Spring Intro 2023

22/03/2023

Toxicity studies to enable phase 1 Clinical study in healthy volunteers * [ICH M3 R2] – therapeutic dose of small molecules

1. Mutagenicity + genotoxicity (2-3 studies) DNA damage in bacteria & cells 2. Pharmacokinetic profiling cells & animals (4-6 studies) Absorption & Excretion 3. Safety pharmacology studies cells & animals (2-4 studies) Heart Respiration & Brain 4.“Max tolerated dose” study in 1 or 2 species (rodent & non-rodent), including the route of human exposure (2 studies) 5. 14 or 28 day toxicity study in 2 species (rodent & non rodent) by route of human exposure (2 studies) Safe exposure level in blood 6. 10-15 studies, cost: > circa £1 Million, 12 months, up to 4-5 kg drug

* Excludes women of childbearing potential

Data from these studies must justify the proposed clinical trial

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Genotoxicity Tests [ICH S2R1]

For Human Phase 1 Studies 1. Gene Mutation in Bacteria – Ames Test 2. Chromosomal Damage or Gene Mutation in Mammalian Cells in vitro and Mammalian cell test in vivo – now done in repeat dose tox study Or in vivo genotoxicity tests in 2 different tissues 4. Additional Tests may be required

24 Colour Fluorescence In-situ Hybridisation

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