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GLP Toxicology Services

PRE-IND STUDIES REQUIRED FOR PHASE I TRIALS

ACUTE TOXICITY

Single dose at 3-5 dose levels
Two routes of exposure (oral and IV ?)
Two species (rodent and non-rodent)
Observations for 14 days
Evaluate clinical and gross morphological effects
Study Examples

SUBCHRONIC TOXICITY

Daily dose from as few as 14 up to 90 days
Expected clinical route
Two species (rodent and non-rodent)
Three dose levels plus controls
Recovery groups
Clinical, toxicokinetic, clinicopathologic evaluations
Study Examples

GENETIC TOXICITY

Ames reverse-mutation assay
CHO-HGPRT mammalian cell forward gene mutation assay
Cytogenetics assay in primary human lymphocytes
Micronucleus study in rodents

SAFETY PHARMACOLGY

There are ~ 15 short term studies in this series
Assess adverse effects of compounds on the cardiovascular, respiratory, central and peripheral nervous system, renal and gastrointestinal functions.

Studies normally recommended are dog cardiovascular, rat pulmonary function, Irwin CNS behavior study in rats, HERG Tail Current Test.

TOXICOKINETICS

Can be included in the Subacute studies

POST-IND STUDIES REQUIRED FOR AN NDA

CHRONIC TOXICITY

Daily dosing of rodents 6 months, non-rodents 12 months
Daily dosing via the clinical route
Two species (rodent and non-rodent)
Three dose levels plus controls
Clinical, toxicokinetic, clinicopathologic, and morphological evaluations

CARCINOGENICITY

Daily dosing for two years
Clinical route
Two species (rat and mouse)
Three dose levels plus two controls
50-60 animals/sex/group
Assess carcinogenic potential of material
May substitute a six month transgenic mouse study for the 24 month mouse

REPRODUCTIVE TOXICITY

Fertility (Male and/or Female) - Segment I

Fertility and early embryonic development to implantation
Rat dosed via the clinical route
Three dose levels plus controls
Dose males 4 weeks prior to mating, females 2 weeks
Assess maternal toxicity, development and maturation of gametes, estrous cycles, mating, fertility, and effect on implantation

Embryo-fetal Development - Segment II

Embryo-fetal development
Two species, rat and rabbit does via the clinical route
Three dose levels plus controls
Dose during organogenesis
- Rat – gestation days 6-18
- Rabbit – gestation days 6-18
Assess ovarian CLs, implantation sites, resorptions, dead fetuses, gross fetal malformations and development variations

Prenatal and Postnatal Development, including Maternal Function - Segment III

Prenatal and Postnatal Development
Female rat dosed via the clinical route
Three dose levels plus controls
Dose Gestation Day 6 through Lactation Day 20
Assess maternal toxicity, pregnancy duration, parturition, lactation, implantation, embryo/fetal changes, stillbirths, growth development, behavior and reproductive changes

STUDY EXAMPLES

ACUTE TOXICITY STUDY EXAMPLES

Acute Oral Rat Limit Test

Study will be conducted under GLP conditions
Rats approximately 6-8 weeks old at initiation
Acclimation period, minimum 5 days
Each group containing 5 rats/sex
Dosing solutions/suspensions will be prepared once prior to study initiation. Rats will be dosed once by oral gavage
Body weights prior to study initiation and on Days 7 and 14 post-dose
Clinical signs will be recorded daily
Gross necropsy on all animals 14 days post-dose
A draft report will be available 8 weeks after necropsy

Acute Dermal Toxicity

Study will be conducted under GLP conditions
Rats approximately 6-8 weeks old at initiation
Acclimation period, minimum 5 days
Each group containing 5 rats/sex
Test article will be applied as received. Rats will receive a single 24-hour exposure
Body weights prior to study initiation and on Days 7 and 14 post-dose
Clinical signs will be recorded daily
Gross necropsy on all animals 14 days post-dose
A draft report will be available 8 weeks after necropsy

Primary Dermal Irritation Rabbit Study

Study will be conducted under GLP conditions
Rabbits approximately 2-3 kg at initiation
Acclimation period, minimum 5 days
One group containing 4 rabbits
Test article will be applied as received. Rabbits will receive a single 4-hour exposure
Body weights prior to study initiation
Dermal irritation will be scored immediately prior to application, approximately 60 minutes after unwrapping, and 24, 48, and 72 hours after application
A draft report will be available 8 weeks after completion of the animal phase

