What will be the likely variation in patient response?

Predicting variability in patient response

In order to ensure the safe administration of compounds to humans, it is important to evaluate the potential interindividual variability in response. Two major factors influencing the human response to drugs are the genetic variability of populations and differences in the environments in which they live.

The profile of drug metabolising enzymes in individual subjects is highly variable, depending upon both genetic polymorphism and environmental modulation of enzyme expression. The cytochrome P450 family of Phase I drug metabolising enzymes is particularly polymorphic, but many clinically-important Phase II enzymes (e.g. N-acetyltransferases, glutathione-S-transferases and UDP-glucuronyl transferases) also exhibit polymorphism.

The CXR approach

Genetic polymorphism: CXR Biosciences has internationally renowned expertise in polymorphic drug metabolism in addition to state-of-the-art molecular biology technologies which is used to determine the likely extent of individual variability in the metabolism of drug candidates. A customised series of staged studies can identify the P450 system involved in metabolism of lead compounds, and then compare this with the known genotypic and phenotypic polymorphism of that system in the human population. Specialist interpretation of the results can then accurately predict the likely patient variability in response.

Environmental modulation: During the development of new drugs, great care needs to be taken to minimise the risk of environmental effects on efficacy by, for example, excluding smokers from early clinical trials. This means that the potential effects of environmental chemicals on the efficacy and toxicity of drugs is often not known when they enter the market. In particular, some classes of environmental chemicals (e.g. polycylic aromatic hydrocarbons found in cigarette smoke) can have a significant impact on drug efficacy by inducing drug metabolising enzymes and hence increasing clearance. CXR Biosciences has considerable experience in this area and can help develop strategies to minimise the risk of problems caused by environmental exposure to inducing agents.