Often, in early pharmaceutical compound development, the available toxicology information for a discovery compound is very limited. Here at Affygility Solutions’ one of the questions that we get asked in order to help determine appropriate occupational health categorization is “Are there similar, chemically-related active pharmaceutical ingredients to the current compound of interest?”. The thought behind this is that while there may be limited toxicology information for the current compound, developed pharmaceuticals that are similar in structure may provide clues to toxicological behavior.
While there is merit in this approach, there are also many reasons for caution. Chemicals that are structurally similar often do show similar physical and biological properties. However, some of the “catches” with this approach are the questions : “What is similar?” and “What is similar enough?”
There are many different approaches and in silico algorithms for determining chemical similarity. While each can provide a similarity determination, each is different, providing different qualitative and quantitative results. Many have shown that compounds that are similar enough by their measure can share similar biological profiles. At the end of the day, however, similarity is like many soft concepts that we all feel we will “know it when we see it” and, like beauty, it can be in the eye of the beholder.
When the expert toxicologists at Affygility Solutions are asked to develop an occupational health classification (OHC) report, and we are offered similar comparator compounds, we must proceed in a very cautious manner. An example of why this is the case can be seen below, where we compare nifedipine and felodipine, two compounds with a high degree of structural similarity.
While both compounds are for the treatment of hypertension and they share a clear structural similarity, their occupational exposure bands, occupational exposure levels (OEL) and acceptable daily exposures (ADE) are all dramatically different.
The biological properties of pharmaceuticals, including their toxicological profiles, can vary dramatically even with similar chemical structures.
Another example involves the very structurally similar diclofenac and lumiracoxib (below):
Diclofenac is considered to be a safe non-steroidal anti-inflammatory agent (NSAID), with an occupational health categorization of Band 2. On the other hand, lumiracoxib, which differs from diclofenac by only two small substitutions (F for Cl, and the addition of a methyl) on the other hand, was withdrawn from the market in numerous countries due to significant liver toxicity.
Despite these cautions, there is an aspect of similarity that is always useful in determining an occupational health categorization and that is the mechanism of action (MOA) of the active pharmaceutical ingredient that is in development. There are certain mechanisms of action that are highly expected to lead to certain toxicological profiles. For example, pharmacologies that affect cell growth and division will be expected to result in developmental hazards at some level. Understanding the MOA for drug candidates and comparing that to known compounds with similar MOAs can be a significant advantage in determining an occupational health categorization.
The expert toxicologists at Affygility Solutions have significant experience in preparing occupational health categorization reports for clients throughout the world. It you have any questions please contact us.
Published April 17, 2020
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