In terms of pharmacokinetic pharmacodynamic relationships of the anti-cancer drugs, the relevant pharmacokinetic parameter is usually the AUC, which represents total systemic exposure of the body to the drug. AUC results from the bioavailable dose (administered dose weighted in case of extravascular administration by the bio-availability) and the patient plasma clearance (CL) which represents the elimination capacity for the drug:
AUC = F x Dose / CL (F=bioavailability) Since anti-cancer drugs are administered intravenously, F is equal to 1 and the dose required to provide an optimum AUC may be calculated with knowledge of individual plasma clearance. Then, variability in elimination becomes the more determinant pharmaco-kinetic process involved in pharmacokinetics/pharmacodynamics.
The modified Hill equation, which corresponds to a sigmoidal curve, is frequently used to describe the relationship between a pharmacokinetic parameter (e.g. AUC) and a pharmacodynamic effect (E):
Pharmacokinetic profiles of three individual patients with variation in profile resulting in variable clinical effect (pharmacodynamics).
Emax represents the maximum possible effect and AUC50, the AUC that induces 50% of Emax. H is Hill's constant (or shape factor) which defines the degree of sigmoidicity of the model.
The relationship between AUC and haematological toxicity is closer than that between pharmacokinetic parameters and clinical outcome. This observation is explained by numerous other causes of variation in tumour-cell response to a drug (cellular metabolism, drug resistance, biochemical and molecular factors, etc.).
Other pharmacokinetic parameters such as duration of concentration above a threshold may be more relevant than AUC, especially for drugs having a schedule-dependent cytotoxicity.
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