Chiral Separation A pharma Industry Perspective

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  • 1. CHIRAL SEPARATION: A PHARMA INDUSTRY PERSPECTIVE Presented at the Chiral India 2013 Conference, Mumbai, November 14-15, 2013 1 Dr. Bhaswat S. Chakraborty Sr. VP & Chair, R&D Core Committee Cadila Pharmaceuticals Ltd., Ahmedabad
  • 2. CONTENTS  Chirality – the Tragic lessons from Thalidomide  Importance of separation of single enantiomers  Chiral stationary phases  Racemic switch & life-cycle management  Development of single enantiomer  Science vs efficacy  Stereoselective assay in Bioequivalence  Regulatory issues  Concluding Remarks 2
  • 3. THALIDOMIDE     Thalidomide (late 1950s) was marketed as a sedative, in the treatment of nausea in pregnant women in Europe, Australia, and Japan From the user mothers, ~10,000 children were born with phocomelia Thalidomide was banned in most countries in 1961 This tragedy was averted in the USA, because of its non-approval by Dr. Frances Kelsey of the US FDA  She was recognized by President JFK as a recipient of the Gold Medal Award for Distinguished Civilian Service. 3 Kim J. et al. Toxicological Sciences 122(1), 1-6 (2011)
  • 4. THALIDOMIDE   The (S)-isomer has the desired antinausea effects the (R)-form is teratogenic and causes phocomelia Thalidomide transformed the drug regulation scenario or ever. Now all developed regulatory jurisdictions demand an examination of isomeric purity and its clinical and toxic implications thoroughly studied 4
  • 5. 5
  • 6. IMPORTANCE OF CHIRAL SEPARATION Chiral drug Biological activity of enantiomers Albuterol D-isomer may provoke airway constriction; L-isomer avoids side effects Ethambutol (S,S)-form of ethambutol is a tuberculostatic (R,R)-form causes optical neuritis that can lead to blindness L-Dopa has anti-Parkinson’s disease effect D-Dopa causes serious side effects, e.g., granulocytopenia (S)-enantiomer has antiarthritic activity (R)-form is extremely toxic Levodopa Penicillamine Propoxyphene α-L-isomer is antitussive (cough) α-D-isomer is analgesic (pain) Propranolol The drug is racemic. However, only the (S)-(–)-isomer has the desired βadrenergic blocking activity 6
  • 7. CHIRAL STATIONARY PHASES (CSP) Enantiomers are separated based on their interaction with a CSP  Different CSPs are developed for GC, HPLC, CE and other techniques  CSPs include   Derivatized cyclodextrins  Macrocyclic antibiotics  Proteins/polypeptides  Polysaccharides  Chiral surfactants  Chiral crown ethers  Special chiral techniques, e.g., SFC and SMB Li B. et al. Encyclopedia of Chemical Processing 7
  • 8. 8 Gubitz G. et al. Biopharm Drug Dispos 22: 291-336 (2001) Williams K et al. Journal of Chromatography A, 785 (1997) 149-158
  • 9. USEFULNESS OF A SINGLE ACTIVE ISOMER     Fewer or diminished side effects, which may result from the unwanted isomeric form Automatically halved dosage for a patient Decreased waste due to decrease in manufacturing of unwanted isomer New commercial opportunities for ‘‘racemic switching’’   A racemate can be redeveloped as an enantiomerically pure form, possibly useful for extending patent protection of a key product Typically when a specific enantiomeric ratio is expected to improve the therapeutic profile, single isomers are developed 9
  • 10. WHEN DEVELOPMENT OF A RACEMATE MAY BE JUSTIFIED The enantiomers are configurationally unstable in vitro or undergo racemization in vivo  The enantiomers have similar pharmacokinetic, pharmacodynamic and toxicological properties  It is not technically feasible to separate the enantiomers in sufficient quantity and/or with sufficient quality   Decision to develop a racemate or a single isomer is purely that of the sponsor or manufacturer 10
  • 11. RACEMIC (CHIRAL) SWITCH  Potential advantages of a chiral switch Less complex, more selective PD profile  An improved therapeutic index  Less complex PK profile  Reduced drug interactions  Less complex relationship between plasma concentration and effect  11
  • 12. ENANTIOMERS AFTER CHIRAL SWITCH 12
  • 13. LIFE CYCLE MANAGEMENT 13
  • 14. SCIENCE VS EFFICACY 14 Mansfield P. et al. Clin Pharmacokinet 2004;43(5):287-90
  • 15. PRECLINICAL AND CLINICAL CONSIDERATIONS The in vivo stability of the enantiomer must be established.  If the antipode is formed in vivo, it should be considered to be a metabolite.  The metabolism and disposition of the enantiomer should be followed using enatioselective methods   In each species in preclinical  In phase I in clinical (humans)  If racemization or inversion does not occur, enantioselective methods may not be necessary in all studies 15
  • 16. STEREOSELECTIVE ASSAY IN BIOEQUIVALENCE  A steroselective assay may be necessary  When changes in oral input cause changes in vivo ratio of enantiomers due to a phenomenal such as high fist pass metabolism of the active enantiomer.  When there is a relatively low first pass metabolism of the active enantiomer but a specific isomer ratio is important for optimal therapeutic effect.  BE comparisons should be made between pharmaceutically equivalent products that meet standards for enantiomeric purity. 16 Canadian TPP Guidelines on Stereochemical Issues in Chiral Drug Development
  • 17. ENANTIOSELECTIVE PK 17
  • 18. 18 Chiral Drugs: Chemistry and Biological Action, Edited by Guo-Qiang Lin et al
  • 19. REGULATORY ISSUES  What to develop?  Racemic,  pure single isomer or a fixed ratio of isomers? What should be motivation for chiral switch?  Life cycle management, patent extension or actual gain in efficacy or safety?  Clear understanding of situations where an enantioselective assay is a must  Chemistry and manufacturing (QC) requirements especially for an artificial fixed ratio of isomers  Species differences in preclinical studies (PK only?)  Study design issues in clinical trials 19
  • 20. CONCLUDING REMARKS  Thalidomide has taught us that isomeric purity of enantiomers and its clinical and toxic implications must be thoroughly studied  Chiral switch should be motivated by both science (patent extension) and safety/efficacy improvement  In vivo stability, metabolism and disposition of each enantiomer must be established for preclinical and clinical (phase I) purposes For bioequivalence, a steroselective assay may be necessary for differential in vivo metabolism of enantiomers (e.g. high fist pass metabolism of eutomer)   All regulatory issues including chiral switches must be addressed in consultation with the regulators 20
  • 21. Acknowledgement: Ms. Raji Nair THANK YOU VERY MUCH 21