Researchers from Cardiff University, in collaboration with Liverpool John Moores University and AstraZeneca, have developed a new tool to assess the likelihood of a drug undergoing racemisation once inside the body.
risk assessment
Racemisation — where a pharmaceutical compound converts from being enatiomerically pure into one where both enantiomeric forms are present — can occur once a drug enters the patient. It is this process that can have detrimental effects as was witnessed with thalidomide, which upon racemisation caused adverse reactions to the developing foetus of patients administered with the treatment resulting in birth defects.
Unfortunately, despite attempts by pharma companies to make only the active and desired enantiomer for a drug it is possible for racemisation to occur once the drug enters the body and thus form the inactive or potentially dangerous enantiomer form. This is not only impactful on the health of the patient but also carries a financial implication to the drug developer.
“Following the thalidomide disaster, researchers worldwide have focussed on making compounds enantioselectively — that is containing just one enantiomer,” explained Dr Niklaas Buurma, from Cardiff University’s School of Chemistry, lead author of the study. “However, while compounds are routinely tested to ensure they are inherently stable under physiological conditions, not much thought has been given as to how to prevent configurational instability at the design stage, using suitable predictive models.”
The collaborative work, published in the chemistry journal Angewandte Chemie, the team set up experiments to simulate the chemical conditions of the human body and then introduced a number of drugs to the system, monitoring the rate at which the different drugs underwent racemisation.
From their results, the team were able to generate a simple mathematical model that could quickly predict the rate of racemisation in any drug compound, subsequently indicating how safe and productive that drug would be if administered. This is the first time an assessment tool for this purpose has been developed.
“We believe that this risk-assessment will make it possible to manufacture safer medication by helping the pharmaceutical industry to quickly spot medication that will fail during development and focus their efforts on compounds that are more likely to work,” added Buurma.