Toxicokinetics

Introduction & the two settings of toxicokinetics

• Toxicokinetics (TK) — the application of pharmacokinetic principles to the toxicology setting — the ADME of toxins, of toxic doses of therapeutic agents, and of their metabolites; it is the kinetic dimension of toxicity (what the body does to a toxicant). Its dynamic counterpart, toxicodynamics, denotes the injurious effects of these substances on body function.
• The Paracelsian principle — it is the dose that distinguishes a drug from a poison — a poison endangers life by severely affecting a vital function; poisons of biological origin are toxins. Adverse (side) effects arise at normal therapeutic use, whereas drug toxicity arises from supratherapeutic concentrations — the domain TK addresses.
• Two distinct settings — do not conflate — the same word names two enterprises:
  • Clinical / overdose TK — the altered ADME of a drug or poison in the intoxicated human, used to predict the time-course of toxicity and to guide observation periods, antidote timing and extracorporeal removal (data here are largely case reports and observational studies).
  • Preclinical / regulatory TK — generation of PK data within non-clinical toxicity studies to assess systemic exposure in animals, so toxicological findings can be related to human clinical safety; the domain of ICH S3A.
• Overdose is absolute or relative — an absolute overdose is an excessive amount (accidental, suicidal, homicidal); a relative overdose is a usual dose in the presence of organ dysfunction (e.g. a usual gentamicin dose in renal failure).
• TK governs Type A reactions — toxicity that tracks systemic exposure is the Type A (Augmented) reaction — dose-related, predictable, largely preventable and reversible. Type B (bizarre — allergy, idiosyncrasy) reactions are non-dose-related and lie outside pure TK.