were purchased from Charles River Laboratories France (Domaine des Oncins - 69592 L0Arbresle Cedex, France).

Experimental procedure :

Mortality and morbidity were recorded twice a day.

General observations were performed before the first dosing and at 60 min post dose (± 30 min) on D1 and once a day up to the end of the study.

Blood samples for pharmacokinetics were taken on D1 (at predose and at 0.25, 0.5, 1, 2, 4, 8, 10, 24, 48 and 72h postdose).

Urine were collected in the 24h period pre-dosing and then during 3 periods : at 0-24h, 24-48h, 48-72h post-dosing.

Results :

Mortality and clinical signs

There was no mortality during the study period. Under the experimental conditions adopted, animals dosed with LAB 3822 and ISOSORBIDE did not exhibit any significant clinical signs.

Toxicokinetics

The toxicokinetics (TK) analysis was performed on mean concentrations from three males and three females sampled per time point and per group using a non-compartmental analysis (NCA). The linearity of exposure was evaluated from comparison of the AUC/Dose and Cmax/Dose ratios.

Concentrations of ISOSORBIDE were found LLD/LLQ (Lower than the Limit of Detection / Lower than the Limit of Quantification) in all predose samples. Results given as indicative values were not taken into consideration for TK parameters calculation. In mean tables and individual tables LLD/LLQ values were considered as concentration zero for the TK parameters calculation.

Toxicokinetics results confirmed that all treated animals were exposed to LAB 3822 for both gender with a moderate inter-individual variability. The peak plasma concentration Cmax was observed between 0.5 and 2 hours post-dosing for males and at 1 hour after dosing for females. The half-live of LAB 3822 was between 1.9 to 3.4 hours.

Comparison of exposure of AUCall of LAB 3822 or ISOSORBIDE in males and females (from 1.43 to 1.75) suggests that males were slightly more exposed to LAB 3822 or ISOSORBIDE than females. Furthermore, AUClast increased with the dose level. There was a good linearity between exposure or Cmax and the dose levels.

Urinary excretion

The maximum observed excretion rate and the AURC all increased with the dose of LAB 3822. The

amount of LAB 3822 found in urines was greater in males than in females whatever the dose, probably

as a consequence of the greater exposure in males. When compared to LAB 3822 at 2 g of DEI/kg,

values of all urinary parameters of ISOSORBIDE administered at 2 g/kg was twice higher.

In conclusion, animals dosed with LAB 3822 at the doses of 0.5, 1 and 2 g of DEI/kg were exposed to LAB 3822.