HSL l
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`Acta
`Psychiatri ca
`Scandinavica
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`EDI T OR
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`Povl Munk-J0rgensen
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`ASSOCIATE EDITORS
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`VOLUME 104 NO 3 SEPTEMBER 2001
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`Roxane Labs., Inc.
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`Page 001
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`
`Acta
`P sychia trica
`Scandinavica
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`Eo1r01c
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`Rl>l1'0tt's ADD REss:
`Department of Psychiatric Demography
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`AssOC'IAH Eot I'ORs:
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`E D I TO R lA I. SEC RETARY:
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`Acta
`P sychiatrica
`Scandinavica
`
`Editorial
`can lil11ium help to prevent suicide?
`R eview artir/es
`Lower suicide risk with long-tenn lithium tr~atment in major affectiVe
`illness: ~ meta-a nalysis
`CYP2D6 and CYP2CI9 genotype-based dose recomm~ndations for
`antidepressants: a first step towards subpopulation-specilic dosages
`
`Original article:>
`Lithium and suicidal behavior in major atlcctive disorder: a case control
`StUd}
`
`Suicidal behaviour and family f:tctors among Dutch and Slovenian high
`school students: a comparison
`The validity of pro~y-based data in suicide research: a study of patients
`50 years of age and older who atlemptec.l suicide. I. Psychiutric diagnoses
`Depression in relation to age and gender in tlte general population: the
`Nord-Trondelag Health Study (HUNT)
`Sociopsychiatric characteristtcs of adolescents who usc computers to
`excess
`Tekps)chiatry: assc~sment of tclcvideo p~ychiatric interview reliability
`with present- and next-generation internet infrastructures
`
`Dysfunction of transcallosally mediated motor inhibition and callosal
`morpholusy in patients with schizophrenia
`
`161
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`163
`
`17J
`
`193
`
`198
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`210
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`217
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`223
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`227
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`Case report
`Dose- response relationship of selecti\ e serotonin reuplllkc inhibitors
`treatment-emergent hypomania in depresstvc Jisorders
`Tnvited comm enr
`Biography
`
`236
`
`R. Ramtmtbbt•
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`23~
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`240
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`K. B. Sw~;e
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`P. Mtmi.-Jorgettsell
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`Abstracted or indexed in: Biological Abstraci;/ BIOSIS. ADOI\'lS.
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`MUNKSGAA RD . COPEN HAGEN
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`Exhibit 1019
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`

`
`C'up,~u'tsltt 4 Muuk.\l!.tuml l(J(JI
`. i tT4 PSlT'/1/A r ii.I CA
`SC. l N DINA 1'/Crl
`/S.\ N IJ{)(]f.6QIIA
`
`Review article
`cYP2D6 and CYP2C19 genotype-based
`dose recorr1mendations for antidepressants:
`a first step towards subpopulation-specific
`dosages
`
`Ktrchheiner J, Br0"sen K, Dahl ML Gram LF, Kasper S. Roots I.
`Siiiqvlst F, Spina E, Broc:kmoller J. CYP2D6 and CYP2CI9 genotype(cid:173)
`b;~:>ed dose re.;omm_endatmns for anttdepressants: a fi rst step towards
`~ubpopulation·spectfic dosages.
`,\da Psychiatr Scand 2001: 104: 173 192. ' ' Munksgaard 200 I.
`
`Objective: This review aimed to provide distinct dose recommendations
`lll r an!idepressants based on the genotypes of cytochrome P450 enzymes
`('YP2D6 and CYP2C I9. This approach may be a useful complemen(cid:173)
`lt~liou to clini~.:al monitoring and therapeutic drug monitoring.
`I \lcthod: Our literature search covered 32 antidepressants marketed in
`lliurope. Canada, and the United States. We evaluated studies which had
`
`eomp<~red pharmw.:okinetic parameters of antidepressants among poor,
`Intermediate. extensive and ultrarapid metabolizers.
`Results: For 14 antidepressants, distinct dose recommendations for
`, c~tensive, intermediate aJ1d poor metaboli7.ers of either CYP2D6 or
`CYP2CI9 were given . Foor the tricyclic antidepressants, close reductions
`around 50'Yo were generallly recommenJed for poor metabolizers of
`~ubstrates of CYP2D6 or CYP2C 19. whereas differences were smaller
`for the selective serotonin reuptake inhibitors.