Primary Ocular Irritation Rabbit Study

Study will be conducted under GLP conditions
Rabbits approximately 2-3 kg at initiation
Acclimation period, minimum 5 days
Two groups containing 3 rabbits/group (rinsed and un-rinsed)
Test article will be applied as received. Rabbits will receive a single ocular instillation
Body weights prior to study initiation
Eye irritation will be scored at 24 hours before instillation; at 3 minutes, 1, 24, 48, 72 and 96 hours after instillation
A draft report will be available 8 weeks after completion of the animal phase

Guinea Pig Dermal Sensitization Study

Study will be conducted under GLP conditions
Guinea pigs approximately 4-6 weeks at initiation
Acclimation period, minimum 7 days
One test group 20 guinea pigs. One control group 10 guinea pigs
Test article will be applied as received. Guinea Pigs will receive 3 dermal induction doses and one challenge dose
Body weights prior to study initiation and then weekly
Dermal irritation will be scored immediately prior to application, and following each induction and challenge dose
A draft report will be available 8 weeks after completion of the animal phase

SUBCHRONIC TOXICITY STUDY EXAMPLES

28-Day Dog Oral Capsule Study

This will be GLP study.
There will be 3 dose groups plus a control with 4/sex/dose group. N=32.
Dogs will be individually housed in in-door runs with epoxy painted cement floors and equipped with resting boards and automatic waterers in a room dedicated to this study. A small amount of wood fresh shavings will be placed on the floor daily, changed weekly and the runs sanitized bi-monthly.
Dogs will be dosed once daily via capsule for 28 days.
Capsules will be prepared at BASE.
Food (PMI Certified Canine Rations) and water will be ad-libitum except on the nights prior to blood collection for clinical pathology or necropsy.
Hematology, serum chemistry, coags and urinalysis pre-dose and at 28 days.
Ophthalmology by veterinarian (ACVO) prior to dosing and during Week 4.
ECG’s prior to dosing and during Week 4. N=64 ECG’s ECG’s evaluated by a veterinarian (ACIM, Cardiology).
TK blood samples at 6 time points from each animal on Days 1 and 27. Plasma to be separated, frozen and shipped to a laboratory selected by the sponsor for analyses.
TK report will be prepared by the sponsor. N=384 samples.
After 28 days dosing, the animals will be euthanized using sodium pentobarbital and necropsied. Approximately 60 tissues/animal will be collected and preserved in 10% NBF. N=1,920 tissues.
The following organs will be weighed: adrenals, brain, epididymides, heart, kidneys, liver, lungs, ovaries, spleen, thyroid/parathyroid, testes and uterus.
Tissues from each animal will be trimmed, processed, embedded in paraffin, and slides prepared for examination by a veterinary pathologist (ACVP) employed by Experimental Pathology Laboratories. N=1,920 tissues.
An audited draft report will be available 13 weeks after necropsy.
The final signed report will be available 4 weeks after receipt of the edited draft report and the TK report from sponsor.

