CHIRALITY
`
`12-5 1959
`
`The FDA Perspective on the Development
`of Stereoisomers
`
`Division
`
`WILSON
`
`Os CAMP
`Food and Drug Athninistration
`Anti-Infective frug Products
`20857
`RoclevuleMarylcnd
`
`ABSTP.ACT
`
`The custent
`
`Circumstances
`
`to ensure the safety
`
`and efficacy
`
`of
`
`interpreted
`
`for applications
`
`for
`
`raoemate is marketed
`
`of
`
`efficacy
`are drawn
`
`its enantiomera
`
`situations
`
`of the Food
`and Drug Administra
`position
`regulatory
`racematea and pure atereolaomera
`tion is discussed with regard
`to the approval
`in which stereochemlcaliy
`sensitive analytical methods
`drug are described
`of
`the approval
`for the approval of either
`which neither
`and for clinical
`is marketed
`racemate end
`from historical
`
`of
`
`are necessary
`
`ltegulatory
`
`guidelines
`
`are
`
`enantionier
`
`Ira which the
`
`pure
`racamate or
`
`pure enantiomer
`and
`to compare
`the safety
`investigations
`Examples of the baths for such regulation
`as well as currently
`thalidomide
`benoxaprofen
`
`in
`
`.f
`
`-/
`
`Li Fit
`
`L1
`
`acid
`
`--
`
`been recognized
`
`marketed
`
`drugs arylproplonic acids disopyramide
`
`indserinone
`
`KEY WORDS
`
`optical
`
`isomers stereochemistry enantiomera
`drug development
`
`Food arid Drug
`drug regulation
`
`Administration
`
`Isomerism of tartaric
`the significance
`
`activity
`
`of
`has
`
`that
`
`the
`
`stereoiso
`
`and
`ficacy
`of whether
`
`ehiral
`
`of
`
`knowing
`
`that
`
`it
`
`of
`
`separation
`mets presented
`tude than did
`thesis As
`result
`bypassed
`
`largely
`
`of the optical
`Since the discovery
`by Louis Pestaur
`in 1848
`atereoiaomerism in relation
`to biological
`by scientists
`It was
`soon seen
`racemate into its component
`greater megni
`challenge
`of
`immensely
`syn
`of
`the development
`stereospecific
`such mixtures were
`efforts to resolve
`century The
`for more
`then
`rare
`often
`treated
`was
`separation
`end
`the succees
`or as
`trial
`to the
`systematic approach
`few special
`in
`as feasible
`unthink
`
`instance
`
`of
`
`successful
`
`either
`
`as happenstance
`In either event
`error
`problem wee not seen
`cases Commercial
`
`exploitation
`
`of
`
`except
`was
`
`certainly
`
`Why should
`racemate
`seperste
`was not en exercise in rhetoric
`The primary regulatory
`end Drug
`focus of the Food
`Administration
`of both clinical
`is on considerations
`ef
`consumer
`in making its determination
`safety
`to show
`drug to be msrketed
`Because
`the
`found in vivo
`environment
`affects the biological
`drug the approval
`of stereoisomerlc
`activity
`drugs
`The cue of
`for marketing
`can present
`special
`challenges
`thalidomide is an example of
`problem that may have
`of stereochemi
`been at
`by ignorance
`least
`complicated
`cal effects Much has been
`from the
`learned
`tragedy
`conclu
`associated with its marketing
`variety of other
`drug in vivo may be
`about
`sions
`the behavior
`of
`by the isomeric ballast
`in
`present
`racernate
`by Arlºna.2 In particular
`to use
`phrase popularized
`will be shown how the use of racemates can lead both to
`erroneous models of phermacokinetic
`end
`the potential
`for opportunities
`to manipulate
`pharniaco
`Through
`this it should be rernern
`logical
`activity
`bored that
`it Is within the realm of
`tecbnicsl
`feasibility
`that will answer with little
`the cuestion Is
`ambiguity
`stereochernically
`pure
`drug more effective
`than the
`race
`and/or
`mate
`When
`from synthetic
`as often
`results
`processes
`equimoleculsr mixture of enantiomwe
`is prepared
`racemate Although
`we use
`this as
`referred
`to as
`term today
`it
`to recall
`is interesting
`original effort was en attempt to discover
`between
`difference
`tsrtsric acid
`natural product
`racesnic acid
`its isomer which was then called
`
`general
`Psstairs
`
`en
`
`It
`
`la
`
`that
`the
`
`end
`
`affected
`
`behavior
`
`it
`
`to
`
`to
`
`design
`
`experiments
`
`all
`
`less toxic
`
`able
`The result of
`
`among sci
`this perception particularly
`of new drugs was
`on the development
`entists working
`that
`by the
`their
`research
`directed
`efforts were
`more
`feasibility of the experiment
`than by
`concern
`technical
`with the biological
`the drug Questions
`effect of
`end safety
`in one
`whether
`were
`efficacy
`greeter
`asked only when
`member of an enantiorneric
`pair ware
`eco
`wee
`both stereospecific
`and
`that
`route
`synthetic
`nomic was available
`The succful
`development
`for high-performance
`liquid chromatography
`The separation
`altered this situation
`1970s
`from
`basis
`pure material
`of optically
`amounts adequate for clinical
`fea
`became
`investigations
`aible Bnsntiomeric purity
`could be determined
`for the
`bulk drug for its formulations
`fluids The
`could
`
`clinical
`
`of
`
`of chiral stationary
`phases
`in the late
`
`on
`
`routine
`
`racaiiate
`
`in
`
`investigator
`
`arid often
`in biological
`now ask the question
`
`___.
