The Journal of Clinical
`Pharmacology
`
`http://www.jclinpharm.org
`
`Defining the maximum tolerated dose: investigator, academic, industry and regulatory perspectives
`NR Cutler, JJ Sramek, DJ Greenblatt, P Chaikin, N Ford, LJ Lesko, B Davis and RL Williams
` 1997; 37; 767
`J. Clin. Pharmacol.
`
`
`
`
`The online version of this article can be found at:
`http://www.jclinpharm.org
`
`Published by:
`
`
`
`http://www.sagepublications.com
`
`
`On behalf of:
`
`American College of Clinical Pharmacology
`
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` can be found at:The Journal of Clinical Pharmacology
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`
` at NIH LIBRARY on October 23, 2009
`
`ATI 1016-0001
`
`ATI v. ICOS
`IPR2018-01183
`
`

`

`SYMPOSIUM
`
`Tolerated
`the Maximum
`Defining
`Industry
`Academic,
`Investigator,
`Regulatory
`Perspectives
`
`Dose:
`and
`
`Neal
`
`R. Cutler,
`Chaikin,
`MD,
`
`Philip
`
`John
`MD,
`PharmD,
`Brian
`
`J. Sramek,
`Neville
`Davis,
`
`MD,
`
`David
`PharmD,
`PhD,
`Ford,
`MD,
`Roger
`L. Williams,
`
`J. Greenblatt,
`FCP,
`Lawrence
`MD
`
`FCP,
`MD,
`J. Lesko,
`
`PhD,
`
`dose
`
`INTRODUCTION
`
`of
`
`there
`an MTD
`the
`from
`the MTD
`to
`state
`their
`as
`
`maximum
`The
`drug
`in
`concept
`range
`dose
`optimal
`the MTD
`in
`of
`tion
`in
`doses
`tested
`the
`potentially
`efficacious
`present,
`is no
`tutes
`in
`arises
`use
`and
`tions
`tigators
`their
`porting
`studies.
`defined
`maximum
`the
`a trial
`no
`toxicity,5
`elicits
`that
`mild
`sublethal
`to moderate
`cant
`individuals,6
`of
`percent
`the
`distribution.7
`tolerance
`help
`sion
`of
`the MTD
`will
`sues
`and
`promote
`standardization.
`A variety
`of perspectives
`are
`
`important
`an
`is
`(MTD)
`tolerated
`determines
`it
`as
`development,
`Determina-
`trials.14
`for
`efficacy
`both
`to
`ensure
`Phase
`I helps
`that
`safe
`and
`Phase
`II
`are
`is
`evaluated.
`range
`dose
`consti-
`what
`regarding
`consensus
`confusion
`Considerable
`humans.
`defini-
`different
`operational
`of
`inves-
`from
`the
`failure
`of many
`in
`re-
`definitions
`of
`the MTD
`The
`MTD
`has
`been
`variously
`dose
`administered
`during
`dose
`that
`produces
`the
`effects
`a
`signifi-
`in
`toxic
`some
`percentile
`or
`believe
`that
`a discus-
`We
`clarify
`the
`important
`
`the
`
`that
`the
`At
`
`of
`
`is-
`
`presented
`
`in
`
`this
`
`arti-
`
`and
`
`(Drs. Cutler
`From California Clinical Trials, Beverly Hills, California
`Sramek),
`Tufts University
`School
`of Medicine,
`Boston, Massachusetts
`(Dr. Greenblatt), Worldwide
`Clinical Development,
`Rhone-Poulenc
`Rorer,
`Pennsylvania
`(Dr. Chaikin), Department
`of Clinical Pharmacology,
`Bristol-
`Myers Squibb Company,
`Princeton,
`New Jersey
`(Dr. Ford), US Food and
`Drug Administration,
`Rockville, Maryland
`(Drs. Lesko
`and Williams),
`and
`Clinical Trials Unit, UK Medicines
`Control Agency,
`London,
`England
`(Dr.
`Davis).
`Presented
`at
`the 25th Annual Meeting
`of the American
`College
`of
`Clinical
`Pharmacology,
`Philadelphia,
`Pennsylvania,
`September
`28,
`1996.
`and
`This
`article
`contains
`personal
`opinions
`of
`authors
`does
`not
`the
`the
`represent
`the
`views
`or policies
`of the US Food
`and Drug Administration
`or the UK Medicines
`Control
`Agency.
`The views
`expressed
`in Dr. Davis’s
`presentation
`do not
`necessarily
`reflect
`the
`official
`position
`of
`the Medi-
`cines
`Control
`Agency.
`The
`views
`expressed
`in the
`presentation
`by Drs.
`Lesko
`and Williams
`do not necessarily
`reflect
`the
`official
`position
`of
`the
`FDA. Address
`for
`reprints:
`Neal R. Cutler, MD, 8500 Wilshire
`Blvd.,
`7th
`Floor, Beverly
`Hills, CA 90211.
`
`based
`
`on
`Meeting
`
`is
`Annual
`Pharmacology
`September
`ranging
`defined
`scientific
`the
`pharmaceutical
`drug
`to
`
`at
`of
`
`to
`em-
`and
`and
`
`to
`
`given
`symposium
`a recent
`which
`cle,
`College
`American
`of
`the
`25th
`the
`Pennsylva-
`Philadelphia,
`in
`Clinical
`has
`distinct
`Each
`author
`1996.
`28,
`nia,
`on
`desire
`of
`investigators
`the
`from
`concerns,
`the
`academic
`to
`definitions
`have
`of Phase
`I studies
`merit
`phasis
`industry’s
`need
`for
`safe
`the
`from
`development
`the
`responsibility
`to
`expeditious
`the
`ensure
`that
`overall
`approach
`of
`regulators
`and
`is valid
`that
`a focus
`is main-
`drug
`development
`information
`necessary
`to
`evalu-
`critical
`tained
`on
`the
`at
`transitions
`in
`develop-
`ate
`compounds
`new
`these
`perspectives
`sheds
`light
`of
`ment
`process.
`Each
`on
`issue
`of
`the MTD
`will
`helpful
`to
`all
`be
`and
`are
`who
`responsible
`for
`conducting,
`evaluating
`clinical
`drug
`
`clearly
`on
`
`the
`
`and
`planning,
`studies.
`
`the
`
`REFERENCES
`
`NR, Sramek
`Development
`
`II, Veroff
`Strategies.
`
`JJ, Kurtz
`Sramek
`NR,
`in Drug
`Development.
