Preclinical Animal Studies

Medicilon provide preclinical animal studies for clients. Animal studies of drug efficacy are an important resource for designing and performing clinical trials. They provide evidence of a drug’s potential clinical utility, inform the design of trials and establish the ethical basis for testing drugs in human. Several recent studies suggest that many preclinical investigations are withheld from publication. Such non-reporting likely reflects that private drug developers have little incentive to publish preclinical studies. However, it potentially deprives stakeholders of complete evidence for making risk/benefit judgments and frustrates the search for explanations when drugs fail to recapitulate the promise shown in animals.

Preclinical Trial – A laboratory test of a new drug or a new medical device, usually done on animal subjects, to see if the hoped-for treatment really works and if it is safe to test on humans.

Preclinical Animal Studies

• In Vitro Toxicology
• In Vivo Toxicology
• Animal Models

In Vitro Toxicology

• In Vitro Toxicology

– The crossover point between drug discovery and drug development
– Provide information on mechanism(s) of action of a drug
– Provides an early indication of the potential for some kinds of toxic effects, allowing a decision to terminate a development program before spending too much money

• In Vitro methods are widely used for

– Screening and ranking chemicals
– Studying cell, tissue, or target specific effects
– Improving subsequent study design

• In Vitro methods are usually

– Less expensive to run than in vivo studies
– Faster than in vivo studies (PLUS they don’t bite!)
– Somewhat less predictive of toxicity in intact organisms

• Screening

– Cytotoxicity
– Protein Binding
– CYP Inhibition/Induction
– Membrane Permeability
– Metabolic Stability
– Inter-species Comparison

In Vivo Toxicology – Purpose

• Results from preclinical toxicology studies should, at a minimum:

– Establish a safe starting dose for clinical studies
– Provide information on a drug-treatment regimen that would produce the least toxicity
– Assess target organ toxicity and its reversibility
– Provide insight into biomarkers for clinical monitoring

Types of Preclinical Safety Studies

• The number and types of studies required depend on the therapeutic indication.
• Drugs for life-threatening illnesses require fewer studies to reach the clinic.
• In general, animal studies are conducted in two species, one rodent (e.g., rat, mouse) and one non-rodent (e.g., dog, nonhuman primate). Biologics may require only one species.
• Other species (e.g., rabbits, ferrets, hamsters, minipigs) may be used for special studies (e.g., vaccine studies).

Usually start with:

Single Dose (Acute/Range-Finding)

• Used to determine the most appropriate dose range in the species to be tested
• Used to get an idea of target organs
• Includes minimal number of animals and evaluations (e.g., body weights, clinical signs of toxicity)
• Usually not required to be GLP-compliant

• Repeated Dose Toxicity

• Animal Models

• Small Molecules – two species (one rodent, one non-rodent)
• Biologics – may require only one species if only one relevant species can be identified

• Should mimic as closely as possible the planned clinical design

• Route
• Duration
• Schedule

• Requirements vary between the different regulatory agencies
• Extensive evaluations of toxic effects

• Body Weights
• Clinical Signs of Toxicity
• Food Consumption
• Clinical Pathology
• Histopathology
• Other

• Large animals usually undergo more extensive evaluation(e.g., ECGs)
• At least one dose should produce dose-limiting toxicity
• At least one dose should be non-toxic

• Safety Pharmacology

• Used to determine the effects of the drug on specialized organ systems (e.g., cardiovascular, respiratory, neurologic)
• Chronic Toxicity/Carcinogenicity
• Used to determine the effects of long-term exposure to the drug, including the ability to produce cancer
• May not be required for drugs that are intended for only short-term use (e.g., antibiotics) and that are expected to have no permanent effects on DNA

• Reproductive Toxicity/Teratogenicity

• Evaluates effects on reproductive function and ability to produce birth defects

Animal Models in Toxicology Testing

Key Assumptions

– Other organisms can serve as accurate predictive models of toxicity in humans
– Selection of an appropriate model to use is key to accurate prediction in humans
– Understanding the strengths and weaknesses of any particular model is essential to understanding the relevance of specific findings to humans

Caveat
– Drugs showing safety and efficacy in preclinical animal models may show very different pharmacological properties when administered to humans

Animal Models

• Development of proper preclinical models which can efficiently predict drug behavior in humans is essential prior to testing a drug in a human subject
• The FDA and other regulatory agencies are more and more requiring Sponsors to provide data to support selection of the specific species (and even strains) used to support testing of new drugs

Some (of the many) reasons that a given animal model may be inappropriate are:

• Lack of appropriate drug target in the preclinical animal model
• Presence of irrelevant target
• Differences in metabolic fate
• Differences in susceptibility to infection by specific pathogens