Page 333 - Chiral Separation Techniques

326 13 International Regulation of Chiral Drugs

13.2.4 Preclinical and Clinical Studies

13.2.4.1 Single Enantiomer

The development of a single enantiomer as a new active substance should be
described in the same manner as for any other new chemical entity. Studies should
be carried out with the single enantiomer, but if development began with the race-
mate then these studies may also be taken into account. Chiral conversion should be
considered early on so that enantiospecific bioanalytical methods may be developed.
These methods should be described in chemistry and pharmacy part of the dossier.
If the opposite enantiomer is formed in vivo, then it should be evaluated in the same
way as other metabolites. For endogenous human chiral compounds, enantiospecific
analysis may not be necessary. The enantiomeric purity of the active ingredient used
in preclinical and clinical studies should be stated.

13.2.4.2 Racemate

The applicant should provide justification for using the racemate. Where the inter-
conversion of the enantiomers in vivo is more rapid than the distribution and elimi-
nation rates, then use of the racemate is justified. In cases where there is no such
interconversion or it is slow, then differential pharmacological effects and fate of the
enantiomers may be apparent. Use of the racemate may also be justified if any tox-
icity is associated with the pharmacological action and the therapeutic index is the
same for both isomers. For preclinical assessment, pharmacodynamic, pharmacoki-
netic (using enantiospecific analytical methods) and appropriate toxicological stud-
ies of the individual enantiomers and the racemate will be needed. Clinical studies
on human pharmacodynamics and tolerance, human pharmacokinetics and pharma-
cotherapeutics will be required for the racemate and for the enantiomers as appro-
priate.

13.2.4.3 New Single Enantiomer from Approved Racemate or New Racemate
from Approved Single Enantiomer

These situations are treated as completely new applications which should include an
explanation of the decision to develop the enantiomer or racemate. Data on the exist-
ing racemate or enantiomer may be included where appropriate with bridging stud-
ies as necessary.

13.2.4.4 Nonracemic Mixture from Approved Racemate or Single Enantiomer

This can be viewed as optimization of the pharmacotherapeutic profile and therefore
is treated as a fixed combination product, for which a separate note for guidance