`
`cu
`
`ii /3 14
`
`from rernerks
`
`deilvered
`
`Adapted
`the American
`Association
`ing of
`Mey 18 1988
`
`Chicaso
`
`Illinois
`
`1989 Alan
`
`Lbs Inc
`
`to the Midwest
`
`Regional Meet
`of Phannacoutical
`Scientists
`
`Received
`
`for publicaUce
`
`August
`
`20 1988
`
`revised
`
`September
`
`12
`
`Address
`rsptiet
`requests
`addrees giva above
`
`to Wilson ft De Camp Ph.D at
`
`the
`
`011137
`
`DR. REDDY’S LABS., INC. EX. 1062 PAGE 1
`
`

`

`RIM PERSPECTIVE
`
`ON STEREOISOMERS
`
`Two
`chemists
`
`types
`
`of
`
`identified
`by stereo-
`racemates
`are
`racentic mixture refers to the rather un
`that Pasteur
`found in which each
`indi
`situation
`
`for
`
`authority
`
`abbreviated
`
`Through
`remained
`
`definition
`
`consider
`
`applications
`
`all of
`
`these
`
`blind
`
`of
`
`its atereochenilcel
`
`of drugs The Kefauver-Harris Drug Amend
`marketing
`ments of 1962
`to the
`extended our authority
`further
`review of efficacy
`preznsrketing
`provided
`authority
`the investigational
`usa of drugs
`and
`the monitering of
`our
`In 1972
`names
`the use of
`established
`required
`OTC drug mono
`was extended
`to include
`and the review of generic
`drugs or new versions
`graphs
`of marketed
`drugs was changed
`in 1984
`to provide for
`for drugs approved after 1962
`the FD
`Act has
`changes
`of stereochemistry The
`to questions
`of drug in the Act3 does not specifically
`the question
`composition
`The Code of Federal Regulations CFR also avoids
`this
`drug substance is considered
`to be
`queatioa Whether
`usu
`the racemete or
`has therefore
`pure stereoisomer
`to the Judgment
`those who are in the
`ally been left
`of
`the Act exports
`of
`by scientific
`language
`qualified
`and experience.4
`training
`names for
`The use of established
`the active
`ents in drug products was as noted first
`by the
`Drug Amendments
`These
`Kefauver-Harris
`those adopted by the US Adopted
`are generally
`names
`the FDA is specifically man
`Names Council However
`dated to continue to publish
`names when
`
`ingredi
`
`required
`1962
`
`of
`
`official
`
`usual
`
`vidual
`
`more
`
`ness
`
`the
`
`other
`
`properties
`
`of
`
`and rotates
`crystal of
`the solid is optically
`pure
`racemic com
`light On
`hand
`polarised
`of plus and ntinus
`contains
`equal numbers
`pound
`in each unit cell of the crystal This case
`molecules
`is far
`commonly encountered Unfortunately
`careless
`such nomenclature
`has led many
`in the use of
`if not all
`that most
`chemists
`racernates
`are
`to assume
`separable by simple selection
`of optically pure crystals
`and chemical
`the physical
`In discussing
`sensi
`the concept
`of
`stereochemically
`enantiomers
`tive test must be Introduced
`In using chemicals in the
`in the macro
`we work
`manufacture
`of pharmaceuticals
`scopic world Considerations
`of stereochemistry
`are sig
`level But
`they must
`be trans
`be applied for example
`to
`lated
`into tests that
`can
`in QC testing Fo
`drum of white crystalline
`powder
`larimetry may be
`the
`tool of choice
`to assess optical
`and will clearly dis
`in the research
`purity
`laboratory
`enantiomers Other properties
`may be
`between
`an
`is necessary
`to distinguish
`On the production line the
`racernate
`is applied may or may not logically
`
`nificant
`
`at
`
`the molecular
`
`between
`criminate
`used when it
`and
`
`anantiotner
`
`complex of tests that
`test
`require auth
`
`Optical
`
`rotation
`
`is clearly
`
`tt
`
`it
`
`rug
`
`al
`
`the
`
`techniques
`
`official
`
`been applied
`names have
`to
`two or more
`single drug or to two or more drugs that are identical
`in chemical
`and
`pharmacological
`action
`structure
`
`and
`
`that
`
`quality
`
`are
`
`substantially
`and purity.5
`
`identical
`
`in strength
`
`resonance
`
`chiral
`
`This has resulted
`
`sensitive
`stereochemically
`between
`and minus
`for it will discriminate
`test
`plus
`ensntins So is melting
`range which will discriminate
`and
`between
`pure ssntiomer
`either
`the racenate
`between
`cannot
`discriminate
`obviously it
`though
`Among the mire sophisticated
`enantiomers
`laser Reman
`X-ray powder
`diffraction
`and nuclear magnetic
`shift
`are all
`reagents
`
`stereochernically
`
`sensitive
`
`using
`
`spectroacopy
`lanthsnide
`So
`too are chiral high-performance
`liquid chromatography
`HPLC methods it is well established
`the order of
`that
`than their
`is more
`of enantiorners
`predictable
`times relative to
`standard
`Retention
`retention
`may be highly
`by the chromatographic
`As
`tions
`the use of chrornatographic
`result
`time on
