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Toxicology in Drug Development


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Part of the MaRS Best Practices Series - Pre-Clinical development workshop …

Part of the MaRS Best Practices Series - Pre-Clinical development workshop

Speaker: Mike Watson. Exec Director Drug Development Services, Ricerca BioSciences

Published in: Business, Technology
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  • 1. Toxicology in Drug Development Michael Watson Vice President Program Management Ricerca Biosciences, LLC May 23, 2007
  • 2. Toxicology • Science to address potential harmful effects of chemicals – Medicine, hunting, warfare, suicide, homicide • Paracelsus – Swiss medical practitioner, 1493 – 1541, Father of Toxicology – “The dose makes the poison”
  • 3. Drug Development Process Chemistry & Biology Target ID & Lead Validation Development Hits IND Phase I Phase III NCE approval ADME/ HTS Tox Phase II Lead ID Lead Optimization
  • 4. Why do Toxicology Testing? • Need to prove new drugs are safe – First administration to man • What dose to use? • What effects to look for? – Later clinical trials • Expanded patient population • Longer duration of treatment
  • 5. Traditional Toxicology • In vitro toxicology – Screening – Aids design of better studies • Mechanistic toxicology – Guides discovery – Explains relevance • Safety assessment – Dose/response relationship
  • 6. In Vitro Toxicology • Screening – Cytotoxicity – Protein binding – CYP inhibition/induction – Membrane permeability – Metabolic stability • Improve subsequent study design – Interspecies comparison
  • 7. Mechanistic Toxicology • Guides discovery – Your lead just died! – Find out why – Medicinal chemistry to identify new lead • Explains relevance – Poor toxicology profile in rats – Demonstrate rats not a relevant model
  • 8. Safety Assessment • Regulatory Guidelines – International Conference on Harmonization Tripartite • USA, Europe, Japan • Technical requirements for registration of pharmaceuticals • for human use – ICH “M3 (M)” Non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals
  • 9. Prior to “First in Man” • Design the testing program – “Target Product Profile” • What do you want to see on the product label? • Sketch out a likely clinical trial program • Design the required “first in man” clinical study • Define testing program required • How much API do I need? – How long is a piece of string?
  • 10. Prior to “First in Man” • Safety Pharmacology – Cardiovascular – CNS – Respiratory • Toxicokinetic and Pharmacokinetic Studies – Exposure data in animals needed prior to human clinical trials
  • 11. Prior to “First in Man” • Single dose toxicity – Acute toxicity in two mammalian species • Repeat dose toxicity – Two mammalian species – Rodent and non-rodent – Route of administration to mimic clinical – Range of dose levels • Having effect (high dose) to no effect (low dose)
  • 12. Route of Administration • Mimic clinical route – Oral, subcutaneous, intramuscular, intravenous – “Specialized” routes • Inhalation • Infusion – Topically applied drugs (dermal) • Toxicology studies in miniature swine
  • 13. Repeat Dose Toxicity • Duration of studies – Single dose (in USA) to support single dose clinical trial – 14 or 28 days to support equal duration of clinical trial – How to decide • Required duration of clinical trial • Cost and time • API material supply
  • 14. Prior to “First in Man” • Local tolerance – Relevant to clinical route – May be part of toxicology study, but……. • Genotoxicity – In vitro tests for mutations and chromosomal damage – Consider adding mouse micronucleus to complete the package
  • 15. Interpretation of Results • Determine “no observed adverse effect level” – In all species tested – May be different from “no effect level” • Convert to “human equivalent dose” – On basis of body surface area • Select most appropriate animal species • Apply safety factor • Result = Maximum recommended starting dose
  • 16. Early Studies in Patients • Toxicokinetic and Pharmacokinetic Studies – Further information on ADME in animals needed to compare human and animal metabolic pathways – Studies in animals with radiolabeled API • Extended duration of repeat dose • Complete genotoxicity package
  • 17. In Vivo Metabolism Studies • Synthesis of radiolabeled material – Which label to use – Where in the molecule • Mass balance • Tissue distribution – Whole body autoradiography • Metabolic pathway elucidation
  • 18. Later Studies in Patients • Extended duration of repeat dose – 3 months to “chronic” duration • Reproduction toxicity studies – Inclusion of women of childbearing potential • Carcinogenicity studies – Depending on duration of drug treatment
  • 19. Reproduction Toxicity Studies • Traditional terminology – Segment 1, 2 and 3 • Segment 1: Fertility and general reproductive performance • Segment 2: Teratogenicity • Segment 3: Peri-post natal – Newer ICH guidelines • Flexibility • Design studies to cover all stages of reproduction
  • 20. Carcinogenicity Testing • Objective: identify tumorigenic potential in animals and assess risk in humans • Required if drug to be administered for substantial part of patient’s lifetime • Review all data to determine if testing warranted • Data overview and protocols reviewed by regulators prior to testing
  • 21. Carcinogenicity Testing • Lifespan studies in rats and mice (2 years) • Difficult to design and interpret – Untreated rodents gets tumors – Different strains have different common tumors – Tumors can be benign or malignant – Tumors earlier in life, incidence unchanged – Decreased body weight makes healthier animals
  • 22. Keys to Drug Development Success Anticipate and expect problems • It is never too early to plan ahead • Maintain flexibility • Trade off between $$ and timing • Plan for success •