`
`AE: Alzheimer’s
`Chichester:
`
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`
`Optimiz-
`& Sons,
`
`NM:
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`
`Compounds:
`John Wiley
`
`Per-
`& Sons,
`
`1. Cutler
`ing Drug
`1994.
`2.
`Cutler
`spectives
`1996.
`NR, Sramek
`3. Cutler
`trials
`in Alzheimer’s
`1995b;48:421-428.
`inacol
`4. Koch
`of bridging
`HJ: Concept
`50:245-246.
`1996;
`J Pharmacol
`SK:
`5. Carter
`Clinical
`trials
`1997;40:544-557.
`6. Geller
`NL: Design
`statistician’s
`view.
`Storer
`BE: Design
`7.
`1989;45:925-937.
`rics
`
`JJ: Scientific
`patients:
`the
`
`ethical
`
`and
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`
`concerns
`study.
`EurJ
`
`in clinical
`Clin
`Phar-
`
`studies
`
`and
`
`ethical
`
`concerns.
`
`Eur
`
`in
`
`cancer
`
`chemotherapy.
`
`Cancer
`
`H clinical
`I and
`1984;2:483-491.
`of phase
`I clinical
`
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`in cancer:
`
`a
`
`trials.
`
`Biomet-
`
`of phase
`Cancer
`Invest
`and
`analysis
`
`REGULATORY
`MAXIMUM
`
`PERSPECTIVE
`TOLERATED
`DOSE
`
`ON THE
`
`Brian
`
`Davis,
`
`MD
`
`requested
`I
`cover
`some
`
`to
`of
`
`speak
`the
`general
`
`first
`
`because
`principles
`
`I would
`associated
`
`like
`
`to
`
`with
`
`J Clin Pharmacol
`
`1997;37:767-783
`
`767
`
`ATI 1016-0002
`
`

`

`CUTLER
`
`ET
`
`AL
`
`the
`then
`dose
`to
`part
`that
`there
`can
`
`assumptions
`introduce
`(MTh)
`determine
`in
`early
`there
`are
`be
`may
`not
`foster
`serious
`
`the
`
`make
`we
`concept
`consider
`and
`the MTD
`develop-
`drug
`no
`definitive
`answers
`discus-
`
`in
`
`and
`I will
`
`and
`but
`we
`
`development
`drug
`the process.
`during
`of maximum
`tolerated
`whether
`designed
`studies
`patients
`a useful
`can
`play
`ment.
`Let me
`emphasize
`experts
`in
`this
`field,
`to all
`questions,
`sion.
`Suppose
`from
`develop
`quite
`does
`loss,
`mercial
`another.
`select
`particularly
`ever,
`discarded
`the
`dropped
`cess,
`another
`their
`cause
`early
`The
`a
`
`the
`
`not
`
`it
`
`a
`
`company
`among
`work
`but
`it
`From
`
`drug
`
`be
`
`to
`
`to
`
`are
`
`the
`
`is
`
`in
`
`about
`hypothesis
`including
`candidate
`ideas
`until
`
`it
`
`if
`
`was
`pro-
`be
`
`be-
`and
`
`The
`path
`both
`
`Figure
`from
`adopted.
`the
`left
`from
`problem
`of
`new
`process
`discovered.
`
`linked
`1. Two
`an
`basic
`assumptions,
`shows
`right
`path
`in
`shows
`steps
`provide
`approaches
`and
`the
`assumptions
`assumptions
`and
`continues
`
`paths
`
`until
`
`in modeling
`used
`approach
`to
`in
`steps
`an
`a mathematical
`insights
`These
`used.
`approaches
`new
`a satisfactoiy
`
`a problem.
`solving
`the
`experimental
`approach.
`the
`about
`insights
`to
`the
`to
`
`Starting
`problem
`approach;
`The
`results
`solution
`to
`the
`form
`basis
`solution.
`This
`the
`problem
`
`is
`
`is
`
`the
`
`solution
`
`a
`
`of
`
`be
`
`for
`pa-
`
`of
`
`to
`
`be
`
`dose
`through
`started
`make
`
`on
`
`the
`
`to
`a drug
`choose
`to
`trying
`drugs.
`If one
`new
`of
`battery
`its
`a disappointing
`com-
`it
`is
`out,
`to
`discard
`is
`reasonable
`and
`point
`of view,
`how-
`the
`patient’s
`untreatable
`disease,
`those
`with
`been
`effective
`but
`could
`have
`development
`of
`a
`suboptimal
`because
`loss.
`It would
`an
`irreplaceable
`could
`if
`concentrated
`patients
`companies
`loss
`drugs
`on
`developing
`“me-too”
`resources
`unnecessarily
`high
`cost
`of discovery
`of
`an
`of
`development
`“breakthrough”
`drugs.
`approach
`drug
`scientific
`to
`developing
`a new
`begins
`with
`the
`sci-
`disease
`research
`basic
`for
`toward
`of
`advances
`the
`discovery
`a
`specific
`ences,
`with
`patient
`and
`ends
`trials.
`Generally,
`a prob-
`agent,
`is
`the
`disease
`related
`to
`identified,
`search
`lem
`literature
`and
`other
`resources
`helps
`investiga-
`the
`the
`to
`develop
`a hypothesis
`why
`a particular
`tor
`should
`work,
`the
`is
`then
`tested
`drug
`experimentation,
`screen-
`through
`animal
`drugs,
`the
`to
`identify
`and
`ing
`tests
`used
`to
`design
`new
`and
`results
`This
`a satisfactory
`solu-
`experiments.
`problem
`tion
`to
`case
`of
`In
`the
`intended
`product
`in vitro
`to
`drug
`affinity
`as
`determine
`organs
`target
`mechanism
`periments
`tential
`knowing
`tient
`process
`is,
`an
`will
`many
`This
`wide
`which
`dose
`too
`
`or
`we
`receptors,
`we
`studies,
`on
`effects
`toxic
`potential
`its
`into
`preclinical
`evidence
`depend
`a drug
`target
`to
`the
`it
`the
`development
`in
`optimum
`dose,
`strategy
`to
`risk
`possible.
`with
`
`these
`
`of
`
`as
`patients
`illnesses
`If
`the
`patients
`in
`clinical
`
`development
`and
`or
`even
`years,
`in
`trials
`tients
`which
`doses,
`many
`Like
`establish
`how
`can
`regimen
`“model.”