A 28-Day Dog Oral Gavage Study

This will be a GLP study.
There will be 3 dose groups plus a control with 4/sex/dose group. N=32.
Dogs will be individually housed in in-door runs with epoxy painted cement floors and equipped with resting boards and automatic waterers in a room dedicated to this study. A small amount of wood fresh shavings will be placed on the floor daily, changed weekly and the runs sanitized bi-monthly.
Dogs will be dosed once daily via oral gavage for 28 days.
Dose formulations will be prepared at BASE weekly. Samples of each preparation will be collected and an entrance analysis performed on the dosed prepared for use in Week 1 and 4 using an analytical method provided by the sponsor and validated at BASi. Concentrations must be within +/- 10% of theoretical to be acceptable. Those samples failing to meet this criterion will be discarded and a new batch prepared and analyzed.
BASi will provide dose preparation stability data for up to 10 days.
Food (PMI Certified Canine Rations) and water will be ad-libitum except on the nights prior to blood collection for clinical pathology or necropsy.
Hematology, serum chemistry, coags and urinalysis pre-dose and at 28 days.
Ophthalmology by a veterinarian (ACVO) prior to dosing and during Week 4.
ECG’s prior to dosing and during Week 4. N=64 ECG’s. ECG’s evaluated by a veterinarian (ACIM, Cardiology).
TK blood samples at 6 time points from each animal on Days 1 and 27. Plasma to be separated, frozen and shipped to a laboratory selected by the sponsor for analyses.
The TK report will be prepared by the sponsor. N=384 samples.
After 28 days dosing the animals will be euthanized using sodium pentobarbital and necropsied. Approximately 60 tissues/animal will be collected and preserved in 10% NBF. N=1,920 tissues.
Tissues from each animal will be trimmed, processed, embedded in a paraffin, and slides prepared for examination by a veterinary pathologist (ACVP) employed by Experimental Pathology Laboratories. N=1,920 tissues.
The following organs will be weighed: adrenals, brain, epididymides, heart, kidneys, liver, lungs, ovaries, spleen, thyroid/parathyroid, testes and uterus.
An audited draft report will be available 13 weeks after necropsy.
The final signed report will be available 4 weeks after receipt of the edited draft report and the TK report from the sponsor.

A 28-Day Dog Bolus IV Study

This will be a GLP study.
There will be 3 dose groups plus a control with 4/sex/dose groups. N=32.
Dogs will be individually housed in in-door runs with epoxy painted cement floors and equipped with resting boards and automatic waterers in a room dedicated to this study. A small amount of wood fresh shavings will be placed on the floor daily, changed weekly and the runs will be sanitized bi-monthly
Dogs will be dosed once daily via slow bolus IV for 28 days.
Dose formulations will be prepared at BASE weekly. Samples of each preparation will be collected and an entrance analysis performed on the doses prepared for use in Weeks 1 and 4 using an analytical method provided by the sponsor and validated at BASi. Concentrations must be within +/- 10% of theoretical to be acceptable. Those samples failing to these criteria will be discarded and a new batch prepared and analyzed.
BASi will provide dose preparation stability data for up to 10 days.
Food (PMI Certified Canine Rations) and water will be ad-libitum except the nights prior to blood collection for clinical pathology or necropsy.
Hematology, serum chemistry, coags and urinalysis pre-dose and at 28 days.
Ophthalmology by a veterinarian (ACVO) prior to dosing and during Week 4.
ECG’s prior to dosing and during week 4. N=64 ECG’s. ECG’s evaluated by a veterinarian (ACIM, Cardiology).
TK blood samples at 6 time points from each animal on Days 1 and 27. Plasma to be separated, frozen and shipped to a laboratory selected by the sponsor for analyses.
TK report will be prepared by the sponsor. N=384 samples.
After 28 days dosing the animals will be euthanized using sodium pentobarbital and necropsied. Approximately 60 tissues/animal will be collected and preserved in 10% NBF. N=1,920 tissues.
The following organs will be weighed: adrenals, brain, epididymides, heart, kidneys, liver, lungs, ovaries, spleen, thyroid/parathyroid, testes and uterus.
Tissues from each animal will be trimmed and processed, embedded in paraffin, and slides prepared for examination by a veterinary pathologist (ACVP) employed by Experimental Pathology Laboratories. N=1,920 tissues.
An audited draft report will be available 13 weeks after necropsy.
The final signed report will be available 4 weeks after receipt of the edited draft report and the TK report from the sponsor.

