CHIRAL SEPARATION: A PHARMA INDUSTRY PERSPECTIVE

Dr. Bhaswat S. ChakrabortySr. VP & Chair, R&D Core CommitteeCadila Pharmaceuticals Ltd., Ahmedabad

Presented at the Chiral India 2013 Conference, Mumbai, November 14-15, 2013

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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

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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)

THALIDOMIDE

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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

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IMPORTANCE OF CHIRAL SEPARATION

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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

Levodopa L-Dopa has anti-Parkinson’s disease effectD-Dopa causes serious side effects, e.g., granulocytopenia

Penicillamine (S)-enantiomer has antiarthritic activity(R)-form is extremely toxic

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 β-adrenergic blocking activity

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 7

Li B. et al. Encyclopedia of Chemical Processing

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Gubitz G. et al. Biopharm Drug Dispos 22: 291-336 (2001)Williams K et al. Journal of Chromatography A, 785 (1997) 149-158

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

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WHEN DEVELOPMENT OF A RACEMATEMAY 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

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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

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MARKETED SINGLE ENANTIOMERS AFTER CHIRAL SWITCH

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LIFE CYCLE MANAGEMENT

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SCIENCE VS EFFICACY

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Mansfield P. et al. Clin Pharmacokinet 2004;43(5):287-90

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

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

ENANTIOSELECTIVE PK

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Chiral Drugs: Chemistry and Biological Action, Edited by Guo-Qiang Lin et al

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 trials19

CONCLUDING REMARKS

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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

THANK YOU VERY MUCH

Acknowledgement: Ms. Raji Nair

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