Khan When and How to demonstrate safety

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Presented by Dr. Safdar Khan at the Alliance for Contraception in Cats & Dogs’ 4th International Symposium on Non-Surgical Contraceptive Methods of Pet Population Control, April 8-10, 2010, in Dallas, Texas, U.S.

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Safety and Toxicity of a Potential Sterilant : 

Safety and Toxicity of a Potential Sterilant Safdar A. Khan, DVM, MS, PhD, DABVT ASPCA Animal Poison Control Center, Urbana, IL

Requirements of an Ideal Sterilant : 

Requirements of an Ideal Sterilant Safe and efficacious (long-term) Easy to administer Effective in dogs and cats Effective in male and female Cost effective (affordable)

Overview of the Hows and Whys of regulations governing medications and chemicals : 

Overview of the Hows and Whys of regulations governing medications and chemicals Safety Studies and GLPs

Drug Development : 

Drug Development Before marketing, must be approved by the CVM (Part of FDA) on the basis of safety and efficacy Generally a new veterinary drug takes 5-15 years to be developed and costs 10-50 Million (human drugs 10-15 y and 800 million on avg)

Drug Development : 

Drug Development Process is similar for human and animal drugs. Differences with animal drugs Can test directly on target spp., so earlier info on safety and efficacy Wider range of weights and spp. to account for Feed palatability and field stability are issues

Drug Development : 

Drug Development Phases 1.Acquisition ID molecules of interest for specific molecular target Preliminary in vitro Potency at target metabolism and then in vivo studies Efficacy and safety, preliminary PK 2. Development Create a formulation, develop analytical methods Full PK studies Determine dose (does it work and is it safe) Also human food safety/residue studies FDA review of INAD (investigational new animal drug)

Drug Development : 

Drug Development Registration Large trials ($$$) Long term safety studies Submission to FDA of new animal drug application (NADA) Launch after FDA approval 4. Support Pharmacovigilance/monitoring

Structure/Activity Relationship : 

Structure/Activity Relationship Often use these tests to determine if a molecule should be investigated further Structure, solubility, stability, pH, electrophilicity, volatility, reactivity N-nitroso or aromatic amine groups can potentially be carcinogens

Acute testsSubchronic Chronic : 

Acute testsSubchronic Chronic Toxicologic Tests

Acute Toxicity Testing : 

Acute Toxicity Testing Acute toxicity = the adverse effects occurring within a short time of single dose of a substance or multiple doses given within 24 hrs Often PO, could be injection or inhalation (depends on substance and expected use or how humans exposed) Quantal response All or nothing: dead or alive Graded response Quantitative: weight loss or feed consumption LD50 is of value for highly toxic substances primarily Acute toxicity is NOT = LD50

Acute Toxicity Testing : 

Acute Toxicity Testing Objectives Define intrinsic toxicity of a chemical Hazard prediction (target and nontarget spp.) Determine susceptible spp. Identify target organs Provide info for the design and selection of doses for prolonged studies Provide info for treatment of acute overdose Often, oral, dermal, and ocular acute tests are done

Acute Oral Toxicity : 

Acute Oral Toxicity In general: Test substance given by gavage or by gastric intubation Group of animals observed at specific intervals for clinic signs, morbidity, mortality Necropsies are done, usually on all animals

Acute Oral Toxicity : 

Acute Oral Toxicity Species Ideally, chosen if response is suspected to be similar to human response Usually this is difficult or impossible Usually chosen based on convenience, cost, and existing database of information about the species Rats, mice, rabbits, guinea pigs Healthy young adults

Acute Oral Toxicity : 

Acute Oral Toxicity Most regulatory guidelines suggest 10 rats 5 male and 5 female Controlled environment Temperature, light and dark cycle Caged appropriately Rodents may be together (usually no more than 3/cage) Otherwise, housed individually Quarantined for at least 1 week to acclimatize Fasted prior to dosing Randomly assigned to dose groups

Acute Oral Toxicity : 

Acute Oral Toxicity Dose levels 3-5 levels usually enough to show a dose – response relationship The doses should bracket the expected LD50, with at least one level higher, but not causing 100% mortality and one dose lower, but not causing 0% mortality. May need to do a pilot study to decide what doses to use Or dose may be based on information from other spp In general, 5 g/kg (some say 2) is considered to be “practically nontoxic” Usually no need to go higher If higher doses given, could see signs that are not intrinsic to the compound itself GI blockage

Acute Oral Toxicity : 