`or
`egy
`researchers
`lem,
`if possible),
`ple,
`the
`results,
`ine
`theoretical
`solution
`whether
`conclusion
`a satisfactory
`solution
`is not
`satisfactory,
`and
`cycle
`repeat
`the
`simplified
`A typical
`problem
`finding
`an
`dose-response
`in
`for
`body
`reflects
`ulation.
`when
`preclinical
`we
`sumption
`sufficiently
`sumption
`the
`effects
`humans
`how
`the
`population,
`because
`of
`the
`the
`results
`also
`inadequate
`an
`The
`assumption
`
`they
`
`the
`
`of
`
`weight
`However,
`studies,
`not
`is
`that
`is
`indicate
`but
`
`disease,
`provide
`next
`
`is
`
`that
`
`sometimes
`delayed,
`may
`some
`cases,
`in
`Also,
`abandoned.
`essentially
`placebo
`receiving
`may
`be
`if
`it
`avoidable.
`is
`raises
`ethical
`concerns
`the
`“problem”
`scientific
`questions,
`or
`administration
`the
`optimum
`a recursive
`addressed
`solving
`To
`get
`assumptions
`some
`must
`experiments,
`initial
`conduct
`and
`terms
`them
`in
`interpret
`problem.
`They
`to
`the
`the
`experiments
`of
`problem.
`the
`to
`review
`must
`1).
`(Figure
`assumption
`optimum
`the
`animal
`adjusted,
`that
`the
`target
`we
`examine
`usually
`conclude
`accurate.
`of
`the
`will
`drug
`the
`subjects
`from
`solution
`the
`
`strat-
`prob-
`(sim-
`exam-
`of
`the
`ask
`
`must
`provides
`solution
`the
`assumptions
`
`If
`
`the
`
`the
`at
`dose
`
`start
`is
`
`of
`
`in
`
`the
`the
`
`of
`as-
`as-
`
`that
`example,
`for
`human
`pop-
`the
`results
`that
`the
`The
`next
`healthy
`in
`target
`the
`effects
`the
`may
`studies
`the
`problem.
`of
`the
`drug
`
`drug
`act
`lack
`
`in
`
`these
`
`to
`effects
`
`biologic
`test
`
`the
`such
`can
`the
`
`of
`
`ex-
`po-
`on
`pa-
`
`that
`that
`as
`
`a
`
`for
`initial
`
`is
`
`trials
`
`new
`new
`get
`continues
`is
`found.
`entity
`new
`chemical
`for
`as
`a medicine,
`examine
`effects
`on
`selectivity.
`In
`animal
`pharmacologic
`and
`some
`and
`gain
`insight
`Although
`action.
`convincing
`provide
`benefits
`the
`full
`administer
`best
`to
`challenge
`major
`the
`determine
`to
`administration
`dose
`or
`benefit
`without
`substantial
`in
`target
`population
`the
`generally
`includes
`and
`in
`age
`co-existing
`other
`take
`medication.
`exploratory
`studies
`be wasted
`during
`
`a
`
`use
`
`its
`
`and
`its
`
`of
`may
`efficacy,
`how
`
`One
`group.
`is how
`effective
`provide
`patients
`population
`variability
`they
`selected
`low,
`time
`
`may
`
`for
`may
`
`768
`
`#{149}J Clin Pharmacol
`
`1997;37:767-783
`
`ATI 1016-0003
`
`

`

`effects
`these
`popula-
`elimi-
`to the
`condi-
`the
`to
`in
`from
`be
`far
`
`models
`phar-
`those
`
`in
`
`they
`of
`the
`techniques
`take
`the
`
`not
`at
`alter
`
`be
`
`in
`
`to
`
`the
`of
`representative
`may
`in a few patients
`although
`However,
`population.
`in
`the
`target
`target
`the
`represent
`to
`selected
`patients
`are
`they
`that
`in a way
`chosen
`to be
`tion,
`may
`have
`other
`the
`response
`that may
`alter
`nates
`criteria
`such
`drug,
`as
`advanced
`age,
`other
`medical
`and
`tions,
`concomitant
`medication.
`Therefore,
`an
`inadequate
`solution
`still
`may
`results
`provide
`problem.
`the
`The
`estimate
`of
`the
`dose
`be
`used
`to
`in
`exploratory
`trials
`patients
`that
`emerges
`larger
`in
`approaches,
`these
`even
`combination,
`may
`the
`or
`far
`higher
`lower
`than
`optimum
`dose.
`examine
`It may
`be
`helpful
`to
`why
`animal
`to mimic
`effects
`of drugs
`in humans.
`When
`fail
`macokinetics
`in
`animals
`compared
`with
`are
`in
`humans,
`many
`drugs
`major
`differences
`show
`absorption,
`distribution,
`metabolism,
`excretion.
`and
`When
`sufficient
`data
`be
`used
`are
`available,
`can
`to make
`a
`rough
`approximation
`likely
`safe
`in
`exposure
`level
`humans
`using
`such
`as
`allometric
`scaling.
`This
`does
`account
`into
`that
`any
`differences
`may
`exist
`sites
`receptor
`in
`or
`local
`conditions
`that may
`organ
`target
`the
`response
`the
`drug.
`Physiologic
`animals
`to
`in
`effects
`also
`often
`differ
`substantially
`humans
`in
`those
`from
`re-
`in
`and
`may
`be
`of
`limited
`use
`human
`predicting
`sponse,
`particularly
`a target
`in which
`population
`likely
`diseased.
`some
`be
`Moreover,
`organs
`are
`methods
`used
`determine
`human
`physiology
`to
`through
`clinical
`measurements
`are
`crude.
`For
`exam-
`ple,
`smooth
`muscle
`contraction
`in
`the
`airway
`of
`an
`animal
`can
`be
`determined
`by measuring
`it
`directly
`in
`with
`a strain
`gauge,
`but
`humans
`airway
`contrac-
`tion
`is inferred
`from indirect
`measures
`of pulmonary
`function.
`There
`are
`also
`significant
`differences
`tween
`animal
`models
`humans
`in toxic
`responses
`and
`to
`drugs.
`The
`results
`from
`animals
`serve
`as
`a guide
`to
`dangerous
`drug
`concentrations
`types
`of
`toxic
`and
`effects,
`but
`that
`is
`all.
`does
`model
`The
`healthy
`human
`with
`patients
`in
`dict
`effects
`a drug
`alter
`may
`ease
`because
`the
`disease
`in
`concentration
`local
`receptor
`activity
`and
`physiologic
`the
`receptor.
