Preclinical Pharmacology

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Preclinical Pharmacology

• Pacific BioLabs
• Hercules, CA

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Preclinical Pharmacology

• Early work may be performed in cell cultures,
  when appropriate
• Performance of candidate drugs in an animal
  system provides early evidence of its potential
  

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Preclinical Pharmacology

• Preclinical evaluations use cell culture and
  animal responses as predictors of human responses
  with the goals of assuring safety and
  effectiveness in humans

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Pharmacology/Toxicology

• Preclinical pharm/tox data are used to
• Identify target organs/tissues
• Identify need for specialized safety monitoring
• Identify toxicological profile
• Select starting doses/regimens

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Developing a Strategy

• Case by case assessment based on clinical
  application
• Start with standard methods
• Postulated mechanism of action will drive more
  specialized investigations into a drugs activity

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Developing a Strategy

• Pharmacokinetics/pharmacodynamics
• Bioavailability
• Dose ranging/dose confirmation
• Potency determination
• Immunogenicity
• Custom animal models

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Pharmacokinetics

• Absorption
• Distribution
• Metabolism
• Excretion
• Need to track the drug in specimens
• Bioanalytical determination (cold)
• Radiolabel counts (hot)
• Species mouse or rat, then dog and/or primate

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Bioavailability

• Compare blood levels of drug delivered by
  intravenous route to intended route of
  administration
• Commonly oral or topical
• Species mouse, rat, or rabbit, then dog and/or
  primate

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Topical Drug Delivery

• Significant focus on transdermal drug delivery
• Iontophoretic delivery
• Passive patch
• Creams
• Formulations to promote absorption or deposition
• Delivery devices require dual assessment as drug
  and device
• Specialized studies look at layers of skin
• Species rabbit and pig

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Dose Ranging/Confirmation

• Multiple dose levels to discover optimum
  therapeutic level
• Minimum adverse effects (risk vs. benefit)
• Dose confirmation to verify earlier findings
• Maintain same species for comparability
• Species mouse, rat, dog, primate

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Potency Determinations

• Some drugs have a readily measured therapeutic
  effect
• Insulin, therapeutic toxins
• Response can be quantified
• Potency of preparation can be calculated based on
  dose response compared to standard

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Immunogenicity

• Development of an immune response to the test
  article may be desirable or undesirable
• Studies look at antibody response after multiple
  doses of the test article over time
• Species rabbit

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Animal Models

• Simulations of human condition
• May be normal state in animal that is very
  similar to human
• May be a diseased condition that is created in
  order to be treated

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Normal Animal Models

• Cardiovascular system pigs, dogs, primates
• Skin pigs, primates
• Eye rabbits

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Animal Models of Disease

• Photo aging in hairless mice
• Psoriasis in SCID mice
• Tumors in rats
• Obesity in mice
• Transgenic/knockout mice
• Some work, some dont

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Summary

• Every program is different, tailored to the
  activity of the test article
• Use same species throughout pharm/tox program
• Get regulatory buy in on plan

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Pacific BioLabs
THANK YOU!