`chirel column may not be as generally
`is on standard
`an
`ble
`as
`as
`identity
`However
`comparison
`to these
`ary phase
`racemate may have
`test
`that
`is suitable
`
`of
`ave
`ml
`sly
`clu
`be
`
`ate
`
`it
`tto
`
`to
`
`3m-
`
`lity
`tUe
`
`ure
`
`tee-
`
`an
`
`is
`
`sa
`hat
`
`the
`md
`
`elution
`
`affected
`
`test
`
`it
`
`time
`condi
`
`retention
`
`applica
`columns
`
`of such times
`
`observed
`
`for
`
`the potential
`
`chiral station
`on
`the two peaks
`for being
`an identity
`
`in
`
`for
`
`regulatory
`purposes
`and Drug Adminis
`the Food
`to fully present
`on stereolsomerism brief consid
`perspective
`eration of the historical
`the Food Drug
`background of
`and Cosmetic Act seems appropriate it is necessary
`to
`few of the highlights
`mention only
`of
`its history
`FDA has been with regard
`to the applica
`show where
`the Act
`the molecular struc
`to the regulation
`tion of
`of
`ture of drugs From its initlsl
`in 1906 the Pure
`passage
`document
`Food
`and Drug Act has been
`dynamic
`the Wiley Act was
`FDAs original mandate
`under
`to
`guarantee the purity
`foods and drugs For the latter
`of
`this was approached through labeling of the active
`ingre
`of the U.S Phsrmacopeia
`and
`as an
`dients
`designstion
`of drug standards
`Following the
`compendium
`tragic elixir of sulfanilamide incident FDAs authority
`was extended to safety by the passage of the FDC Act
`to the Wiley Act New
`this successor
`NDAa were
`the
`for
`required
`
`In order
`
`trations
`
`to
`
`official
`
`in 1938 Under
`Drug Applications
`
`first
`
`in the general
`practice
`the same established
`tiomer is not given
`
`that an enan
`the
`name as
`
`racernate
`
`though
`
`enantiorner
`
`the
`
`of
`
`used
`
`in
`
`under
`
`is
`
`Last year FDA issued
`of guidelinee
`on
`set
`of New Drug Applications The question
`submission
`in the guideline
`was approached directly
`stereochemistry
`of drug aubstanc The FDC
`on the manufacturing
`the methods
`Act
`of
`full description
`requires
`of the drug which includes
`the manufacture
`testing to
`and purity
`demonstrate
`its identity strength quality
`we require
`that submissions
`show the appli
`Therefore
`cants
`of the molecular structure of
`the drug
`knowledge
`substance For chirsi compounds
`this includes
`identifi
`centers The
`ratio al
`cation
`of all chiral
`5050
`should
`be
`for
`by definition
`racemate
`The
`for any other admixture of stceoisomers
`defined
`stereochemistry and
`should consider
`proof of structure
`of the molecular struc
`provide appropriate descriptions
`ture The
`do not
`guidelines
`discuss
`conditions
`which
`determination of absolute configuration
`is desir
`able or entiat Obviously
`though it would be appro
`priate data for supporting the manufacture
`of optically
`pure drugs
`For approved NDAs in which the marketed drug is
`FDA policy is already
`An optically
`clear
`racanate
`pure
`enantlamer
`racemate may be marketed
`of an approved
`new NDA This application
`likely as
`only under
`the
`like new ester Consider
`to chemicel
`signed
`type
`and controls
`various
`issues in
`chemistry manufacturing
`The synthesis
`such en application
`of the new drug must
`be fully described
`is actu
`the manufacturing
`commercial
`
`ally
`
`drug as aynthmized
`
`If
`
`scale
`resolution
`under
`
`process
`the racemic bulk
`the approved NDA then the
`
`of
`
`.1
`
`011138
`
`DR. REDDY’S LABS., INC. EX. 1062 PAGE 2
`
`

`

`liE CAMP
`
`ta
`
`VI
`
`1131
`
`11
`
`tj
`
`as an additional
`
`Investiga
`
`identical
`
`optically
`racemate
`
`could
`
`reasonably
`carried out under
`
`optical
`
`resolution may be considered
`step or
`in the manufacturing
`the con
`steps
`process Obviously
`bulk drug cannot
`trols on
`the purified
`be completely
`for the racemate and the enantiomer
`the
`since
`be distinguishable
`pure drug must
`from the
`obvious that many of the controls
`It is equally
`be identical
`trials must
`be
`Clinical
`new Notice of Claimed
`New Drug 11W for the specific
`for
`tional Exemption
`isomer as appropriate
`and bio
`to show efficacy
`equivalence
`Suppose
`marketed
`
`for
`
`it
`
`market
`
`the decision
`
`of
`
`the
`
`clinical
`
`all
`
`drugs
`limited
`
`fonts
`
`it is clear
`
`on
`the other
`that
`hand
`drug is already
`pure form What
`in its optically
`is necessary
`to be marketed
`racesnate
`This is purely
`as
`to have ever
`speculative since no such application
`seems
`been submitted
`that such
`It seems unlikely
`step could
`ever be shown to improve safety The focus would have
`to be
`on
`and
`the
`of efficacy
`comparison
