Question

Final report of GLP animal study

Study Groups

The groups in the study are as follows: Group 1 (Vehicle), Group 2 (Low Dose), Group 3 (Medium Dose), Group 4 (High Dose) Group 5 (High Dose with a 14 day Recovery Period) 10 male and 10 females per group Group 6 (Toxicokinetic Group - Vehicle (5 males & 5 females) & High Dose (5 males & 5 females).

Outcomes:

1) The test item was stated to be >98% pure by the Sponsor; however no Certificate of Analysis was received.

2) Following issuing of the study plan the Sponsor asked that the higher dose of the test item be administered at 600 mg/kg/day rather than 700mg/kg/day.

3) Due to an experimental error during the study, animals from Group 1 (vehicle) were administered vehicle twice rather than once on the 14th day of dosing.

4) During acclimatisation period some females and males were housed together for a single day. Fortunately assessment of the females during the course of the study indicated that they were not pregnant and therefore this error did not influence the study outcomes.

5) Three animals that received a low dose of the test item were without water for the 24 hours before necropsy. The Study Plan stated that they were to be fasted but have access to water.

6) The humidity of the room the animals were housed in reached 90% on day 14 of dosing. The Study Plan stated limits of 30-70%.

Biochemical Analysis

Group 1: Values for all parameter were within historical and literature range

Group 2: Values for all parameter were within historical and literature range

Group 3: Values for most parameters were within historical and literature range, with the exception of slightly elevated Alanine aminotransferase (ALT), Aspartate aminotransferase (AST) and Sorbitol dehydrogenase (SDH)

Group 4: Values for most parameters within historical and literature range, with the exception a significantly higher level of Alanine aminotransferase (ALT), Aspartate aminotransferase (AST) and Sorbitol dehydrogenase (SDH). ALT, AST and SDH were very high (ALT>AST) in the animals that were euthanised.

Group 5: For those animals that completed the study the values for all parameters, after a 14-day recovery period, were within historical and literature range.

Haematology

White blood differentials were normal in all animals.

The Haematocrit was elevated in 3 animals that received the low dose otherwise all other animals had Haematocrit levels within the normal range.

Histology

Light microscopy of tissue sections showed an increased recruitment of inflammatory cells in the liver. There were no changes in the spleen, kidney or any other organ examined.

General Observations

The vehicle and low dose groups exhibited no signs of toxicity.

The mid-level group showed mild to moderate signs of toxicity manifesting as an altered gait and lack of grooming in 3 of the 10 animals.

The high dose group showed moderate signs of toxicity manifesting as an altered gait and lack of grooming in 5 of the 10 animals. Three animals (2 male, 1 female) from group 4 and 4 animals from group 5 (2 male and 2 female) were found to exhibit severe signs of toxicity and were euthanised between the 19th and 24th day of dosing. These animals also exhibited a decrease in body weight of 5% per day for the 3 days prior. Blood was collected from these animals and all clinical biochemistry and haematology performed.

Toxicokinetics/Dose formulation

Toxicokinetic analysis indicated that mean Cmax, AUClast& T1/2 for the test item were comparable between males & females on Day 1.

Both Cmax & AUClast increased on Day 28, with mean values consistently higher for males compared to the corresponding females. T1/2 remained similar to Day 1 values for both males and females.

Analysis of the dose formulation indicated that the doses administered were as stated in the study plan.

Question

Please summrize the result in the way blow

Results

a) A summary of results;

b) All information and data required by the study plan;

c) A presentation of the results, including calculations and determinations of statistical significance;

d) An evaluation and discussion of the results and, where appropriate, conclusions.

Answer 1

Summary

• Toxixity studies of the particular drug was studied in mice .
• The study is carried in 6 groups with each containing 10 males and females .
• The test sample is 98% pure.

Materials and methods

• Group 1 is control group . Group 2 is injected with low dose of the drug , Group 3 with Medium dose, Group 4 with high dose, group 5 with high dose and 14 days recovery period, group 6 is called as toxicokinetic group. In this group 10 animals ( 5 males and 5 females ) are vehicle and another10 animals are used studied for toxicokinetics.
• The dug is injected into the respective groups according to the protocol provided.
• The highest dose of drug admistered was 600mg/Kg /day.
• Due to experimental error group 1 animals were administered with vehicle twice rather than administering it on 14th day.
• This error didnot influence the outcomes because the animals were not pregnant when assessed .
• In the group 2 which receives low dose of drug , 3 animals were sacrificed and they were without water before necrospy.
• There was increased humidity compared to the study plan.

Results and Discussion

• In the group 1 and 2 the values were normal and it is compared with the literature.
• In group 3, the values of alanine amino transferase, aspartate amino transferase and sorbitol dehydrogenase are elevated slightly.
• In group 4 , all the parameters are high and alanine amino transferase , aspartate aminotransferase and sorbitol dehydrogenase are elevated more.
• In group 5, the values are same for animals that undergo recovery period according to the literature.
• In the hematology studies , all animals have normal hematocrit range except 3 animals that under received low dose of drug.
• The white blood cells are normal in all animals .
• In the light microscopy , the liver showed increased recruitment of cells and no other organ damage is observed.
• In the toxicity studies , low group and vehicle group showed no signs of toxicity. medium group showed mild toxicity . 2 animals from high group showed moderate toxixity.
• In group 4 and 5 here is higher toxixty in 3 and 2 animals respectively and also found to have weight loss.
• From the toxicokinetic studies , the values of parameters obtained are according to the study plan .

Conclusion

• Based on the toxicity results , the dose which doesnot affect animals (low and medium ) can be followed.