Back to the Top
Dear Members,
By going through following statements in Bioanalytical Method
Validation guideline of US FDA under the heading of Selectivity ;
"Potential interfering substances in a biological matrix include
endogenous matrix components, metabolites, decomposition products, and
in the actual study, concomitant medication and other exogenous
xenobiotics"
My question is-
During Phase I sample analysis of one of our NCE, we have planned for
safety and PK evaluation in elderly subjects as well. They will be
allowed to continue with prescribed medicines. As per the protocol,
subjects with metabolic disorders (hypertension, diabetes etc.) will
be included in study. So we can derive a probable list of drugs being
used during study period with NCE and not the confirmed one.
How to proceed with bioanalytical method validation particular in
terms of proving selectivity of method prior to study? And in addition
to this we are planning to extend for recovery experiments as well
i.e. in presence of concomitant medication.
Kindly share your experience.
Regards,
Jignesh
Back to the Top
You can do in silico and determine which are likely to intefere with
analysis, then run the candidates in the actual assay. The potential
for this to become a black hole is very real and it is perhaps best to
ask the FDA.
For example you make come up with a list of 100's even discounting
what the patient takes on their own, then run those in your assay
extending validation time.
And this has nothing to do with the effect of the concomitant drugs on
ADME of the target drug, which is perhaps of equal or greater value.
Back to the Top
It is better to evaluate the interferance of the other drugs(s) or
their metabolites (if concentrations are very high) and ven, if
possible the effect of excepients on the bioanalytical methods.
Dr Zafar
Back to the Top
The following message was posted to: PharmPK
Good Morning
Sir what i understand from your question is that - whether the MV
experiment is effected by concomitant drugs or not.
In this case you have to proof that your method is selective for your
analyte of interest not for concomitant drugs, and for this you have
to perform selectivity experiment for concomitant drugs.
Here i share my idea with you-- that in our lab we did this experiment
in some of the projects. In this case you have to spike these
concomitant drugs ( at Cmax level) in your LLOQ sample and observe the
response is effected or not and measure the %CV that should be within
20%. or you can prepare the QC sample at each level and spike these
concomitant drugs ( at Cmax level) and measure the % accuracy. If your
% accuracy is with in range than you can proceed with your analysis
otherwise you have to work on the method.
If i am wrong please correct me.
Hope this will help you.
Regards
laxman kaswan
Back to the Top
The following message was posted to: PharmPK
Jignesh,
In this case, mass spectrometry with selective ion monitoring is
likely your
best option.
Hope it helps.
-Shawn
Shawn D. Spencer, Ph.D., R.Ph.
Assistant Professor of Biopharmaceutics
Florida A&M College of Pharmacy
Tallahassee, FL 32307
shawn.spencer.-at-.famu.edu
Back to the Top
I agree that it is very much required to consult FDA on this. Because
this guideline is meant for HPLC assays as well, where it is required
to have chromatographic separation from concomitant medication.
But in absence of that...
With LC-MS/MS, based on Q1 and Q3 m/z of concomitant drugs can we
qualify method for its selectivity?
And for recovery, selecting representative drug from each class and
spiking Cmax conc. as suggested by Laxman would give us comfort in
terms of extraction and source ionization in presence and absence of
concomitant drugs.
As suggested by Edward, one can extend the validation till
qualification is done with each one. But practically this may end up
with problem if couple of drugs interfere in terms of selectivity and
recovery. And by that time actual analysis is over.
Kindly suggest further.
regards,
Jignesh
Back to the Top
The following message was posted to: PharmPK
The problem you are having is your appreciation of "selectivity".
Selectivity is not guaranteed... only reasonably assured.
The method will be validated for XYZ. As the range of potential
analytes
expands, the validation becomes dynamic. You have to continually
check the
selectivity of the method during the application of the method...
hopefully
not to throw out the analysis per se, but to verify that the power of
the
high resolution LC-MS/MS, "has held up" with the introduction of new
analytes.
Back to the Top
The following message was posted to: PharmPK
Not strictly a matter of selectivity or specificity but also one of
interference affect detection and/or derivatization/ionization
processes.
Back to the Top
Dear Jignesh,
As per my view you just have to do the experiments that are effect of
concominant drug on your analyte of intrest i.e. specificity in
presence of concominant drug, ion suppression in presence of
concominant drug and recovery with and with out concominant drug.
correct me if i am wrong.
Regards
Dipak S Harwani
Want to post a follow-up message on this topic?
If this link does not work with your browser send a follow-up message to PharmPK@boomer.org with "Selectivity in presence of concomitant medication" as the subject | Support PharmPK by using the |
Copyright 1995-2011 David W. A. Bourne (david@boomer.org)