`Conclusion: We have proovided prelimina ry average dose suggestions
`based on the phenotype or genotype. This is a first attempt to apply the
`new pharmacogenetics to suggest dose-regimens that take the di fferences
`in drug metabolic capacity into account.
`
`J. Kirchheiner1, K. Br.osen2
`
`,
`, S. Kasper4
`M. L Dahl3
`, L. F. Gram2
`,
`I. Roots1
`, F. Sjtiqvise . E. Spina5
`,
`J. Brockmtiller6
`'Institute of Clinical Pharmacology, Cha1ite. Humboldt
`University of Berlin, Berlin, Germany, 'Institute of
`Public Health, Climcal Pharmacology, OdensP.,
`Denmark. ~Department of Clinical Pharmacology,
`Karolinska Institute, Huddinge University Hospital.
`Huddinge, Sweden, ''Department of General
`Psychiatry, University of Vienna, Vienrta, Au~tna,
`51nstotute of Clinlcal Pharmacology. University of
`Messina, Messina. Italy and "Department of Clinical
`Pharmacology, GP.org·August·Universoty, Gtittingen.
`Germany
`
`Key words polymmphism; anttdepressanl therapy:
`pharmacogenetics; cytocltrome P-450. CYP2D6:
`CYP2CI9
`
`Prof Dr JOrgen Brockmiiller. Universitatsklinikum,
`Abteilung K/inische Pharmakologie. Roberi·Koch·Str
`40, 37075 Gfittingen, Germany
`E-mail: jbrockm@gwtly.de
`
`Accepted for puhlir.atmn 13 Ma1ch. 2001
`
`Introduction
`Genetic factors have long been known to cause
`mterindividual differenoes in pham1acokinetics,
`entcacy and adverse effects of antidepressant
`Jrugs (ADs) ( I, 2). Numerous studies have now
`been performed on the impact of genetic po ly(cid:173)
`ITJorphisms in cytochrome P450 enzymes (CYP)
`un
`the disposition olf antidepressant drugs.
`P~rticularly well cha racterized is the significant
`cftcc·t of the CYP2D6 and CYP2CJ9 polymorph-
`1'lllS on
`the pharmacokinetics of almost all
`lr1~Y~Iic and many other antidepressant~. The
`J~IIV,Jties of" these two en:zymes are both bimodally
`dtstnbuted in the Ca ucasian population. allowing
`•lassification of individuals into extensive (EM)
`
`and poor (PM) meta bolizers. The CYP2D6
`polymorphism was discovered in the 1970s as
`sparteine and debrisoquine oxidation polymorph(cid:173)
`isms (3, 4). The CYP2Cl9 polymorphism was
`initially identified as S-mephenytoin hydroxylation
`polymorphism (5). The frequency of CYP poly(cid:173)
`morphisms has now been investigated in different
`populations a nd the allele frequencies have been
`found
`to differ substantially. Consideration of
`interethnic differences is therefore necessary (6, 7).
`The effects of these polymorphisms on the
`clinical pharmacology of antidepressants have
`been reviewed previously (8- 12). Poor metaboli(cid:173)
`zers of C YP2D6 or CYP2C l9 substrates may be
`more likely to suffer from adverse drug effects
`than extensive metabolizers when laking nonnal
`
`173
`
`Roxane Labs., Inc.
`Exhibit 1019
`Page 004
`
`

`
`Kirchheiner el al.
`
`doses of drugs that <lre active per sc and are
`these pathways. The
`metabolized main ly via
`exten t of these potential problems largely depends
`on the relative contrihution of the respective CYP
`enzyme to the total elimination of the drug and
`the drug ( 11). The
`index of
`thera peutic
`the
`molecular genetic ba is of CYP polymorphi ms
`has been elucidated to an extent which allow a
`clinically useful prediction of a patient's drug
`metabolic phenotype (13 15). Such a genotyping
`before treatment has already earlier been postu(cid:173)
`lated as a useful tool to prevent adverse effects,
`especially for drugs with a relati vely narrow
`in forma t ion
`( 16. 17). This
`range
`therapeutic:
`in provision of average dose
`might be used
`recommendations for different genetic subpopula(cid:173)
`turn provide
`tions of patients. This may in
`therapeutic and pharmacoeconomic benefits ( 18,
`19). Genetic analyses of the metabolizer s tatus
`will become more common for clinicians in the
`it
`tha t
`the advantage
`future. Genotyping has
`needs to be performed only once in life for each
`patient and the costs of this analysis are tower
`I day of stay in hospital. With current
`than
`technology, such genotype analyses may be
`performed within a few hours. Analogous to the
`routinely used dose adjustment tables for the
`dosage of digox in or aminoglycosides in patients
`to do e
`with kidney disease, or analogous
`the specific age
`for
`tables used
`adjustment
`groups in paediatrics. specific recommendations
`will be required about how to adjust the drug
`dosages to an intlividual's specific drug metabolic
`phenotype. For CYP206, the overall sensitivity of
`genotyping tests to predict the phenotypical poor
`metabolizer is more than 99% when testing for the
`common inactive alleles (*3. *4. *5. *6, *7, *8,
`* 16) in the Caucasian population ( 15, 18. 20).