`resulting
`the ensntiomer
`and
`racemate
`As
`ratios of
`risk/benefit
`with the opposite
`cue manufacturing
`information would
`have
`to be submitted At least one teat would be neces
`the racemate and
`the ensntiomer
`sary to distinguish
`Now turn to the situation
`to approval
`prior
`NDA In practice
`about whether
`to develop
`the racernic
`drug is made by
`pure form of
`or optically
`the finn well
`time that
`before
`the
`an application
`to
`new drug is submitted In the course of drug
`both enen
`development
`manufacturer
`should consider
`tiomers as well
`as the racemate
`to be potential
`The
`choice may even
`be to carry
`out at
`least
`studies
`three
`on
`and/or
`predlinical
`before making
`final determination However
`that economics enters
`into this decision As
`the
`result
`stereoisomer for prod
`decision
`to select
`raceniate
`or
`uct development may be made well before clinical trials
`are begun
`The major effort
`tween
`enantiomers
`
`in
`
`be
`takee
`
`to characterize
`the differences
`racemic drug therefore
`place during its investigational
`phases and possibly
`even
`as an illustration
`that
`esrlier Suppoee
`racemic inves
`for an NDA submis
`drug Is bdng prepared
`tigational
`that data are needed
`sion and
`this decision
`to support
`end pharmacological
`In addition to physical chemical
`studies clinical studies
`and effi
`the safety
`to compare
`of
`the racemate with the enantiomers may
`cacy
`needed
`Such trials in contrast
`to the case
`for
`drug
`already marketed
`racetnate can
`be carried out
`as
`IND for
`under
`the existing
`the racemate
`as
`as
`long
`appropriate chemistry manufacturing
`and control
`data
`isomers
`are submitted for the optical
`How has the FDA approached
`sions Consideration of questions
`of either
`safety
`in isolation from other leads
`to the trivial
`efficacy
`that
`obvious
`conclusion
`one
`the three
`of
`possibili
`and
`tiestwo
`racematemust
`one
`be
`best
`three must be
`equal
`essentially
`Whether
`Is to msrket
`in prefer
`the reverse it should be
`ence to
`or
`pure enentiomer
`of appropriate data Let us
`justified by the submission
`examine
`the situations
`encountered
`in the past
`to see
`where our policy may be headed
`Until recently the studies
`necessary
`about
`the relative
`and
`
`be
`
`review of such deci
`
`or
`
`and
`
`enanticinera
`
`or else
`the
`the decision
`
`raceinate
`
`asfety
`or even
`expensive
`were difficult
`technically
`to carry out As an example of such
`
`efficacy
`
`to provide data
`of enantiomers
`
`impossible
`the
`
`consider
`
`case
`
`tragedy of thalidomide in the early 1960s Ultimately
`the Kefauver-Harris Amend
`this led to the passage
`of
`ments
`Thalidomide
`
`and
`
`thus ex
`
`that
`
`KefauverHsrris
`
`contain
`
`tiveness
`
`of
`
`ss
`
`race-
`
`developed
`
`did
`
`not
`
`effec
`
`to resolution
`
`clinical
`
`that
`
`contains
`chiral
`carbon
`isomerism It was synthesized
`hibits optical
`mate although
`were
`aterecepecific
`syntheses
`the routine
`resolution
`of
`later Considering that
`race-
`mates was not feasible at
`time it is not surprising
`that
`did not carry
`out studies
`its developers
`of
`the
`effects of the pure enantiomers Ass result
`physiological
`it is understandable
`the
`these issues
`that
`in addreasing
`Amendments
`of 1962
`Drug
`the clinics
`requirement that
`specific
`racemic drug be evaluated
`relative to the
`of which the mixture is composed
`pure stereoisomers
`It
`should be kept
`in mind that
`even
`if thalidomide had
`been subjected
`and thorough
`test
`ing there
`is no proof
`the catastrophe would have
`been avoided
`Although
`thalidomide was
`United States it entered
`consideration
`apparent
`
`of
`
`logical activity
`
`described
`
`as
`
`Within
`
`affects were seen
`
`It was
`
`greatest
`
`small
`
`of
`
`irregularly
`its supposed
`of thalido
`
`properties
`it for morning sickness
`of
`
`to prescribe
`The tragedy
`teratogenicity
`into this problem for many years
`
`its
`
`synthesis
`by Casini
`obtained
`by the
`
`Its
`
`synthesis
`
`in
`
`reaction
`
`involvas
`
`never marketed
`in the
`in Europe with no
`commerce
`the relation
`between
`its bio
`and its stereochemistry It was
`initially
`sedative
`to be nontoxic
`that was alleged
`few months of
`its first use its terrible side-
`found to be irreversibly
`neuro
`neuritis that
`remained after
`the
`toxic
`causing
`peripheral
`drug was discontinued Then it was found to be terato
`The
`of
`fetal sbnorxnalitiea
`genic
`causing
`variety
`wss attracted
`birth defect known
`attention
`by