A 28-Day Dog Continuous IV Infusion

This will be a GLP study.
There will be 3 dose groups plus a control with 4/sex/dose group. N=32.
Dogs will be individually housed in in-door runs with epoxy painted cement floors and equipped with resting boards and automatic waterers in a room dedicated to this study. A small amount of wood fresh shavings will be placed on the floor daily, changed weekly and the runs sanitized bi-monthly.
Dogs will be dosed continuously via IV infusion using surgically implanted access ports or catheters for 28 days.
Dose formulations will be prepared at BASE weekly. Samples of each preparation will be collected and an entrance analysis performed on the doses prepared for use in Weeks 1 and 4 using an analytical method provided by the sponsor and the validated at BASi. Concentrations must be within +/- 10% theoretical to be acceptable. Those samples failing to these criteria will be discarded and a new batch prepared and analyzed.
BASi will provide dose preparation stability data for up to 10 days.
Food (PMI Certified Canine Rations) and water will be ad-libitum except on the nights prior to blood collection for clinical pathology or necropsy.
Hematology, serum chemistry, coags and urinalysis pre-dose and at 28 days.
Ophthalmology by a veterinarian (ACVO) prior to dosing and during week 4
ECG’s prior to dosing during week 4. N=64 ECG’s. ECG’s evaluated by a veterinarian (ACIM, Cardiology).
TK blood samples at 6 time points from each animal on Days 1 and 27 Plasma to be separated, frozen and shipped to sponsor for analysis.
The TK report will be prepared by the sponsor. N=384 samples.
After 28 days dosing the animals will be euthanized using sodium pentobarbital and necropsied. Approximately 60 tissues/animal will be collected and preserved in 10% NBF. N=1,920 tissues.
The following organs will be weighed: adrenals, brain, epididymides, heart, kidneys, liver, lungs, ovaries, spleen, thyroid/parathyroid, testes and uterus.
Tissues from each animal will be trimmed, processed, embedded in paraffin, and slides prepared for examination by a veterinary pathologist (ACVP) employed by Experimental Pathology Laboratories. N=1,920 tissues.
An audited draft report will be available 13 weeks after necropsy.
The final signed report will be available 4 weeks after receipt of the edited draft report and the TK report from the sponsor.

A 28-Day Oral Gavage Rat Study

This will be a GLP study.
There will be 3 dose groups plus a control with 6/sex/group. N=48.
There will be a TK satellite group consisting of 9 rats/sex/dose group (no controls). N=54 rats. Samples are to be collected 3/sex/group at 6 time points on Days 1 and 28. Plasma will be separated, frozen and shipped to a laboratory selected by the sponsor for analyses. N=216 samples. After the final blood collection the TK animals are to be euthanized and their carcasses discarded.
Sponsor will prepare the TK report.
Rats will be dosed once daily via oral gavage for 28 days.
Dose formulations will be prepared at BASE weekly. Samples of each preparation will be collected and an entrance analysis performed on the doses prepared for use in Weeks 1 and 4 using an analytical method provided by the sponsor and validated at BASi. Concentrations must be within +/- 10% of theoretical to be acceptable. Those samples failing to meet those criteria will be discarded and a new batch prepared and analyzed.
BASi will provide does preparation stability data for up to 10 days.
Food (PMI Certified Rodent Rations) and water will be ad-libitum except on nights prior to blood collection for clinical pathology or necropsy.
Hematology, serum chemistry, coags and urinalysis at termination.
Ophthalmology exams by a qualified veterinarian prior to dosing and during Week 4.
After 28 days dosing the animals will be euthanized with CO2, exsanguinated and necropsied. Approximately 60 tissues/animal will be collected and preserved in 10% NBF. N=2,880 tissues.
The following organs will be weighed: adrenals, brain, epididymides, heart, kidneys, liver, lungs, ovaries, spleen, thyroid/parathyroid, testes and uterus.
Tissues from each animal will be trimmed, processed, embedded in paraffin, and slides prepared for examination by a veterinary pathologist (ACVP) employed by Experimental Pathology Laboratories. N=2,880 tissues.
An audited draft report will be available 13 weeks after necropsy.
The final signed report will be available 4 weeks after receipt of the edited draft report and the TK report from the sponsor.