`intermediate
`Molecular genetic prediction of
`metabolizers (I M) was less accurate considering
`the allele variants given above. but precisio n of
`intermediate metabolizers
`identification of
`the
`may be improved consideriJlg CYP2D6 allele *2
`variants (2 1 ). For CYP2C l9, genotyping is able to
`identify bet ween 93 and I OOtV,, of the phenotypic
`poor metabolizers ( 13. 22- 26).
`The goal of this review was to derive anti(cid:173)
`depressant dose recommendations based on drug
`metabolic phcno- or genotype and. if such data
`for
`identify priorities
`to
`were not available.
`:.tudie:.
`further clinical studies. Since efficacy
`have not been performed for each genotype, we
`have assu med that equa l plasma concentrations
`imply equal drug effects.
`Dose adjustments based on the genotype or the
`polymorphic drug metabolizing enzymes are
`
`174
`
`complicated by the existence of active mt:tabolitc~
`therefore
`turn arc metabolized. We
`in
`that
`provide references to several reviewers who huve
`studied the role of active metabolites for the
`overall antidepressa nt effects (17- 29). The elim.
`ination of antidepressants may be profoundll
`influenced by metabolic drug interactions. Severjl
`reviews focus on the inhibitory properties on
`drug metabolism of antidepressants. and e~pc­
`cially elaborate on the prediction of mctabohc
`drug interactions and the possibilities to avoid
`them (28, 27 38).
`To adjust optimally fo1· drug interactions and
`other factors such as compliance, age or liver
`function impairment , close clinical monitoring ol
`the patients and therapeutic drug monitoring are th~
`essential tools in dose optimization (39. 40). General
`problems in dose finding for antidepressant drug~
`have been discu ed previously (41). There is little
`convincing evidence that different types of depre,.
`sion require different doses but in other condition>.
`such as pain, enuresis, anxiety, etc. the dol>~!
`req uirements may be different compared to tlepre,.
`sion (42). For the tril:ydi,c antidepressants, earb
`experiences with severe tolerability problems apJ)Uill
`to have determined the rather cautious dosing polic)
`often employed. Concentration efTect studie'
`revealed clear-cut relationships for some tric~clic
`antidepressants (imipramine, nortriptyline) wluc:h
`became the ba is for recommended therapeutic dru~
`monitoring procedures (43, 44). However, in general
`there appears to be no simple relationship bet"een
`dosage, plasma concentration and clinical outcome
`of antidepressants as a whole. The newer antide(cid:173)
`pressants. especially the selective serotonin reupw~c
`inhibitors (SSRls) such as fluoxetine revealed Oal
`and overlapping dose- effect curves for the mllt
`depressant and adver e effects (45). Unfortunatcl)(cid:173)
`these dose- effect studies contain little infonn;Jll011
`on the underlying pharmacokinetic and phannaCl ...
`genetic variability which may explain interpatJetl!
`response variability on a given dose. i\ssessmenl'11
`the genetically determined variability in drug con·
`centration may indeed contribute to impro1 ~ 111'
`therapeutic effect and reduce the risk of dropollb
`due to tolerability problems.
`
`Methods of data analysis
`Definitions and study tnclusiOn cntena
`nt•
`We considered all studies on .:~utidepr~''j1
`.,t
`except those on lithium, antipsychotics 11~1e1 rtll
`'ewct <1
`W
`·
`··lilt)
`e rev-t
`epress1on and on herbal drugs.
`d
`.tl er ht•l
`.
`I
`d
`:1'
`·rn tl''
`e1 1
`stuatc$ con uctec
`tn humans,
`volunteers or patients. in which th~ ph11
`,,
`'
`'
`kinetic and/or pharmacodynamic puramelct·~
`
`Roxane Labs., Inc.
