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The following message was posted to: PharmPK
Dear all,
Does anybody have any experience on conducting the bioequivalence
(BE) study of Clopidogrel? To be more specific, should it be
performed through a systemic exposure profile obtained by measuring
the unchanged drug concentration, or just the metabolite
concentration, or both?
My best regards,
Rodrigo Cristofoletti
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The following message was posted to: PharmPK
Dear Rodrigo,
you no need to measure inactive carboxylic acid metabolite.
You have to measure clopidogrel concentrations only.
Hope this will help
Nagesh
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Dear Rodrigo,
Clopidogrel inhibit ADP-induced platelet aggregation. In-vivo, it is
getting metabolized rapidly. Clopidogrel itself is inactive. It is
metabolized by CYP monoxygeanse to active thiol metabolite (minor).
Its major metabolite is inactive carboxylic acid. The plasma levels
of Clopidogrel are difficult to determine as the levels fall
immediately due to its major metabolite, inactive carboxylic acid.
The levels of active metabolite are also difficult to measure. The
carboxylic acid metabolite is generally used for pharmacokinetic
study to determine the exposure.
For a BE study, the main aim is to determine how much drug is getting
absorbed from the formulation.
So, in this case, the carboxylic acid metabolite (inactive) can be
used to determine the exposure as parent drug levels are low. This is
due to the fact that the concentration of metabolite will reflect the
exposure of parent drug.
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Dear All,
Regarding clopidegrol, we can do the estimation of the parent drug
using LC MS/MS.
We have done one Bioequivalence study using LC MS/MS System and
estimated clopidegrel.
Regards,
Haresh Dodia
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Dear Rodrigo,
International Guidances suggest that parent drug (unchanged drug) may
be quantified in BE studies. Metabolites may be measured only in
special situations. Considering clopidogrel is possible to find
published LC-MS/MS method in the literature to quantification of the
parent drug (Nirogi RV et al. Rapid Commun Mass Spectrom. 2006;20(11):
1695-700) as well as a BE study (Lainesse A et al.
Arzneimittelforschung. 2004 Sep;54(9a):600-4).
Regards,
Daniel Rossi de Campos
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What is your experience with intra-subject variability of
clopidogrel? In the paper of Robinson (J. Chromatogr. B 2007; 848
(2): 344-354) the intra-individual CV was 56% for AUC and 70% for
Cmax, while in the paper of Lainesse cited in the previous message
these values were 13% and 20%. Such a big difference cannot be caused
by random fluctuations.
Regards,
Jan Macek
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The following message was posted to: PharmPK
When you seriously measure unchanged clopidogrel by a TRULY specific
method,
you will find high ANOVA - CV's, that's for sure.
The "Lainesse-method" probably measured the metabolite. The results
there:
"...Mean AUC0-inf, AUC0-t and Cmax were 29.94 ng x h/mL, 29.53 ng x h/
mL and
7.386 ng/mL, respectively..." are simply NOT unchanged clopidogrel
levels.
Those have to be in the pg/mL - range. We performed several studies
with the
agent and can confirm that. Generally, some separation between facts and
fiction seems necessary in the literature on the PK-data of clopidogrel.
Fritz Sorgel, IBMP, Nurnberg, Germany
www.ibmp.org
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