`in which the hands or
`as phocomelis
`feet are attached
`to the shoulder or hip by
`single
`bone Unfortunately
`because
`shaped
`and antinausea
`safety the sedative
`mide led physicians
`in early
`pregnancy
`stimulated research
`afterward
`The developmental
`for thalidomide took place
`research
`the modem technological
`without
`tool of chiral HPLSC
`The initial
`to understand
`its hszerds was
`of attack
`point
`its synthesis Even though
`for
`stereospecific
`thalidomide was ultimately
`and
`developed
`in 1964 the
`Ferappi
`racemate was
`methods
`used at
`the time of
`synthetic
`use
`in
`initial
`Germany The stereospecific
`starts from glu
`No step
`tsmic acid
`or
`its derivatives
`one of
`the
`the chiral center so the abso
`is known
`of the product
`thalidomide
`
`sequence
`lute configuration
`Dextrorotatory
`which
`figuration
`corresponds
`to
`Ingold and Prelog nomenclature.12
`Resolution
`useful
`of
`the pure enantiomers
`cally
`supplies
`not appear
`batch
`the racemate
`of
`does
`to have
`described in the opat
`literature However
`the racsmate
`has
`been
`resolved
`by Elaschke
`chrornatographically
`et aL3 using an HPLC chin stationary
`phase
`and efficacy of
`the
`investigations
`of
`the safety
`of thalidomide have
`been published All of
`stereoisomers
`than were carried out after
`the fact of the tragedy The
`results of
`these
`studies
`that
`the enantiomers of
`suggest
`thalidomide differ significsntly
`in their biological activ
`ity This Ma in turn led
`others
`to conclude that
`is found In only
`the tragedy
`that
`
`has the
`
`absolute
`
`con
`the Calm
`of clini
`
`using
`
`Several
`
`tsratogenic
`
`effect of
`
`thalidomide
`
`ensntlomer
`
`and
`
`to speculate
`
`from
`
`been
`
`the
`
`one
`
`could
`
`DR. REDDY’S LABS., INC. EX. 1062 PAGE 3
`
`

`

`us briefly review
`The earliest
`of stereoisomerism
`investigation
`in thalidomIde was by Fabro
`and
`activity
`biological
`the Lt in SAS 111
`found that
`albino
`et si.5 They
`mice was greater
`factor of approximately 20 for the
`by
`to either of
`racemate relative
`the pure stereoisomers
`found
`They
`in teratogenic
`no difference
`action
`enentiomera
`or between
`an enantiomer
`either
`from the
`at an oral dose of 150 mg/kg
`and the racemate
`In New
`seventh to twelfth
`days of pregnancy
`inclusive
`Zealand white rabbits No
`stereocheanicel
`differences
`were noted in the hypnotic
`Some years
`review article Sinionyi pointed
`in
`later
`out an observation
`the original authors had over
`that
`The ratio of malformed
`to normal
`fetuses
`for
`found for the
`that
`either enantiomer was less
`than half
`racemata
`It should also be noted that both the pure
`and the racemate were administered at
`enantiomars
`the
`one enan
`same dose If as has been hypothesized
`only
`tlomer
`than
`between
`comparison
`the racemate
`of
`with that
`
`reported
`
`also
`
`between
`
`effect
`
`looked.0
`
`the
`
`is
`
`ad
`
`ag
`
`he
`
`It
`
`he
`
`ot
`
`he
`
`lt
`
`id
`
`wa
`
`ta
`
`to
`
`0-
`
`ly
`
`.c
`
`9-
`
`0-
`
`0-
`
`is
`
`have been avoided if the other had been marketed.4
`data
`
`these experimental
`
`Let
`
`are not necessarily
`
`valid if they assume
`
`involve
`
`only
`
`single component
`
`that
`
`such pro
`changing with
`
`FDA FERSLECTIVg ON MtREOSOMERS
`
`is teratogenic
`effect of an enantiorner
`being made between
`drug administered
`in the other
`the dose
`one group and half
`later study by Blsschke et aL showed
`significant
`between
`the enantiomers with the terato
`in the -5
`appearing to be concentrated
`ganic activity
`this latter study used SWS mice
`isomer Unfortunately
`than the New Zealand white
`and Natal
`rather
`rats
`known
`to be
`the most sensitive
`that were
`to
`
`at one dose in
`
`differences
`
`rabbits
`
`different
`
`route
`
`of administration
`
`strated
`
`of
`
`behavior
`
`contributor
`
`of
`
`suggest
`
`established
`
`ing to speculate
`nate incident
`
`stereoisomer
`
`ii
`
`If
`
`pure
`
`effects
`teratogenic
`was also used
`An investigation
`graft-versus-host
`both -S and
`
`reaction
`
`rae-thalidomide
`
`of
`
`the effects
`
`of thalidomide on the
`
`in chick embryos reported that
`had
`significant
`-R-thalidomide
`seriously compromised
`their work
`
`whereas
`
`the authors
`
`of
`
`of
`
`the stereochanical
`
`tnt
`
`by felling to
`of
`
`identity
`
`cesses
`time5
`the family of
`primary example of such
`effects is
`single ex
`drugs With
`nonateroidal
`antlinflammatory
`the drugs
`arid its sodium salt all of
`naproxen
`ception
`In this family that have
`been approved for marketing
`in