`Likewise,
`the
`phase
`frequently
`a healthy
`organ
`to
`a drug
`sponses
`of
`are
`These
`differ-
`different
`to
`those
`a diseased
`organ.
`make
`predictor
`for
`ences
`the
`subject
`a poor
`group.
`Obviously,
`healthy
`drug
`response
`subjects
`cannot
`to measure
`potential
`thera-
`of
`peutic
`effects
`Although
`healthy
`humans
`some
`may
`provide
`of
`prediction
`the
`toxic
`of
`the
`effects
`of
`a drug,
`and
`severity
`the
`reac-
`of
`tions
`may
`be modulated
`the
`diseased
`state.
`by
`The
`purpose
`of
`the
`symposium
`is to examine
`tional
`assumptions
`and
`approaches
`that
`might
`
`of
`
`at
`
`of
`healthy
`in the
`target
`be
`used
`a drug.
`level
`extent
`
`be-
`
`pre-
`dis-
`as
`bio-
`re-
`
`not
`
`usually
`the
`target
`factors
`such
`the
`
`addi-
`be
`
`DEFINING
`
`THE MAXIMUM
`
`TOLERA
`
`TED
`
`DOSE
`
`to
`
`estimate
`The
`
`in
`
`it
`
`in
`in
`
`pop-
`target
`the
`group
`a small
`of
`the
`as
`part
`for most
`of
`is
`an
`inter-
`could
`be
`ap-
`that
`when
`an
`adverse
`of doses
`that
`if
`the
`candi-
`effect
`on the
`for
`devel-
`
`a
`
`ethical
`been
`
`in
`
`the
`
`on
`
`concerns
`reviewed.1
`optimum
`preclin-
`sought
`a
`refer-
`The
`
`the
`
`and
`
`is
`
`dose
`optimum
`the
`used
`of MTD
`determination
`ulation.
`population
`target
`from
`the
`of
`patients
`dose
`effective
`an
`determine
`to
`approach
`diseases
`certain
`population
`the
`target
`that
`a concept
`and
`possibly
`esting
`idea
`is
`assumption
`widely.
`The
`plied
`more
`causes
`dose
`is
`reached
`consistently
`that
`range
`reaction,
`it must
`at
`the
`upper
`be
`can
`be
`and
`tolerated
`the
`target
`group,
`by
`date
`does
`produce
`the
`desired
`not
`drug
`then
`is not
`likely
`to be
`suitable
`disease,
`opment.
`and
`approaches
`scientific
`The
`recently
`study
`have
`type
`of
`this
`to determining
`approach
`in this
`Briefly,
`based
`is
`selected
`safe
`dose
`initial
`an
`dose,
`is
`dose
`tolerated
`a maximum
`and
`work
`ical
`as
`used
`volunteers
`(MTDHV)
`and
`healthy
`in
`regimens.
`subsequent
`administration
`for
`ence
`population,
`target
`of
`patients
`from
`cohort
`first
`careful
`observation
`very
`under
`is
`monitoring,
`and
`the
`50% of
`to an
`exposed
`initial
`dose
`approximately
`to a dose
`of drug
`The
`next
`cohort
`is exposed
`MTDHV.
`so
`on,
`increas-
`by
`25%
`of
`the MTDHV,
`increased
`cohorts
`of very
`similar
`increments
`in
`further
`ing
`in
`a dose
`reached
`monitored
`patients,
`until
`carefully
`not
`tolerated
`adverse
`reactions
`that
`that
`causes
`are
`the
`patients
`(50%
`or more).
`This
`dose
`of
`by most
`defined
`as
`the minimum
`intolerated
`dose
`be
`could
`dose
`preceding
`this
`be
`(MID).
`The
`in
`patients
`the
`maximum
`tolerated
`in
`as
`defined
`(MTD).
`these
`However,
`definitions
`of
`can
`agreed
`The MTD
`yet
`been
`beyond
`which
`unacceptably
`safe
`dose
`verse
`reactions
`begin
`to
`occur
`in
`patients.
`close
`to the
`optimum
`dose
`potential
`to be
`and
`therefore
`used
`as
`an
`early
`can
`the
`optimum
`dose.
`addition,
`this
`In
`can
`indicate
`a range
`of doses
`within
`could
`be
`expected
`to have
`adverse
`type
`of
`adverse
`reactions
`that
`can
`relatively
`small
`size
`and
`cost
`these
`may
`also
`encourage
`companies
`to
`in
`special
`patient
`groups
`such
`as
`tients
`with
`concomitant
`disease
`of
`the
`target
`population.
`exploratory
`When
`starting
`larger
`be made
`assumption
`could
`an
`75% of
`the MTD
`would
`be
`but
`potentially
`efficacious
`such
`as
`cancer,
`it
`is often
`chance
`of being
`effective
`of
`the
`target
`population
`the
`tolerated
`dose
`
`on.
`
`be
`
`of
`
`could
`patients
`have
`
`be
`
`dose
`not
`terms
`as
`described
`ad-
`frequent
`the
`It has
`for
`efficacy
`approach
`study
`kind
`of
`which
`patients
`reactions
`and
`be
`expected.
`types
`of
`determine
`the
`elderly
`that
`might
`
`a
`
`to
`
`the
`The
`studies
`MTD
`or
`pa-
`be
`part
`
`that
`a good
`dose.
`assumed
`throughout
`lies
`in
`the
`In
`other
`
`II,
`in Phase
`to
`of 60%
`of a safe
`diseases,
`greatest
`range
`
`trials
`a dose
`estimate
`In
`some
`the
`that
`a broad
`of
`upper
`portion
`diseases,
`a dose
`
`range.
`
`SYMPOSIUM
`
`769
`
`ATI 1016-0004
`
`

`

`CUTLER
`
`ET
`
`AL
`
`grateful
`I am very
`their
`helpful
`
`to Professor
`contributions
`
`for
`
`John
`the
`
`to
`
`Lewis
`revision
`
`and
`
`Snodin
`Dr. David
`this
`manuscript.
`
`of
`
`REFERENCES
`
`1. Cutler
`Sramek
`NR,
`trials
`in Alzheimer’s
`1995;48:421-428.
`macal
`
`JJ: Scientific
`patients:
`the
`
`ethical
`and
`bridging
`
`concerns
`study.
`EurJ
`
`in clinical
`Clin Phar-
`
`Question
`
`and
`
`Answer
`
`From
`with
`
`the
`this
`
`such
`may
`way
`
`(industry),
`perspective
`our
`Question:
`especially
`issue
`of MTD,
`the
`struggles
`drugs.
