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Enantiomeric drug development: Issues, considerations, and regulatory requirements

2001; Elsevier BV; Volume: 90; Issue: 9 Linguagem: Inglês

10.1002/jps.1074

1520-6017

Nuggehally R. Srinivas, Rashmi H. Barbhaiya, Kamal K. Midha,

Drug Transport and Resistance Mechanisms

The therapeutic implications of chirality in medicinal compounds is now well recognized. 1. Tucker G.T. Lennard M.S. Enantiomer specific pharmacokinetics. Pharmacol Ther. 1990; 45: 309-329 Crossref PubMed Scopus (197) Google Scholar , 2. Nation R.L. Chirality in new drug development Clinical pharmacokinetic considerations. Clin Pharmacokinet. 1994; 27: 249-255 Crossref PubMed Scopus (53) Google Scholar , 3. Islam M.R. Mahdi J.C. Bowen I.D. Pharmacological importance of stercochemical resolution of enantiomeric drugs. Drug Safety. 1997; 17: 149-165 Crossref PubMed Scopus (81) Google Scholar Indeed, the failure to recognize chirality while describing the drug disposition, including pharmacokinetic characteristics, pharmacology, pharmacodynamics, and toxicology, can result in far‐reaching untoward effect as exemplified by the toxicity associated with thalidomide, 4. Blaschke G. Kraft H.P. Fickentshcer K. Kohler F. Chromatographic separation of racemic thalidomide and teratogenic activity of its enantiomers. Arzneim–Forsch. 1979; 29: 1640-1642 PubMed Google Scholar benoxaprofen, 5. Marshall E. Guilty plea puts Oraflex case to rest. Science. 1985; 229: 1071 PubMed Google Scholar and terodoline. 6. Connolly M.J. Astridge P.S. White E.G. Morley C.A. Cowan J.C. Torsades de pointes ventricular tachycardia and torodiline. Lancet. 1991; 338: 344-345 Abstract PubMed Scopus (68) Google Scholar Although some years ago it was not considered fashionable to develop the more active enantiomer of the chiral molecule, the present day scene has seen a surge in popularity for the development of the single enantiomer. In addition, regulatory agencies are increasingly scrutinizing New Drug Applications (NDAs) of racemates, requiring the sponsor(s) to research and fully characterize the contribution of each component of the racemate. As a result of the heightened awareness of chirality, one has to apply a rational approach to justify the selection of the chiral entity for the NDA filing, which is going to be used to obtain safety and efficacy parameters.