`as racemates Hutt and
`the United States
`are marketed
`CaldwelI4 as well as many other investigators
`have
`adds
`shown
`the enantiomers
`that
`of 2-arylpropionic
`in their disposition ki
`show stereoselectivity
`frequently
`Furthermore metabolic inversion
`of the inactive
`netics
`form has been demon
`enantlomer
`to the active
`for many members
`of drugs
`this family
`there
`acid is an exception30
`and of course
`Tiaprofenic
`nay be others
`The
`of aten
`different
`pharmacokinetic
`to the
`been
`to have
`tiomera appears
`the withdrawal
`adverse
`that
`to
`reactions
`lad
`in 1982 Inversion
`from the market
`benoxaprofen
`of
`in humans
`to its -S-enantiomer
`-R-benoxaprofen
`the racemate
`of either
`or
`oral administration
`following
`Subea
`has been demonsfratedJ
`the pure It enantlomer
`the Inversion
`that
`in vitro studies
`occurs
`quent
`the intestinal wallI The
`the drug passes
`as
`through
`to the decreased rate of
`this inversion
`contribution
`of
`in some elderly
`metabolism end excretion
`which
`patients
`the suspension
`that prompted
`led to the hcpatotoxicity
`to have been
`of the drug does not appear
`of marketing
`As in the case of
`thalidomide it is interest
`shout
`the possibility that
`this unfortu
`would
`have
`occurred
`the
`not
`had been developed for the market
`drug that shows stereoaelec
`is another
`Disopyrsmide
`tive pharmenokinetics
`Its binding to plasma protein
`has been shown to be both stereeselective
`and conceutra
`lion dependent This combination
`of kinetic
`factors leads
`by
`be explained
`data that
`csnnot
`to phermacokinetic
`model
`that assumes
`the drug is
`single component
`appears to be com
`Such an assumption
`unfortunately
`mon practice
`drug not yet marketed In the
`In at least one case
`for
`United States the enantiomeric ratio has beat varied
`to
`Indacrinone
`affects
`improve
`therapeutic
`relatively
`both enen
`enantiomer
`
`that
`
`high-ceiling
`
`diuretic
`
`uricoauric
`
`activity
`
`is
`
`Although
`the
`
`is
`
`ii
`
`ii
`
`II
`
`.1
`
`long-acting
`tiomers have
`more potent
`the natriuretic
`
`as
`
`natriuretic
`
`balance between
`agent
`effects was found for
`41
`and uricosuric
`and minus enantioma
`of the phannacoltinetica
`of
`understanding
`thorough
`for the determination of
`safe and
`any drug is essential
`In the case of
`drug
`effective dosage
`regimen
`the in vivo behavior
`of
`this implies
`knowledge
`therefore
`given adequate Infor
`of the pure stereoisomers Indeed
`mation
`about
`the kinetic
`behavior
`of both enantiomers
`to
`drug it is tempting to speculate as to the extent
`of
`to be varied
`which its phermacokinetics
`might be able
`by the use of partially
`than fully resolved drug
`rather
`The use of combinations
`thera
`of drugs to improve
`FDAs regulations
`is not unusuaL
`
`ratio of plus
`
`recernic
`
`peutic
`
`that
`
`efficacy
`in such
`
`combination
`
`require
`
`action
`munosuplresssnt
`had none
`However
`the potential
`significance
`any evidence
`provide
`the drugs used
`The evidence
`action
`
`teratogenic
`comes
`from
`
`this conclusion
`
`of
`
`the
`
`its
`
`hydrolysis
`should be ac
`of
`
`teratogenic
`
`published
`
`of
`
`effects
`
`of
`
`ohiral
`
`interactions
`
`cell
`
`seems to be moat
`that
`indicative
`being restricted to .S-thelidomide
`on
`series of
`studies
`However
`products.t9
`cepted with caution since the mechanism
`in thalidomide rainsins uncertain
`action
`None of
`in an
`has succeeded
`the published
`studies
`swering the questions without ambiguity The definitive
`does not yet appear to have been done The
`experiment
`have focused
`on stereocheinical
`investigations
`the hypnotic and
`teratogauic
`aspects
`thalidomide to the neglect of its neurotoxicity which is
`also an undesirable
`aide-effect Finally although
`it may
`and
`be an oversimplification
`to assume
`that desirable
`actions must be separable
`between
`enan
`undesirable
`it may be necessary to
`tiomers it should he realized that
`using the pure enentiomers
`test such an hypothesis
`the body
`it is clear
`that within
`drug exists in
`in which
`environment
`absorption
`its
`release
`and elimination may in
`transport action degradation
`etc4
`with enzymes
`surfaces
`volve
`two enantiomeric
`molecules will
`Thus
`it is expected that
`by the body The factors
`be acted
`on differently
`differ between
`enantiomera are not limited to pherniaco
`models for racemic drugs
`logical effects Phsrntscoldnetic
`
`that
`
`to the claimed
`makes
`each component
`contribution
`is such
`effects and the dosage of each component..