`Typically,
`system
`tral
`nervous
`healthy
`individuals,
`in
`Phase
`I
`studies
`the
`safety
`windows,
`encouraged
`to find
`in
`when
`higher
`doses
`subsequent
`trials
`required,
`safety
`would
`support
`in
`ever,
`process,
`of
`colleagues
`be
`it
`“human
`toxicology.”
`should
`at
`striking
`with
`drugs
`efficacy
`much
`lower
`doses?
`to find
`end
`those
`surrogate
`for
`that
`MTh
`and
`show
`cen-
`tral
`nervous
`system?
`a surro-
`to have
`enough
`fortunate
`If you
`are
`Answer:
`clini-
`required
`the
`reflects
`gate marker
`that
`accurately
`drug
`to approach
`cal
`benefit,
`then
`that
`is another
`way
`development.
`However,
`there
`are many
`conditions
`in which
`a
`surrogate
`marker
`is
`lacking.
`in
`MTD
`study
`be
`used
`diseases
`for which
`is
`no
`other
`estimate
`the
`optimum
`to
`range
`accurately
`target
`population.
`in the
`the MTD,
`you
`ascertain
`a dose
`can
`for
`the
`target
`population
`hope
`observe
`efficacy
`of
`in
`tients.
`This
`could
`of
`
`we
`and
`such
`patients
`this.
`
`are
`in
`
`have
`we
`cen-
`with
`conduct
`we
`that
`were
`How-
`called
`we
`
`data
`our
`some
`balance
`What
`have
`perhaps
`preferable
`it not
`than
`pushing
`rather
`is getting
`into
`the
`
`that
`Would
`points
`the
`
`drug
`
`be
`
`The
`there
`dosage
`defining
`is
`safe
`also
`pa-
`
`of
`safety.”
`
`will
`
`By
`that
`
`you
`range
`
`range
`that
`a wide
`as
`“human
`
`and
`drug
`the
`thought
`
`be
`
`companies
`in
`normal
`In
`to
`patients.
`risk!
`and
`the
`the
`disease
`should
`
`efficacy
`of widespread
`certain
`used
`or after market-
`development
`may
`therapeutic
`The
`impor-
`ing
`the MTD
`tance
`reduces
`the
`company
`will
`the
`develop-
`chance
`drug
`because
`of
`ment
`tested
`at
`a dose
`low.
`was
`that
`greatest
`the
`Certainly,
`proach
`to determining
`with
`any
`clinical
`adverse
`reaction
`stances,
`patients
`event
`occurring,
`must
`accept
`have
`an
`adverse
`study.
`Patients
`formed
`of
`this
`posed
`study
`an
`proved
`by
`wide
`experience
`science
`and
`verse
`events
`that
`are minor;
`vomiting
`would
`cer.
`Each
`patient
`for
`unexpected
`professionals
`care
`for
`patients
`would
`probably
`a less
`well-supervised
`such
`as
`is
`often
`important
`advantage
`that
`the
`investigator
`about
`the
`setting
`occur.
`Additional
`include
`the
`ability
`mark
`dose
`above
`reaction
`likely
`to
`is
`causing
`toxic
`effects
`diseases
`or
`special
`Determining
`the
`cess
`in
`developing
`lem
`is
`finding
`of
`target
`the
`the
`development
`all
`regulators
`have
`this
`trying
`to solve
`one
`this
`in
`article,
`for
`problem
`proach
`to
`this
`of
`of
`the MTD
`determination
`carefully
`monitored
`of
`groups
`as a basis
`for
`selecting
`this
`traditional
`exploratory
`ment.
`
`to
`
`be
`during
`the
`
`initially
`be
`reduced
`to
`improve
`of
`knowing
`that
`a
`a new
`too
`
`index.
`that
`is
`abandon
`it was
`
`it
`
`an
`
`concern
`dose
`
`trial,
`exists.
`agree
`the
`in
`they
`drug
`would
`give
`
`that
`
`of
`
`ethics
`that
`
`used
`
`In
`
`or
`
`the
`
`the
`
`of
`can
`in which
`applications
`to
`identify
`which
`occur
`in
`groups
`best
`a new
`effective
`an
`population
`program.
`devoted
`problem.
`very
`
`at
`
`studies
`
`770
`
`#{149}J Clin Pharmacol
`
`1997;37:767-783
`
`of
`area
`is
`effective
`for
`the
`potential
`most
`Whereas
`under
`an
`to the
`possibilityof
`study,
`case
`of
`an MTh
`likely
`more
`than
`are
`point
`reaction
`as an
`end
`have
`to
`be
`adequately
`consent.
`addition,
`and
`be
`have
`to
`reviewed
`would
`ethics
`independent
`committee
`levels
`high
`expertise
`of
`and
`clinical
`Typically,
`trials.
`considered
`tolerable
`are
`are
`or
`instance,
`headache,
`nausea,
`for
`can-
`trials
`acceptable
`in
`drug
`for
`be
`would
`have
`to be monitored
`closely
`serious
`adverse
`reactions
`skilled
`by
`in a unit
`designed
`to provide
`intensive
`in
`drug
`trials.
`In this
`setting,
`a study
`be more
`acceptable
`and
`safe
`than
`inpatient
`outpatient
`setting,
`in
`a Phase
`II
`study.
`Another
`study
`MTD
`inpatient
`provide
`information
`more
`the
`reaction
`adverse
`studies
`of MTD
`markers
`surrogate
`serious
`a more
`the
`likelihood
`or
`patients
`with
`of patients.
`is a key
`strategy
`dose
`One
`major
`medicine.
`the
`widest
`for
`dose
`of
`enough
`early
`an
`and
`academia,
`Industry,
`money
`time
`and
`of
`a lot
`detail
`is discussed
`As
`ap-
`plausible
`additional
`the
`is
`certain
`diseases
`small
`a new
`using
`drug
`use
`patients
`and
`further
`strategy
`for
`a dose
`in Phase
`II of develop-
`
`ap-
`As
`
`this
`in
`safety.
`a
`serious
`circum-
`adverse
`they
`
`the
`and
`
`to
`not
`to the
`in-
`pro-
`ap-
`with
`the
`ad-
`those
`
`in
`
`in
`
`is
`
`will
`may
`that
`adverse
`a drug
`of
`concomitant
`
`to suc-
`prob-
`range
`stage
`
`in
`
`of
`
`expect
`volun-
`
`we
`
`pharmaceutical
`Most
`safety/tolerability
`administering
`before
`in which
`patients
`relationship
`not
`exist,
`
`do
`
`that
`what
`
`the
`
`testing
`the
`disease
`accompanies
`type
`of
`approach
`
`drug
`
`state
`
`Question:
`extensive
`teers
`those
`benefit
`state
`take?