Acute Oral Toxicity Administered in appropriate vehicle If toxicity of vehicle is unknown, need to do a vehicle control group Need to bear in mind that a vehicle could cause problems Diarrhea from an oil, could impair absorption of the toxicant, if GI motility is increased Small a volume as possible should be used Observation period Varies depending on substance Onset of signs could be very short to days Usually not more than 14 days

Other Acute Tests : 

Other Acute Tests Acute dermal toxicity Acute hypersensitivity Acute ocular toxicity

Subchronic Toxicity Testing : 

Subchronic Toxicity Testing 90 days is most common duration Usually need data from short term studies to design this type of testing Doses/ dose-response May need to do short-term, repeated dosing studies to determine this 14-28 days Target organ(s) palatability

Subchronic Toxicity Testing : 

Subchronic Toxicity Testing Objectives ID longer term adverse effects ID LOAEL and NOAEL Provide information for chronic studies Spp. to use, doses

Subchronic Toxicity Testing : 

Subchronic Toxicity Testing Requirements/guidelines (EPA/FDA) overview Animals At least 3 groups and a control group +/- vehicle control group At least 10 animals/sex/group Weigh weekly Weekly feed consumption Observe daily Pre and post ophthalmology exams At end of study Organ weights, all animals necropsied and histopathology

Subchronic Toxicity Testing : 

Subchronic Toxicity Testing Test material May be part of the diet or water for entire testing period and animals have free access Dermal or inhalation studies Intermittent exposure, usually 4-6 h per day Parenteral or oral Usually once a day

Subchronic Toxicity Testing : 

Subchronic Toxicity Testing Dose groups (at least 3) High dose should not result in more than 10% mortality, but should show evidence of toxicity Mid-dose group, no more than slight toxicity Low dose group, ideally should show the NOAEL If substance is thought to be almost nontoxic, may be only one group used

Subchronic Toxicity Testing : 

Subchronic Toxicity Testing Animal models Usually one rodent and one nonrodent Often rats and dogs Others include: rabbits, guinea pigs, mouse, hamster, swine, primates Dosing is usually started at 6 w in rodents, 6 m in dogs Selection based on What is required by the regulatory agency Similar metabolism to humans Prior data Sensitivity of the species, most sensitive is best Cost and availability Daily monitoring CBC, chemistries, necropsied

Chronic Toxicity Testing : 

Chronic Toxicity Testing Done much as the subchronic studies Defined as > 3 months Duration is from 6 months to two years in rodents; 5-7 yrs in dog; duration depended on intended use of the test substance Used to assess the cumulative toxicity Usually done to fulfill a regulatory requirement

Chronic Toxicity Testing : 

Chronic Toxicity Testing Dose selection Need to avoid mortality Usually, goal is toxic effects at one or more dose levels, and no effect (NOEL) or NOAEL at one or more of the lower doses Usually, high dose is the MTD (maximum tolerable dose) MTD= the highest dose predicted not to alter the animals normal longevity MTD = does in which in a 90 days study causes not more then 10% decrease in weight, no mortality, no clinical signs, no path lesions

Chronic Toxicity Testing : 

Chronic Toxicity Testing Species : rodent and nonrodent Chosen much as in the subchronic studies Need to start with more animals to make sure that enough survive for the duration of the study May need to start with twice as many as needed at the end of the study Similar to subchronic testing; chemistries, necropsies are done in these studies as in the subchronic studies

Other Toxicity Tests : 

Other Toxicity Tests Genetic tests Carcinogenicity Developmental toxicology testing Pharmacokinetic/analytical methods Environmental fate/effects Secondary toxicity risks Analytical methods Species differences

Species Differences : 

Species Differences Dogs Indiscriminate eater More sensitive to methemoglobin formation than humans 4 vs 2 sulfhydryl groups on hemoglobin Aceytylation limited Some dogs have deficient P glycoprotein on bbb increased sensitivity Cats More selective eating habits; grooming habits Concentrated urine Eight reactive sulfhydryl groups on hemoglobin increased susceptibility of RBC to oxidative damage; Short RBC life span (66-79 days) Limited glucuronidation highly susceptible to xenobiotics that require glucuronidation for metabolism (acetaminophen, aspirin, etc).

Summary : 

Summary Safety and efficacy---long tedious process Expensive; years of efforts; millions of dollars Must show safety in lab animals and target animal; LD50s not enough Species differences important; significant metabolic differences among spp.

Questions? : 

Questions?

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