Managing ‘positives’

Part of Gentronix’s unique service is to advise on strategies for handling positive results from genotox testing.

The following points consider why positive genotoxicity screening data might arise and what action may be taken to follow up the screen, such as following up with a second test or attempting to elucidate the mechanism

The compound is a mutagen, pro-mutagen, clastogen or aneugen.

It is therefore a potential carcinogen. This might be acceptable for a life threatening disease, where it might be the mode of action for an anticancer drug where there is no other effective cure.

Action: continue development and alert the safety assessment teams or consultants. They will consider likely dose and exposure for the patient as well as those involved in manufacture, and administration. The decision may be to consider an investigation to determine if the genotoxicity shows a clear threshold effect as the effective pharmacological dose might be below the threshold.

The compound has been tested in a genotoxicity test.

No test is infallible and hence none has 100% specificity, so the result might be a misleading positive.

Action: continue development and alert the safety assessment teams. They will know the prevalence of misleading results, and will determine whether it is a test specific positive. For example a bacterial or cell-line specific liability.

It is a protocol or test-specific genotoxin

Too high a dose, or too toxic a dose can confound interpretation.

Action: Safety assessment teams will identify data to be rejected

It is a species specific genotoxin (divergent target or different metabolic fate)

The metabolism in rodents and rodent liver extracts, may not represent the fate of a compound in humans

There can be genotoxic impurity issues identified by mass-spectrometry

  • Co-purified genotoxic synthesis intermediates
  • Genotoxic degradation products. ICH Q3B(R2) provides guidance for reporting, structural identification, and qualification
  • Reactive intermediates used in synthesis (alkylators etc)
  • Impurities in the compounds used in synthesis. ICH Q3A(R2) provides guidance for qualification and allowed limits

Action: have a conversation with chemistry teams to address these possibilities.If high purity reduces genotoxic potency, it might be appropriate to consider alternative synthetic routes that avoid such intermediates more readily.