`the major
`is one
`Answer:
`the
`Briefly,
`explores.
`symposium
`one. One
`option
`be
`a conservative
`starting
`mine
`the MTD
`with
`a very
`based
`on
`preclinical
`studies,
`using
`of patients
`to be
`to
`drug
`possible
`conditions.
`these
`likely
`suggest
`doses
`exploratory
`studies.
`
`This
`
`of
`
`exposed
`
`Data
`safe
`
`a
`
`the
`from
`range
`
`of
`
`to
`
`this
`that
`questions
`should
`approach
`to deter-
`be
`would
`initial
`dose
`low
`a
`small
`number
`the
`safest
`under
`patients
`are
`for
`
`further
`
`ATI 1016-0005
`
`

`

`DEFINING
`
`THE
`
`MAXIMUM
`
`TOLERATED
`
`DOSE
`
`INVESTIGATOR
`
`PERSPECTIVE
`
`ON
`
`THE
`
`MAXIMUM
`
`TOLERATED
`
`DOSE
`
`Neal
`
`R. Cutler,
`
`MD,
`
`and
`
`John
`
`J. Sramek,
`
`PharmD
`
`of
`than
`
`in
`
`study
`
`an
`
`Davis
`that
`same
`especially
`and
`
`of
`
`to
`
`in
`
`the MTD
`central
`our
`
`an
`
`study
`of
`
`a
`
`overview
`here,
`an
`
`of
`
`a
`
`number
`of
`also
`discuss
`we
`and
`perspec-
`investigator’s
`with
`these
`in
`dealing
`produce
`to
`trying
`in
`dose
`(MTD).
`tolerated
`define
`the MTD
`and
`how
`discussed
`from
`the
`is
`to
`approaches
`de-
`Three
`approach,
`a conceptual
`a
`pharmacodynamic
`
`and
`
`out
`
`the
`
`experi-
`of our
`safety!
`system
`partic-
`with
`one
`we
`(AD),
`which
`have
`years.
`We
`AD compounds
`the
`we
`have
`had
`inherent
`prob-
`several
`different
`regimen
`population.
`we
`
`for
`
`given
`has
`Dr.
`reiterate
`we
`points
`from
`concepts
`these
`experience
`our
`tive,
`frustration
`our
`issues
`maximum
`the
`definition
`trying
`to
`for
`Our
`strategy
`this
`relates
`administration
`perspective.
`investigator’s
`are
`reviewed:
`fining
`the MTD
`approach,
`an
`operational
`approach.
`modeling
`grows
`interest
`in
`Our
`nervous
`conducting
`ence
`experience
`and
`studies
`tolerance
`disease
`Alzheimer’s
`ular
`disease,
`several
`for
`in
`interested
`have
`been
`different
`20
`to
`almost
`evaluated
`15
`Thus,
`studiest6
`in safety/tolerance
`of
`some
`to recognize
`opportunity
`from
`data
`to
`gather
`trying
`lems
`in
`administration
`to
`determine
`sources
`in
`the
`patient
`a safety/tolerance
`have
`AD
`compounds
`the
`half
`For
`almost
`least
`doses
`at
`tolerated
`patients
`evaluated,
`100%
`healthy
`in
`tolerated
`dose
`highest
`the
`greater
`the
`previously,
`discussed
`Davis
`Dr.
`As
`volunteers.
`can
`population
`in the
`target
`observed
`events
`adverse
`us
`point
`to give
`end
`as
`a pharmacodynamic
`be
`used
`However,
`some
`range.
`dose
`of
`the
`tolerable
`some
`idea
`lack
`of
`a working
`the
`from
`have
`stemmed
`problems
`trying
`combine
`of
`terms
`to
`in
`of
`the MTD
`definition
`pharmacology
`units
`to
`and
`other
`sites
`data
`from
`include
`concerns
`whether
`Other
`the MTD.
`termine
`healthy
`in
`individuals
`conducted
`were
`the
`studies
`whether
`truly
`investigators
`were
`and
`or
`patients
`the
`evaluating
`pharmaco-
`or
`simply
`dose
`pushing
`compound
`of
`the
`and
`pharmacology
`kinetics
`the
`study
`as
`the MTD.
`in
`highest
`dose
`the
`fining
`As Dr. Davis
`out,
`the
`difference
`between
`pointed
`the
`volunteers
`is
`an
`in
`patients
`and
`healthy
`issue
`the
`determination
`of
`the MTD.
`For
`example,
`is
`there
`potential
`receptor
`alterations
`in the
`patient
`target
`population.
`There
`might
`be
`that
`differ-
`support
`ences
`in metabolism
`between
`healthy
`individuals
`and
`a particular
`patient
`population.
`These
`factors
`all
`important
`terms
`of defining
`the MTD
`and
`the
`focus
`symposium.
`We
`have
`the
`concept
`safety/tolerance
`studies
`in
`the
`
`than
`
`the
`or
`
`for
`
`of
`
`in
`the
`called
`
`the
`
`data
`
`de-
`
`de-
`
`are
`are
`
`of
`target
`
`conducting
`patient
`
`early
`popula-
`
`studies.”7
`“bridging
`tion
`a more
`accurate
`allow
`studies
`for Phase
`trials,
`ultimately
`II
`bridging
`study
`The
`opment.
`conducted
`between
`be
`that
`can
`in healthy
`individuals
`dose
`studies
`to determine
`the
`response
`cacy
`studies
`Safety/tolerance
`studies
`population.
`allow
`some
`predictability
`population
`a better
`understanding
`and
`events
`for
`Phase
`II
`studies.
`range
`dose
`emphasize
`the
`need
`and
`portant
`of
`the MTD.
`ing
`definition
`the
`compounds
`of
`In most
`the MTD
`in
`past
`years,
`been
`substantially
`higher
`volunteers.
`This
`trend
`the
`mation
`tolerability
`more
`100%
`or
`potential
`demonstrating
`for
`in MTD
`is
`the
`studies
`by
`various
`pharmacology
`countries.
`One
`example
`mine
`heptylphysostigmine),
`(or
`hibitor
`longer
`in
`development.
