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We recently did a clopidogrel (75mg) study in which the Cmax Fast
(0.6-1 ug/ml) , Fed (5ug/ml). The analytical method was acidic mobile
phase and acidic loading on HLB cartridges.
We came to know that FDA recently has rejected a study of clopidogrel
as it was in acidic condition (maybe because clopidogrel being ester
gets converted to acidic metabolite); therefore we changed the
analytical method to basic loading on MAX cartridges, mobile phase ph
With this new method we are analyzing another clopidogrel study (same
formulation but different study) the Cmax obtained Fast (5 ug/ml) and
Also to check the validity of method we analyzed the previous study
samples also with the new method - Results--the Cmax Fast (5 ug/ml)
and Fed (6ug/ml)? We found significant difference in Fasting results(4
times) ....whereas the Fed results were slightly more with the new
My query is is it possible that analytical method changes results in
differences for only fasting or fed study ? As per my understanding
analytical methodology should alter the result (if it does) for every
study fast and fed both, but these results are misleading..., is it
because clopidogrel is an enantiomer?
I would request the members to comment.
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The following message was posted to: PharmPK
Clearly the bioanalytical method should give consistent results for
all sample types, or it will lead to misleading conclusions.
I suppose bioanalytical data from the original study was reviewed to
check no problems occurred during analysis (consistency of calibration
curves ...), were samples from fasted and fed groups analysed within
the same analytical batch so as to discard possible casual errors ?
Taking for granted the difference is intrinsic to the analytical
method it would seem that the first method (acidic conditions) is
influenced by the matrix: it performs well with "clean" plasma from
fasted subjects, but not so much with plasma taken from people after a
fat meal. I suppose the calibration standards, and other spiked
samples used for validation, were prepared with control plasma taken
from fasted subjects, so that the problem with "fat" plasma did not
show up then.
Such a marked effect between fasted and fed group is not usual and
fairly unfortunate. A possibility to check it, to understand what
happened (or better during validation before analysing study samples),
would be to collect blank plasma (or from placebo group) from fasted
and fed people, then use these to prepare validation samples (QCs) on
which to test for extraction recovery and matrix effect.
I wouldn't think that the product being an enantiomer should influence
the method performance to any great extent.
Noticeably the results obtained with the new method would seem to
indicate that Clopidogrel PK is not much affected by food, as was
concluded from the older studies that measured the main metabolite
rather than parent itself.
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