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Clinical pharmacology overview 

Clinical pharmacology overview
Chapter:
Clinical pharmacology overview
Author(s):

Rachel S. Midgley

, Mark R. Middleton

, and Andrew R. Dickman

DOI:
10.1093/med/9780199664573.003.0001
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date: 17 October 2019

Rationale for combination cancer therapy

Anticancer drug taxonomies

Pharmacokinetics

Pharmacodynamics

Pharmacogenetics

Drug interactions

When any drugs are administered in combination, 3 outcomes are possible, namely: additive effects—the drugs act completely independently of each other, presumably through non-overlapping biochemical pathways, and have no pharmacokinetic interactions which alter the quantum of drug reaching its active site; subtractive or negative synergistic effects—whereby one drug interferes with the other to reduce efficacy. This could be competition at the active site, altered pharmacokinetics, say by inducing one of the enzyme systems responsible for the other drug’s metabolism, or the unexpected consequence that inhibition of a biochemical pathway might have on up/downregulation of the target of the companion drug. Synergy is defined as an interaction between drugs where the effects are stronger than their mere sum and may be driven by both pharmacokinetic and pharmacodynamic interactions. Probably the best way of demonstrating true synergy is to use the Chou–Talalay method for drug combination which is based on the median-effect equation, derived from the mass-action law principle. This is the unified theory that provides the common link between single entity and multiple entities, and first-order and higher-order dynamics. It is possible, therefore, to apply stringent equations in the preclinical setting, both ...

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