A 28-Day Bolus IV Rat Study

This will be a GLP study.
There will be a 3 dose groups plus a control with 6/sex/group. N=48.
There will be a TK satellite group consisting of 9 rats/sex/group (no controls). N=54 rats. Samples are to be collected 3/sex/group at 6 time points on Days 1 and 28. Plasma will be separated, frozen and shipped to a laboratory selected by the sponsor for analysis. N=216 samples. After the final blood collection the TK animals are to be euthanized and their carcasses discarded.
Sponsor will prepare the TK report.
Rats will be dosed once daily via bolus intravenous infusion for 28 days.
Dose formulations will be prepared at BASE weekly. Samples of each preparation will be collected and an entrance analysis performed on the doses prepared for use in Weeks 1 and 4 using analytical method provided by the sponsor and validated at BASi. Concentrations must be within +/- 10% of theoretical to be acceptable. Those samples failing to meet those criteria will be discarded and a brand new batch prepared and analyzed.
BASi will provide dose preparation stability data for up to 10 days.
Food (PMI Certified Rodent Rations) and water will be ad-libitum except on nights prior to blood collection for clinical pathology or necropsy.
Hematology, serum chemistry, coags and urinalysis at termination.
Ophthalmology exams by qualified veterinarian prior to dosing and during Week 4.
After 28 days dosing the animals will be euthanized with CO2, exsanguinated and necropsied. Approximately 60 tissues/animals will be collected and preserved in 10% NBF. N=2,880 tissues.
The following organs will be weighed: adrenals, brain, epididymides, heart, kidneys, liver, lungs, ovaries, spleen, thyroid/parathyroid, testes and uterus.
Tissues from each animal will be trimmed, processed, and embedded in paraffin, and slides prepared for examination by a veterinary pathologist (ACVP) employed by Experimental Pathology Laboratories. N=2,880 tissues.
An audited draft report will be available 13 weeks after necropsy.
The final signed report will be available 4 weeks after receipt of the edited draft report and the TK report from the sponsor.

A 28-Day Monkey Bolus IV Study

There will be 3 dose groups plus a control group each containing 4 monkeys/sex/dose group in this GLP study. N=32. The animals will be purpose bred, approximately 1.5 to 2.5 years of age, drug naïve, herpes B negative, weighing approximately 2.5-3.5 kg.
Monkeys will be acclimated for at least 30 days and tuberculosis tested at least three times prior to dose initiation.
Monkeys will be housed individually in stainless steel cages with wire mesh floors suspended over flush pans. Pans will be cleaned twice daily and sanitized every two weeks. Each caged is equipped with a swing/perch for enrichment along with one or more of the following: Puzzle-Toss™, Kong Toy™, foraging board, or banana puzzle.
Food (PMI Certified Monkey Rations) and water (deep well tested) will be available ad-libitum except on nights prior to necropsy or the collection of blood for clinical pathology.
A qualified veterinarian (ACVO) will perform an ophthalmic examination on each animal prior to study initiation and during Week 4 prior to necropsy. The colony veterinarian will perform a physical examination on each animal prior to the study initiation and during Week 4 prior to scheduled necropsy.
Dose formulations will be prepared at BASE weekly. Samples of each preparation will be collected and an entrance analysis performed on the doses prepared for use in Weeks 1 and 4 using an analytical method provided by sponsor and validated at BASi. Concentrations must be within +/- 10% of theoretical to be acceptable. Those samples failing to meet those criteria will be discarded and a new batch prepared and analyzed.
BASi will provide dose preparation stability data for up to 10 days.
Body weights prior to initiation and then weekly. Food consumption (biscuits consumed) recorded daily.
Blood samples for TK analysis will be collected on Days 1 and 27 at 6 time points from each animal. Samples will be spun down, the plasma separated, frozen and shipped to a laboratory selected by the sponsor for analyses. N=384 plasma samples.
The TK report will be prepared by the sponsor.
Monkeys will be given an ECG prior to initiation and 1 hour after dosing on Days 1 and 28. N=96 ECGs. The ECGs will be evaluated by a veterinarian (ACIM, Cardiology).
Hematology, urinalysis, coags and serum chemistry analysis will be conducted on each animal prior to initiation and during Week 4. N=64 sets of each.
The animal will be necropsied after 28 days of dosing. They will be anesthetized with sodium pentobarbital, exsanguinated and a gross necropsy performed.
The following organs will be weighed: adrenals, brain, epididymides, heart, kidneys, liver, lungs, ovaries, spleen, thyroid/parathyroid, testes and uterus.
A full set of tissues (~60) will be collected from each animal and preserved in 10% NBF.
The tissues from all animals will be trimmed, embedded in paraffin, slides prepared and stained for examination by a veterinary pathologist (ACVP) employed by Experimental Pathology Laboratories. N=1,920 tissues.
An audited draft final report will be available 13 weeks after necropsy.
The signed final report will be available 4 weeks after receipt of the edited draft and the TK report from sponsor.