Page 337 - Chiral Separation Techniques

330 13 International Regulation of Chiral Drugs

13.3.4.1 Developing a Single Enantiomer after a Racemate is Studied

Once a mixture of stereoisomers has been investigated nonclinically, an abbreviated
evaluation of pharmacology and toxicity could be conducted to allow the existing
knowledge of the racemate available to the applicant to be applied to the pure enan-
tiomer. No further studies would be needed if the single enantiomer and the racemate
had the same toxicological profile. However, if the single enantiomer should appear
more toxic, then further investigations would be required to produce an explanation
and the implications for dosing in humans would have to be considered.

13.3.5 Clinical and Biopharmaceutical Studies

Where the individual enantiomers and the racemate show little difference in activity
and pharmacokinetics, the development of the racemate is justifiable. In other
instances, the development of the single enantiomer is especially desirable, for
example where one isomer is toxic and the other is not. Cases where unexpected tox-
icity or pharmacological effects occur at clinical doses of the racemate should be fur-
ther investigated with respect to the properties of the individual enantiomers and
their active metabolites. Such investigations might take place in animals, but human
studies may be essential. The unexpected effects may not relate to the parent enan-
tiomer but may be associated with an isomer-specific metabolite. Generally, it is not
as important to consider developing only one enantiomer if the opposite isomer is
pharmacologically inert. Clinical evaluation of both enantiomers and potential
development of a single enantiomer is more important when both enantiomers are
pharmacologically active but differ significantly in their potency, specificity or max-
imum effect. If both enantiomers carry desirable but different properties, then devel-
opment of a mixture of the two – not necessarily as a racemate – as a fixed combi-
nation might be reasonable.
Where the drug studied is a racemate, the pharmacokinetics, including potential
interconversion, of the individual enantiomers should be investigated in Phase I clin-
ical studies. Phase I or II data in the target population should indicate whether an
achiral assay, or monitoring of only one optical isomer where a fixed ratio is con-
firmed, will be adequate for pharmacokinetic evaluation. If the racemate has already
been marketed and the sponsor wishes to develop the single enantiomer, additional
studies should include determination of any conversion to the other isomer and
whether there is any difference in pharmacokinetics between the single enantiomer
administered alone or as part of the racemate.

13.3.6 Other Relevant FDA Guidance

The FDA’s Guideline for submitting supporting documentation in drug applications
for the manufacture of drug substances makes some specific references to chiral
drug substances. The requirements are similar to those in the EU. Elucidation of the