`Exhibit 1019
`Page 005
`
`

`
`~~~~ucip!ltmn ot CYP206 and CYP2C 19 in the blOtraJJsformatton of
`1
`ts· qualitative data baseli on studies on humans
`~"~san· ·
`___-
`
`Reference
`
`CYP2C19
`
`CYP206
`
`illlOIOB
`
`T.lmme
`
`rboxazode
`Ill amine
`' ijfiline
`
`yes
`
`yes
`
`yes
`
`yes
`yes
`yes
`yes
`yes
`
`no
`
`no
`
`ye~
`
`yes
`yes
`yes
`ves
`yes
`
`00
`no
`
`yes
`yes
`yes
`
`yes
`yes
`yes
`yes
`yes
`yes
`yes
`yes
`yes
`yes
`yes
`yes
`
`yes
`yes
`yes
`yes
`yes
`yes
`yes
`yes
`yes
`
`no
`yes
`
`yes
`yes
`yes
`
`110
`no
`no
`
`no
`yes
`yes
`ye~
`yes
`yes
`yes
`
`No data
`(50)
`(511
`{521
`{53)
`{541
`{52)
`No data
`{55)
`(56)
`(56)
`(57)
`{58)
`{5g)
`{58)
`[60)
`161)
`162)
`163)
`164)
`165)
`1661
`167)
`1681
`169)
`170)
`(71)
`No data
`No dat~
`{72)
`{73)
`174)
`175)
`176)
`(61)
`(62)
`(77)
`t68)
`{77)
`lBO)
`IBl)
`178)
`1821
`No data
`No data
`No data
`(83)
`lf1.41
`1831
`185)
`1481
`1861
`1851
`187)
`1881
`189)
`190)
`1911
`1921
`(93)
`194)
`(95)
`149)
`(96)
`
`I~
`
`CYP206 and -2C19-based dose rocommendations
`
`Table 1 (Contmued)
`
`Phenelzme
`Protriptyline
`Reboxeune
`Sertraline
`Tianepline
`Tranytcypromme
`Trazodone
`Tnmipramone
`
`Venlafaxllle
`
`Viloxazone
`
`IIY
`lltl
`nn
`
`no
`yes
`
`yes
`yes
`yes
`
`Nu data
`No} data
`197)
`1721
`(98)
`No data
`(99)
`(100)
`(101)
`(47)
`(1021
`(1031
`no data
`
`Yer;. effect of CYP2C19 or CYP206 shown
`No: no effect ot CYP2C19 or CYP206,
`
`antidepressants were measured, and where the
`polymorphic traits of CYP2C 19 and CYP2D6
`were determjned. Data from current Medline and
`Embase databases were used. We searched for any
`word combinatio n of antidepressant* or antide(cid:173)
`pressive* with polymorph*, CYP*, cytochrome*,
`P450*, debrisoqu*,
`sparteine*, dextromelhor(cid:173)
`phan* and mephenytoin* and the same search
`was ca rried out for all generic names of the
`specific antidepressants marketed in Japan, the
`United States and major European countries.
`Furthermore, manufacturers of all a ntidepressants
`included in this study were asked to provide
`unpublished data.
`The CYP polymorphisms can be distinguished
`either by genotyping or by phenotyping methods.
`Tn studies usmg genotyping methods, subjects
`with three or more active alleles, i.e. carriers of
`CYP2D6 gene duplications (46) were classified as
`ultrarapid metabolizers (UM). Subjects with two
`active a lleles (* 1. *2, *9. *10 and * 17) were
`classified as extensive metabolizers, heterozygous
`carriers of one active and one deficient a llele, thus
`carriers of one of the a lleles * I, *2. *9, *JO, * 17
`or other more rare active alleles combined with
`one of the a lleles *3, *4, *5. *6, *7, *8 or other
`more rare completely deficient alleles were termed
`intermediate metabolizers (IM)
`in
`the present
`review, because the subpopulation-specific clear(cid:173)
`ance of this group is between extensive and poor
`metabo]jzers. Subjects with two inactive alleles
`(*3, *4, *5, *6. *7. *8) were classified as PM. As
`an exception to this classification, in three studies
`from Asiatic populations
`(47-49) earners of
`two intermediately active alleles *9 and * 10 of
`CYP2D6 were classified as !Ms. R ecent studies
`may even allow to distinguish the intermediate
`metabolizer group into further subgroups based
`on subtypes of allele *2 (21 ), but no data existed
`with respect to a ntidepressants. Much of the data
`on intermediate metabolizers in this review were
`
`175
`
`Roxane Labs., Inc.
