Toxicokinetics

Toxicokinetics

1. Definition, scope and the two settings of toxicokinetics

• Toxicokinetics (TK) is defined as the absorption, distribution, metabolism and excretion (ADME) of toxins, of toxic doses of therapeutic agents, and of their metabolites — i.e. the pharmacokinetics of a substance under circumstances that produce toxicity (Katzung 16e Ch.58, pp.1097; G&G 14e Ch.9, p.156).
• The companion term toxicodynamics denotes the injurious effects of these substances on body function — the toxicity analogue of pharmacodynamics (Katzung 16e Ch.58, pp.1097).
• TK vs PK: "many similarities exist between the pharmacokinetics and toxicokinetics of most substances, but there are also important differences" — the divergence appears specifically when dose rises into the supratherapeutic/toxic range and capacity-limited (saturable) processes are engaged (Katzung 16e Ch.58, pp.1097–8; G&G 14e Ch.9, p.156).
• Two distinct settings are both called "toxicokinetics" and must not be conflated:
  • Clinical / overdose TK — describing the altered ADME of a therapeutic agent (or poison) in the intoxicated human, used to predict time-course of toxicity, guide observation periods, antidote timing and extracorporeal removal. Data here "are generally limited to case reports and observational studies" (G&G 14e Ch.9, p.156).
  • Preclinical / regulatory TK — the generation of pharmacokinetic data within non-clinical toxicity studies to assess systemic exposure in animals, so that toxicological findings can be interpreted and related to human clinical safety; this is the domain of ICH S3A (ICH S3A §1, 1994; Atkinson 4e Ch.30, p.581).
• The unifying Paracelsian principle underlying all of toxicology: "it is the dose which distinguishes a drug from a poison" — a poison is a substance that endangers life by severely affecting one or more vital functions; poisons of biologic origin are termed toxins (KDT 8e Ch.6, pp.94–5).
• Terminology distinction relevant throughout: adverse (side) effects occur with normal therapeutic use, whereas drug toxicity occurs as a result of supratherapeutic drug concentrations (unintentional or intentional) — TK is chiefly concerned with the latter (G&G 14e Ch.9, p.159).
• Toxic effects in the classical (KDT) framing are the result of excessive pharmacological action due to overdosage or prolonged use; overdosage may be absolute (accidental, homicidal, suicidal) or relative (a usual dose in the presence of organ dysfunction, e.g. usual gentamicin dose in renal failure) (KDT 8e Ch.6, p.94).
• TK sits at the interface of the Type A (Augmented) adverse-reaction class: Type A reactions are pharmacologically based, dose-related, predictable, mostly preventable and reversible — the class whose severity tracks systemic exposure and is therefore governed by kinetics. Type B (Bizarre) reactions are largely non-dose-related (allergy, idiosyncrasy) and fall outside pure TK (KDT 8e Ch.6, pp.92–3).