`no
`adverse
`events
`the
`multiple-dose
`healthy
`persons
`were
`vivid
`concentrating,
`whereas
`in
`young
`healthy
`persons
`stopped
`the
`was
`tient
`population,
`severe
`a
`significant
`cerebellar
`dose-limiting
`adverse
`events
`that
`defined
`which
`were
`conducted
`investigators
`without
`MTD.
`Pharma-
`713
`is ENA
`example
`Another
`(Novartis
`which
`NJ),
`Hanover,
`East
`Corporation,
`ceuticals
`of AD.
`Under
`treatment
`the
`development
`under
`individuals
`in both
`healthy
`multiple-dose
`dose-limiting
`was
`the
`and
`patients,
`single-dose
`condi-
`adverse
`event.
`the MTD
`was
`de-
`tions
`young
`Thus,
`the
`problem
`termined
`nausea
`by
`kinds
`differences
`is
`how
`proceed
`to
`determine
`which
`study
`occur.
`It becomes
`range
`dose
`should
`be.
`what
`is
`correct
`and
`contribute
`that
`the
`several
`There
`are
`have
`discussed,
`As we
`an
`incorrectly.
`being
`MTD
`defini-
`used,
`and
`might
`be
`definition
`inappropriate
`the MTD
`could
`tions
`of
`among
`investigators.
`vary
`The
`definition
`of
`the MTD
`might
`extrapolated
`be
`from one
`population
`to another
`when
`there
`differ-
`are
`ences
`between
`the
`patient
`healthy
`populations.
`and
`
`that
`
`feel
`We
`determination
`accelerating
`is a multiple-dose
`the
`single
`and
`
`drug
`
`bridging
`of doses
`devel-
`study
`ascending
`Phase
`II effi-
`in the
`patient
`in
`the
`target
`of
`adverse
`expected
`im-
`are
`a work-
`
`of
`
`the
`issues
`establish
`
`These
`to
`
`have
`
`the
`than
`critical
`of
`
`is
`
`200%
`
`variability
`units,
`this
`
`of
`
`the
`the
`
`dreams
`single-dose
`adverse
`tachycardia.
`sinus
`(which
`ataxia
`of
`the
`effect
`Thus,
`event.
`varied
`the MTD
`at
`different
`a working
`
`in
`sites
`definition
`
`evaluated
`we
`population
`patient
`healthy
`the MTD
`in
`because
`underesti-
`dose
`in
`patients
`a
`certainly
`#{241}ecreases
`efficacy.
`A key
`concern
`definitions
`used
`of
`investigators,
`and
`problem
`is
`eptastig-
`a
`cholinesterase
`The
`dose-limiting
`study
`in
`young
`and
`difficulty
`study
`event
`the
`In
`demonstrates
`drug)
`was
`the
`adverse
`these
`studies,
`by
`different
`of
`
`in
`has
`
`by
`the
`
`in-
`
`in
`that
`pa-
`
`the
`
`the
`
`with
`
`for
`
`conditions
`mild
`headache
`However,
`healthy
`and
`when
`difficult
`the
`
`under
`persons,
`vomiting.
`these
`to
`correct
`factors
`
`set
`
`is
`
`of
`
`to
`
`SYMPOSIUM
`
`771
`
`ATI 1016-0006
`
`

`

`CUTLER
`
`ET
`
`AL
`
`2),
`of
`
`Tolerable Doses
`
`intolerable
`
`Doses
`
`Maximum
`(MTD)
`Dos
`
`Toi.rat.d
`
`Adverse
`Events
`
`I-
`
`0U
`
`i
`U-
`U-
`Ui
`
`Therapeutic
`Dose Range......
`
`I-
`C)
`Ui
`U-
`IL
`Ui
`
`Detectable
`
`Efficacy
`(Phase
`II Study)
`
`log DOSE
`
`Figure
`2.
`safety/tolerance
`defines
`top
`panel)
`to
`investigated
`
`The maximum
`study
`the
`in
`
`be
`
`determined
`dose,
`tolerated
`population
`(a
`the
`target
`in
`of
`the
`therapeutic
`upper
`limit
`a Phase
`H efficacy
`study
`(bottom
`
`a Phase
`study,
`range
`
`in
`bridging
`dose
`panel).
`
`I
`
`tested
`determine
`to measure
`to
`evaluate
`
`separated
`too widely
`be
`may
`there
`the MTD.
`Finally,
`studies
`in
`the MTD,
`as
`only
`the
`pharmacokinetics
`
`to ac-
`may
`be
`that
`
`doses
`The
`curately
`no
`attempt
`are
`designed
`of
`the
`compound.
`There
`are
`several
`with
`determining
`high,
`patients
`and
`the
`resulting
`even
`lead
`to
`development.
`are
`results
`to
`patients.
`is
`the MTD
`doses
`could
`tients
`in
`Phase
`of
`development
`emphasize
`of
`the MTD.
`The MTD
`
`that
`reasons
`If
`the MTD.
`be
`exposed
`intolerable
`discontinuation
`This
`problem
`from
`extrapolated
`Also,
`as Dr. Davis
`set
`low,
`placebo
`too
`be
`administered
`II
`efficacy
`on
`no-effect
`need
`to
`create
`
`could
`
`the
`
`concerned
`too
`is
`set
`doses,
`may
`
`the
`
`if
`
`are
`we
`the MTD
`to
`unsafe
`adverse
`events
`of
`the
`compound’s
`can
`occur
`when
`healthy
`individuals
`has
`pointed
`out,
`or
`subtherapeutic
`pa-
`of
`hundreds
`years
`wasting
`issues
`These
`definition
`
`to
`studies,
`studies.
`a working
`
`defines
`
`the
`
`upper
`
`limit
`
`of
`
`the
`
`dose
`
`range
`
`772
`
`#{149}J Clin Pharmacol
`
`1997;37:767-783
`
`the
`
`up
`
`the
`
`or
`a set
`dosage
`
`with
`also
`for
`results
`although
`
`develop
`the
`
`working
`selection
`example,
`trials
`
`in
`
`the
`
`a
`
`a
`
`if
`
`is
`it
`so
`(Figure
`the MTD
`nitions
`for
`Phase
`H efficacy
`of ENA
`velopment
`adequate
`an
`without
`11 study,
`402
`Phase
`of
`to
`receive
`placebo,
`the
`drug
`daily
`(which
`with
`study
`in
`patients
`dose
`vealed
`that
`6-mg
`the
`and
`ness,
`and
`headache,
`results
`efficacy.