`is safe and effectiveiX
`the combination
`that
`
`DR. REDDY’S LABS., INC. EX. 1062 PAGE 4
`
`

`

`PlC CAMI
`
`The
`for application
`potential
`regulathxi
`though not explicitly stated
`racemates
`seems obvious
`the CFR Our guideline
`
`of
`
`such
`
`notes
`
`to
`
`in
`
`even
`
`in raoeznates.
`ssimpurities7
`
`enantiomera may be considered
`
`of
`
`drug policy
`
`to
`
`ability
`complex
`
`separation
`
`CaalnI
`
`Fereppl
`
`Thalidomide
`
`1965
`
`J.A D-
`
`and
`
`1.-
`
`of one optical
`Preparation
`entipodo of
`Farmeco Ed ScL 19563566
`1964
`2-phthalimidoglutarhnldo
`Chamie Grunenthal
`CLni.b.H
`Aminopiperidlne.2fl-dione
`Derivatives Srlt Pat 768821
`Fob 20 1957
`10 Slmealy 12 Opllger C_a Montgomery
`Chen md 1030-1031
`11 Shealy YE Opliger C.S Montgomery
`
`.1.A Synthesis of
`studies
`.5 Pharrn Sri
`
`and
`
`related
`
`chlrallty
`13 Slaschke
`
`Specification
`
`of molecular
`
`glutarimlde
`
`Optical
`
`derivatives.
`
`resolution
`
`of
`
`Chen Her
`
`of optical
`
`1.967
`
`On chiral
`
`and
`1.-thalidomide
`57157-764 1968
`1.2 Calm ItS Ingold C.K Prelog
`Angew Chein Tnt Ed r386416 1966
`Kreft 11.1 Markgret
`and
`other
`thelidcmncte
`111
`li32s182322
`14 Do Reater CL Crystals X-ray cryatallography
`end drugs in
`and Drug Action Horn AS Di Ranter
`X-ray Crystallography
`Press 1984 pp 3-4
`C.. edt Oxford Clarsmdon
`ItT Toxicity end
`Smith ILL Williams
`tereto
`113 Fabro
`genidty
`isomers of
`thalidomuldo Nature
`London
`216269
`drug action Med Rn Rev 4360413
`16 Simonyi
`1954
`17 BleecIko
`matographic
`
`ICraft H.P Fickentaclier
`thalidomide
`recsiic seperetion
`Its enentiomers Arxieint.Fcrsclt
`
`of
`
`of
`
`lWhler
`
`Chin
`
`sad
`
`teretogenlc
`
`291640-1649
`
`Effect
`
`of
`
`activity
`1973
`.1.5 Tucker DY Flellman
`15 Field ILO Gibbs
`host reaction Nature London
`thalidomide
`on the graft
`1966
`
`211181181310
`Dea L-Isomore aM tentngenes Prinsip
`19 Oclcenfels
`dec N-Phthelyl-oc.-glutomineAure
`2612.36I
`Experientie
`237
`
`KBhler
`
`versus
`
`1971
`20 KohIer
`
`Melee
`
`inide
`21 Melee
`
`nietabolitea
`
`Ockenfels Li Teratoguniclty
`21U49 1160
`1971
`Expalentla
`
`of
`
`tluclido
`
`KShler
`
`Ilinhryotoxic
`Neturforech
`
`activity
`132611811062
`and
`
`of N.phthaloyl
`1971
`
`formal extension
`the combination
`racematea baa not yet been proposed
`U.S regulatory
`requirements include
`requirement
`the drug be demonstrated
`that
`the bioaveilability
`of
`When
`models
`enan
`differ
`between
`pharmacoldnetic
`tiomers it seems obvious that establishing
`the bioavail
`the drug from
`much more
`racemate
`of
`is
`cannot
`task which
`be accomplished without
`and investigation
`of the enantiomera
`of their
`as individual molecular entities
`pharmacoidnetice
`For moat of
`the yess since Pasteurs discovery it was
`to ask shout
`the detailed
`implica
`beyond
`practicality
`tions of stereochemistry for drug action As scientists we
`did not want to spend our time designing
`en experiment
`that could not be done As regulators we did not ask
`questions for which the answers could not be provided
`And all
`too often the resulting
`ignorance was part of
`decision
`Good science
`be based on
`that our conclusions
`requires
`is derived from well-planned
`experimental evidence that
`Such
`level of planning should not neglect
`experiments
`the potential
`for enan
`for differences
`in properties
`tiomers of
`chiral environment
`chiral molecule
`Thus
`not only is it desirable
`to recognize
`the implica
`for drug action but
`is also
`tions of stereochemistry
`the man
`that
`they be investigated
`desirable
`Either
`tiomars should be separated
`or they should be synthe
`sized
`Good sense
`the hazards
`associated with
`requires
`the use of any substancej
`be identi
`or its components
`the toxicity of impurities
`fied It is expected that
`from manufacturing
`end
`dation products
`residues
`the development
