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This is a query regarding Bioequivalence criterion and a problem that
I am facing.Consider a drug product (being developed as a generic
equivalent to an innovator product) containg drug substance "X" with
a half life of about 40 hrs and is a racemate[R(-)&S(+)].Let say that
the activity essentially resides in the S(+) enantiomer.Now, I have a
support of data which certifies me to the extent that, relatively,
there is no change in the ratio of the concentration of the
enantiomers in the biosample upto 24 hours.With the above background,
I have two queries for proving the bioequivalence with the RLD:-
1.Considering the pharmacodynamic characteristic that predominantly
favors the S(+) enantiomer(active isomer), will an achiral assay
estimating the racemate in the sample suffice or should I go for the
analysis of the individual enantiomers.?
2.Taking the drugs half life into account, will the data on relative
pharmacokinetics that I have for 24 hours support the plasma
concn-time profiling upto 5 biological half lives without warranting
an analysis of both the enantiomers(i,e thro an isomer specific
My viewpoint(biased/preformed,perhaps!)is that since the factors that
influence the rate of the release of the drug from the tablets are
purely ACHIRAL ,hence the total concentration of the enantiomers
should adequately represent the biopharmaceutical quality of the
Group, your views/contradictions please!!
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Concerning your query about chiral compounds; since enantiomers should be
recognized as different compounds it is always advisable to apply
enantioselective analytical assays.
On relation to the point that dissolution is an achiral processes, I would
not say that, since the aqueous solubilities and crystal forms of racemates
can differ from those of the individual isomers, and this can be reflected
as differences on dissolution rates at sites of administration.
Some interesting papers on this subject:
1.- Tucker & Lennard "Enantiomer specific pharmacokinetics"Pharmac.Ther.
2.- Caldwell, J. "Chiral pharmacology and the regulation of new
drugs"Chemistry and Industry 6, 1995
3.- Rauws & Groen "Current regulatory (Draft) guidance on chiral medicinal
products: Canada, EEC, Japan, United States"Chirality 6, 72-75, 1994.
4.- Levy & Boddy "Stereoselectivity in pharmacokinetics: A general theory"
Pharmaceutical Research 8: 551-556, 1991.
I hope it helps
Prof. Dra Maria Fabiana Landoni, PhD
Catedra de Farmacologia.
Facultad de Ciencias Veterinarias
Universidad Nacional de La Plata
Calle 60 y 118 cc 296
(1900) La Plata.
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