Bioequivalence and Bioavailability Forum

Dear Chandru

❝ We add the concomitant medications to LLOQ of analyte and compare against the calibration standard.

For concomitant medications, you compare the LLOQ (spiked with concomitant medications) with Blank Samples (also spiked with concomitant medications) and calculate the signal to noise ratio (or %interference). Response of interfering peaks at the retention time of the analyte for the blank samples should be less than 20% of the lower limit of quantification for the analyte and 5% for the internal standard.

❝ Any additional experiment has to be performed to evaluate its effect.

Precision and Accuracy needs to be evaluated for the range of CC standards (spiked with the concomitant medications)

Incurred Sample Reanalysis also give an insight on the effect of concomitant medications.

These are my thoughts.

Regards,

Hi chandru,

❝ How to evaluate the effect of concomitant medications during validation?

Wow, that is actually a great question, and a controversial one.

Some CROs believe that when they do LC-MS/MS they don't have to evaluate it. Interference is impossible, there would never be an interfering transition, testing for it is a waste of time, inteference like ion enhancement has never been seen, and some singing and dancing to that tune.

The better CROs, and here better is in this regard a purely subjective term reflecting just my personal opinion, will test A+P by spiking the QCs at roughly Cmax levels they get from the literature (incl. prescribing info, SPCs, PARs) along with a check of interference on blanks. Some will do the spiking experiment individually, and some will do it with a cocktail. Both approaches seem to be widely accepted by agencies.
It is furthermore becoming a proper practice to have an SOP in place so that the lab is informed of any concomitant meds that are given, and if a drug has been given which wasn't part of the validation, then there will be an adhoc interference experiment for that drug (non-cocktail type).