`of
`cesses will be investigated
`as
`The
`same standards
`should
`Is pursued
`therefore
`applied to the enantioneric molecules in
`racemate
`Whenever
`can
`be obtained
`in
`drug
`variety
`forms such as enantiomern
`good sense
`to explore
`the poten
`between
`forms
`
`degra
`pro
`drug
`be
`
`of
`
`it is
`
`chemically equivalent
`both good science
`
`and
`
`tial
`
`for in vivo
`
`differences
`
`these
`
`in
`
`it
`
`that
`
`baths
`
`far sophisticated
`
`pharmacology
`
`noznenae
`.1 Olin
`
`Eur
`
`and Re
`
`Printing
`
`Office
`
`and Eta
`
`Printing
`
`011cc
`
`D.C
`
`LITERATURE CITED
`Arlene tJ Stereochemistry
`end
`clinical
`in phartnacokinetica
`668 1984
`Pharrescol
`26063-
`AriSne E4 Stereocheenistty
`source of problems in medicinal
`chemistry Med
`Rae Rev 6451486
`1980
`Federal
`Food Drug
`end Cosmetic
`as Amended
`Act
`D.C Government
`Laws Wssbington
`lated
`1986 Sec 201g
`as Amended
`Act
`Federal Food Drug
`and Cosmetic
`D.C Government
`Laws Washington
`latsd
`1986 Sec 201p
`Code of Foderal Regulutlons CFR tile 21 Washington
`Government Printing alIce
`1838 Sec 299.4eX2
`13 Guideline
`Documentation
`in Drug
`for Submitting
`Supporting
`the Manufacture
`of Drug Substances
`OlSca of
`for
`Applications
`Research FlED-lOll Food
`Drug Evaluation
`and Drug
`8600 Fishers 1sae Rockville MD 20657
`Admnlniatratioo
`1887
`pp 34
`London
`Sunday
`tines
`The Story of Thalidomide
`
`end
`
`Insight
`
`Team Suffer
`the Children
`New York Viking Press 1979
`
`91.-isoglutenilne
`22 Meise
`
`KShler
`thalidomide
`
`Syntluals
`
`annie
`23 Melee
`Ockonfele
`KShler
`of hydrolyxed products of thalidomide
`973
`24 Iroyer
`l.li Phanuecodynsniic
`end phermocokinetlc
`in humans An overview
`between
`drug enantlonmers
`ences
`lhamucol Fher 40d211.-
`1986
`133
`25 AriSos 5.3 Wuta ILW Eisa in pharnmcokinetirs
`din Plarmacol That 42351353
`pharmacology
`26 tlutt A.. Caldwell
`.1 The metabolic
`invnsion
`chiral
`ecidaA noval mute with pharmacological
`2-eryiprolonic
`lharm Pharmacol
`1963
`.ln193704
`sequences
`27 Hutt A.. CeIdwell
`The Importance
`of stereochemIstry
`in
`non
`tho clinical
`the 2-aryiproplonic
`acid
`drugs dIm Phsnn
`lk$71313
`
`nietaholites
`
`Plterrnaxls
`
`teratnlnglod
`27418419
`detenninmatlon
`Teretologic
`29423424
`Experientiu
`
`tisiting or
`1972
`
`differ
`Clin
`
`end clinical
`1987
`
`of
`con
`
`steroldal
`
`lltsrmaeokinotics
`anti-inflammatory
`
`of
`
`novel
`
`Inversion
`
`of
`
`gesics
`
`1986
`
`of
`
`of
`
`ucicl
`
`1985
`
`tWa
`
`Guilty plea puts Oraliex
`
`case
`
`to
`
`I.
`
`the
`of
`Pherma
`
`1984
`.3 The metabolic
`28 l-lutt A.J Caldwsll
`chiral
`acidsA
`route with
`plarmecologlcel
`2.arylproplonic
`37288 1985
`Phsnnacol
`consequencesA
`correction
`29 See
`of nonnercotic
`anal
`for exemnple Prescott 1.. Effects
`32 Suppl 4129147
`on the liver Drugs
`Pesutto P.M Russell AS Coutte
`30 Singh N.N Jeniali
`itt Drador KS Phannecokinstica
`the enantlomners
`Sd 75439442
`in humans
`1936
`rest Science
`
`tiaprofenic
`31 Marshall
`2091071
`32 Eopp IL. Nsah J2 Ridolfo AS Shepard Hit Stereoselec
`to the IS4-enenti-
`of R..benoxaprofen
`Inversion
`in humans Drug Mstab Diepoa 7366-386 1979
`omer
`P.3 Duff S.M Green 3M Ste
`33 Sintmonds
`E.G Wooduge
`of R- .bmoxaprofon
`In rat and man
`inversion
`reoepeclflc
`5168liz 1980
`Drug Metab Phannacokinet
`Hut
`34 Giecominl KM Nelson W.L Pershe B-A Valdfvteso
`Bleschke PS In ohio
`Turner-Tamiyssu
`interaction
`in human subjects
`ensntlomere
`of
`disopyrsmnide
`1986
`cokinet Siopharm 14335-366
`35 Tobert J.A Qrillo V.. Hitsenberger
`James
`Pryor
`P.M Enhance
`Hobnee 1.B Lutterbeclc
`Cook
`Eutinx
`ment
`the uricosuric
`of Indecrinone by manipula
`properties
`That 29344-
`ratio Cliii Phsrmacol
`
`of
`
`the eoentiomeiic
`tion
`of
`350 1981
`35 Ref
`Sec 30030
`EL Ref
`p.8
`38 Ref
`Sec 314.50dXs
`
`011141
`
`DR. REDDY’S LABS., INC. EX. 1062 PAGE 5
`
`