Bioequivalence and Bioavailability Forum • Internal Standard Used as Concomitant Medication

nitin
☆

India,
2013-04-14 22:58
(4826 d 03:02 ago)

Posting: # 10413
Views: 3,673

Internal Standard Used as Concomitant Medication [Regulatives / Guidelines]

Hi,
We had developed a bio analytical method for a BE study for EU submission. But the internal standard used in the method was investigated to be given as a concomitant medication to some of the volunteers during the clinical phase. It is expected that the strength of the concomitant medication would affect the area ratios during the study sample analysis (strength of the internal standard in plasma samples as per the bio analytical method is approx. equal to 25 ng/ml and the expected Cmax concentration of the study samples due to concomitant medication is approx. equal to 100 ng/ml). Total five volunteers have been dosed out of 30. 3 volunteers have already being withdrawn/dropped-out due to other reasons. Minimum sample size 25-30 is required. Please suggest any of the following options or other which should be best suitable for regulatory bodies:-

Revalidate the method with different internal standard, preferably with deuterated analogue of the existing internal standard of the bio analytical method, so as to do minimum validation procedures.
Avoid the analysis of the subjects where concomitant medication is given and do an-add on study with additional number of volunteers (numbers considering the already withdrawn subjects and subjects to whom concomitant medication was given).
Process the study samples (to whom concomitant medication is given)first without internal standard to know the peak areas of the internal standard already present as a concomitant medication and then process with internal standard to get the final area ratios.

Thanks & Regards,
Nitin

Ohlbe
★★★

France,
2013-04-15 20:53
(4825 d 05:07 ago)

@ nitin
Posting: # 10416
Views: 2,895

Internal Standard Used as Concomitant Medication

Post reply

Dear Nitin,

❝ the internal standard used in the method was investigated to be given as a concomitant medication to some of the volunteers during the clinical phase.

❝ Total five volunteers have been dosed out of 30.

Selecting a widely used drug as internal standard is a very risky choice...

❝ 1. Revalidate the method with different internal standard, preferably with deuterated analogue of the existing internal standard of the bio analytical method, so as to do minimum validation procedures.

You would have to do some validation experiments anyway: selectivity, matrix effects, some precision and accuracy... If you are ready to go for a stable-isotope labelled IS, use the analogue of your analyte rather than the analogue of the initial IS.

❝ 2. Avoid the analysis of the subjects where concomitant medication is given and do an-add on study with additional number of volunteers (numbers considering the already withdrawn subjects and subjects to whom concomitant medication was given).

IMHO: no way. Regulators will consider you could have re-developped and validated the method with a different IS. Exposing additional subjects to the product because of a lousy bioanalytical method is unethical. Anyway this option would take you more time than changing the bioanalytical method.

❝ 3. Process the study samples (to whom concomitant medication is given)first without internal standard to know the peak areas of the internal standard already present as a concomitant medication and then process with internal standard to get the final area ratios.

IMHO: no way. You will increase the analytical variability (double-measurement, without internal standard for the first determination). And you would need to validate the method for the determination of the IS anyway.

Regards
Ohlbe

—
Regards
Ohlbe

nitin ☆ India, 2013-04-15 21:16 (4825 d 04:44 ago) @ Ohlbe Posting: # 10417 Views: 2,870	Internal Standard Used as Concomitant Medication Post reply
	Thanks for the reply, rework on the bioanalytical method makes more sense. Regards, Nitin Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post! [Helmut]