`After
`the
`performed
`bridging
`study
`was
`in
`the
`patient
`population.
`that
`doses
`to
`12 mg/day
`patients
`AD.6
`A large
`with
`conducted
`approximately
`in
`efficacy
`a key
`psychometric
`on
`to
`detected
`the
`9 mg/day
`for
`may
`Thus,
`development
`time
`defined
`the
`true MTD
`had
`been
`efficacy
`tion
`prior
`to
`large
`scale
`Lack
`care
`in
`determining
`of
`design
`flaws,
`inconclusive
`unsafe
`doses.
`For
`these
`in
`defining
`optimal
`studies.
`through
`to measure
`trying
`are we
`What
`the
`helps
`that
`Do we
`have
`a definition
`MTD?
`are
`we
`points
`to
`understand
`the
`end
`gator
`the MTD
`From
`a conceptual
`standpoint,
`for?
`acceptable
`maximum
`dose
`having
`an
`the
`profile
`the
`target
`population,
`in
`event
`prospective
`criteria.
`indication
`in
`point
`adverse
`the
`establish
`that
`to
`level.
`Again,
`the
`push
`conditions.
`multiple-dose
`defined
`must
`be
`The
`MTD
`several
`There
`are
`population.
`example,
`study.
`For
`in the MTD
`fixed
`or
`titrated?
`Tolerability
`doses.
`titrated
`than
`fixed
`must
`tion
`considered
`be
`criteria
`the
`acceptable
`toxicology
`can
`criteria,
`they
`dictive.
`practice,
`In
`the minimum
`erance/efficacy
`the
`no-effect
`benefits
`are
`high,
`toxic
`edly
`outweigh
`one
`dose
`below
`
`For
`II
`
`essential
`to
`optimize
`studies.
`Phase
`713,
`determination
`patients
`were
`4 mg
`the
`was
`MTD
`AD).
`caused
`there
`of
`
`to
`
`The
`
`defi-
`of doses
`the
`de-
`initiated
`were
`the MTD.
`In
`of
`assigned
`randomly
`drug,
`or
`6 mg
`of
`in
`the
`outpatient
`re-
`The
`study
`data
`nausea,
`some
`dizzi-
`was
`a
`trend
`toward
`Phase
`II
`study,
`this
`determine
`the MTh
`to
`study
`bridging
`found
`were
`well-tolerated
`by
`III
`study
`was
`then
`Phase
`700
`patients.
`Significant
`measure
`for AD was
`12 mg/day
`dose
`range.
`have
`been
`reduced
`in the
`patient
`popula-
`trials.
`the MTD
`results,
`and
`reasons,
`the MTh
`dosage
`range
`for
`
`to
`
`lead
`can
`potentially
`is
`critical
`Phase
`11/HI
`
`use
`
`an
`
`of
`investi-
`looking
`defines
`adverse
`on
`should
`and
`to
`
`the
`
`based
`we
`profile
`applies
`
`Thus,
`event
`this
`
`the
`for
`variables
`is
`the
`be
`
`can
`The
`when
`
`patient
`target
`to consider
`dose
`scheme
`different
`with
`patient
`popula-
`establishing
`events.
`Animal
`guide
`for
`these
`always
`be
`pre-
`
`adverse
`provide
`may
`
`not
`
`a
`
`is
`
`determining
`by
`established
`the MTD
`a tol-
`Consider
`dose
`(MID).
`intolerated
`left
`is
`far
`(Figure
`3). To
`the
`spectrum
`or
`events
`dose,
`at which
`adverse
`no
`a very
`far
`observed.
`The
`represents
`right
`mark-
`dose,
`which
`events
`with
`adverse
`benefit.
`conceptually,
`Speaking
`toxic
`is
`the MID.
`Intolerable
`
`any
`this
`
`dose
`
`ATI 1016-0007
`
`

`

`DEFINING
`
`THE
`
`MAXIMUM
`
`TOLERATED
`
`DOSE
`
`LDOSO
`
`Dose
`
`Dose
`
`No Adverse
`
`Tolerated
`
`Intolerated
`
`[ts
`
`AEs
`
`AEs
`
`Dose
`
`T
`
`NOBeneficI&BOflOfldalAE,Effect
`
`AEs>>Effec
`
`MTD
`
`MID
`
`-
`
`Toxic Dose 1
`
`3. A representation
`Figure
`and minimum
`intolerated
`
`the
`of
`dose
`
`tolerated
`maximum
`(MID)
`in a dose-effect
`
`(MTD)
`dose
`spectrum.
`
`no
`
`strong
`we
`have
`the
`
`from
`to
`
`in
`
`can
`of
`
`any
`design
`serious
`is
`
`institutions
`an
`opera-
`disease
`the
`dose
`1)
`by
`objective
`or
`2)
`(defined
`occurs
`hypoten-
`
`is
`at
`
`the
`as
`in
`
`of
`
`dose
`
`Having
`guidance
`attempted
`literature,
`or
`a
`for
`MTD
`tional
`definition:
`which
`the MID,
`defined
`by
`reaching
`(defined
`events
`which
`limiting
`adverse
`((cid:18)50%),
`subjects
`criteria)
`occur
`in most
`event
`adverse
`dose
`at which
`a
`serious
`population)
`the
`medically
`unacceptable
`or
`severe
`seizure
`(e.g.,
`one
`or more
`subjects
`changes).
`cardiac
`sion
`with
`associated
`bridging
`by
`generated
`profiles
`The
`adverse
`event
`I studies
`construct
`to
`be
`used
`studies
`and
`Phase
`the
`dose-response
`models
`pharmacodynamic
`In
`studies
`of cholin-
`of compounds.
`a class
`for
`curve
`in AD,
`ergic
`compounds
`example,
`the
`number
`for
`dose,
`increases
`exponentially
`with
`adverse
`events
`is
`ap-
`of
`adverse
`events
`the MTD
`at
`the
`and
`number
`the
`no-
`to
`three
`times
`the
`number
`at
`two
`proximately
`have
`of
`the
`dose-response
`curve
`Models
`effect
`dose.
`for
`safety
`and
`escalation
`implications
`important
`studies.
`of MTD
`design
`in
`the
`a working
`that
`like
`to reiterate
`We would
`facilitating
`for
`is necessary
`the MTD
`of
`that
`ensuring
`for
`and
`among
`studies
`have
`defined
`We
`safe
`accurate.
`and
`indication,
`the
`ally,
`considering
`criteria.
`point
`end
`regimen