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I am seeking the PharmPK comments on the use of "total drug
concentrations" in bioequivalency assessment. In majority of cases I
am against combining concentrations of drug and it metabolites for
the reason that they not only have different molecular weights but
they also have different PK and PD profiles. Just as determination of
PK parameter for total radioactive compounds is not meaningful so
determination of bioequivalency on the basis of total drug
concentrations should also not be useful.
However, for every rule there are bound to be exceptions. For example
with Simvastatin the parent drug has very low concentrations, is not
as active as its acid metabolite and has a very short half life so it
can not be detected in the plasma after 4 to 6 hours, In such cases
and others like Simvastatin, is it valid to sum the concentrations of
the parent drug and its metabolites and assess bioequivalency of the
test and reference formulations using total concentrations? Any
thoughts, comments, recommendations, advice would be highly appreciated.
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Dr. Karim: A basic chemical fact is that amounts can be added, but
concentrations cannot. For example, 1 gm NaCl + 1 gm NaCl equals 2
gm NaCl. But 1 N NaCl + 1 N NaCl is still 1N. 1 N NaCl + 1 N KBr
equals what? Unless the parent drug and metabolite have the same
volume of distribution (generally a fudge factor) at every time
point, then adding concentrations and computing AUC are
mathematically incorrect. I have heard arguments that for
bioequivalence this is acceptable, because the same components are
compared in 2 treatments. However, the fact still remains that
chemical laws are being disregarded.
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The total concentration (parent drug and metabolite(s)) cannot be
considered acceptable in a bioequivalence decision because the
measuring of concentrations is a substitute for the clinical
efficacy. In the bioequivalence decision is it assumed that
equivalent blood concentrations lead to the same pharmacological/
As you pointed out, different chemical entities have different
pharmacological effects and different degree of efficacy within the
Consequently, the total concentration cannot be correlated with the
total pharmacological/clinical effect.
There may be situation where different formulations may lead to
different concentration-time profiles of the parent drug and
In the extreme case where the parent drug and the metabolites have
the same pharmacological degree of efficacy, adding their
concentrations may be considered acceptable.
Note: The difference in the molecular weight of different chemical
entities is not an obstacle in calculating the total concentrations.
One must express their concentrations in molar terms (moles/L) in
order to add them.
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