The cost benefit ratio of enantiomeric drugs

Several drugs possess a chiral structure, i.e. they contain one or more stereogenic centres in their molecule. While naturally occurring active principles usually contain a single enantiomer, most chiral drugs produced by chemical synthesis are used in the form of racemic mixtures of two or more diastereoisomers. These stereoisomers (including enantiomers) may interact in different ways with biological structures and, therefore, may exhibit widely different pharmacokinetic properties. In the pharmaceutical industry, partly in response to increasing demands raised by regulatory authorities, these considerations justify the current trend to develop the single enantiomer characterized by the most favourable profile of activity (eutomer). The availability of new chemical and analytical technologies facilitates stereoselective synthetic processes and separation of individual enantiomers from racemic mixtures. Any decision to develop a drug as a single enantiomer, however, should be made only after careful evaluation of the cost-benefit ratio, i.e. when the advantages of the eutomer in terms of efficacy and tolerability outweigh the associated increase in production and development costs with respect to the racemic drug. This article takes into consideration synthetic procedures and pharmacological profiles for a number of chiral drugs in therapeutic use (naproxen, labetalol, and warfarin) or selected for clinical development, such as the beta-blocker dilevalol or the mucokinetic agent 3'-hydroxyfarrerol. These examples demonstrate that the kinetic, pharmacological and toxicological properties of individual enantiomers need to be clearly characterized before any decision can be made concerning the development of a chiral drug. The choice of preferentially developing a single enantiomer should be based on careful consideration of production and development costs and actual therapeutic advantages especially in terms of improved safety.