Animal Toxicity Studies

Animal Toxicity Studies (Preclinical Safety Evaluation)

1. Definition, scope & objectives

• Toxicology is the study of the adverse effects of substances on living organisms; any substance is a poison when exposure produces a damaging physiological (toxic) effect. Agents producing toxic effects include pharmaceuticals, illicit drugs, plants/botanicals, and environmental chemicals/pollutants (G&G 14e Ch.9, p.155).
• Toxicity study (also termed hyperpharmacology) is an ethically necessary stage of drug development, run alongside pharmacological and pharmacokinetic evaluation, to deliver a safe and efficacious drug (Medhi Ch.9, p.115).
• Toxicological testing is performed in preclinical studies to assess toxicity of a substance in animals and in in vitro models; additional studies — carcinogenicity, teratogenicity, and effects on fertility — are performed concurrently with the first stages of a clinical trial; still more adverse effects emerge in post-marketing surveillance as more patients are exposed (G&G 14e Ch.9, p.155).
• Because of species-to-species variation in pharmacological response, two or more species are always preferred in toxicity testing (Medhi Ch.9, p.115).
• All protocols must be reviewed and approved by an Institutional Animal Ethics Committee (IAEC) before the experiment (Medhi Ch.9, p.115).
• Objectives of the toxicity study (Medhi Ch.9, p.115):
  • Identify any toxic substance prior to clinical use.
  • Qualitative assessment — nature of the drug effect seen in target organs.
  • Quantitative assessment — drug level (plasma and tissue) at which effects are definitely seen and not seen.
  • Characterise the cumulative toxicity of the drug (especially in subchronic/chronic studies — not predicted by single-dose toxicity).
  • Allow careful selection of doses for further studies (including carcinogenicity studies).
  • Permit identification of different dose descriptors — maximum lethal dose (MLD), median lethal dose (LD₅₀), maximum tolerated dose (MTD), median effective dose (ED₅₀), etc.
  • Enable calculation of the therapeutic index (TI = LD₅₀/ED₅₀).
• General principle: assess all relative toxic effects of the drug with respect to dose, duration, and effect on organs — to define an adequate therapeutic margin of initial dose levels and dosing duration, and to guide special measures for initial clinical trials (Medhi Ch.9, p.115).
• Toxicological study comprises two arms (Medhi Ch.9, p.115):
  • Toxicodynamics — the toxic effect/mechanism on the organism (analogue of pharmacodynamics).
  • Toxicokinetics — the pharmacokinetics of a drug under circumstances that produce toxicity (G&G 14e Ch.9, p.156).