`Exhibit 1019
`Page 006
`
`

`
`Kirchheincr et al.
`
`Table 2- Classification of antldepressar11 dwg metabolites
`
`Substance
`
`Principle metabolites •
`
`Fwther acllve metabolites
`
`Nortriptyline
`
`N -desmethyl-r.lt~miptamine
`
`1 0-hydroxy-arnitr ipty1ine. 1 0-hydroxy-nmu ipl)lline
`1!-butythydroxy-bupropion. Threohydro·bupropion
`N·desmethyl-citalopram, N·didesmetllyl-c•talopram
`B-hydro~y-clomipramine
`2-hydroxy-desipramine
`N·desmethyl-doxepin
`
`2 -hydroxy· 11r11prarn~ne
`N-desmethyl·maprotilllle, 2, 3-hydroxy-marrotlllne
`8-hydroxy-mianserin
`N·desmethyl·mirtazapine
`Ro-5637
`2·hydroxv·nelazodone. P-hydro~y-nefazodone, Triazole dione,
`M·chlorophenyl-plperozine tmCPPI
`1 O·hvdro~v·nortriptyline
`
`lnactiVP. merabolltes
`
`N-dP.srnethyl nortllptyline
`Erythrnillydro-llupropion
`Citalopram N-o~rde
`
`N-desmethvl·lluvoxamrne
`
`Mianserin N-oxide
`B·hydroxv·mirtazapute
`Ro-12-8095
`
`Oxidized and phase-It intermediates
`
`1\nlltllptylina
`Bupropron
`tR.S)-Cita1opram
`Clomipramine
`Desrpramlne
`IU~Ooxepin
`IR.S)-Fiuoxetine
`Fluvoxamrne
`hnr~ran11ne
`Mattrotiline
`(R.S~Mranserin
`(R.S)-Mirtazapine
`Moclobemide
`Nela1odone
`
`Norlluoxetine
`
`Des•pramlne
`
`N·dP.smethvl·mianserin
`
`Nortriptyline
`Oxaprotiline
`Paroxetine
`Phenelzine
`Prot11ptyline
`Reboxetine
`Sertraline
`Tianept111e
`T ranylcyprom•ne
`Trazodone
`Troniipramine
`(R,S}-Venlataxine O·desmethyl-ventafaxine
`
`N-desmethyl·sertral•ne
`
`EthOXy-phenoxy·hydroxy-reboxetrne, D-desethyl-rebo1e\l
`N·livdroxy-sertrallne
`
`m·CPP
`N-desmethyl·trimrpramrne. 2-hydroxy trlmtpramrne
`
`Chlurophenyl-hydroxv·TRA
`
`N·deslnethyl-venlafaxine. N·,O·drdesmethyl·venlafa>•flf
`
`mainly on experimental data on receptor ,,,
`transporter binding.
`In some cases. such a'
`different
`described
`below
`for
`nortriptyline,
`approaches gave Incongruent results. Besides thei1
`intrinsic potency, the clinical effects of metabolite'
`depend on their vol ume of distribution and rate ol
`d iffusion into the central nervous systern (CNSJ
`The lipid solubility of most metabolites is decreaMJtl
`compared to the parent drug which may result i~ a
`smaller volume of distribution and a reduced ubthll
`to pass the blood- brain barrier.
`
`Handling of pharmacokinetlc data
`We have based the dose recommendations oJT
`pharmacokinetic parameters which are gencr:tlll
`linear and thus proportional to dose such as ar(a
`under the curve (AUC). total cleantnce (CI) Hn•!
`(Css ) because
`steady-state
`trough
`levels
`tilt'
`~ . ~
`'
`~
`method of dose adjustment may be sutnc1er• ·
`accurate in most cases. For druus with non-line<ll
`pharmacokinetics. such as clomfr>ramine, degi~r:r·
`.
`.
`.
`.
`I b
`'d
`. ·pranJIII~
`mtne,
`tmtpntmtne. moe o emr e,
`tn tllt
`•
`paroxetine, Auvoxamine and possib ly O~toxetlll~
`the genotype-based dose adjustments ure tn theO
`11
`studl~l
`17
`. 1
`. r,
`"
`.
`,,1
`tn
`s pecwc
`.o r
`the doses
`tested
`Furthermore. because the relative t.:ontnbutto~ 111
`s pecific cytochrome P450 enzymes m<•Y depen.
`,
`1
`the substrate concen tration, the recomlnendillll ·
`
`11 1
`
`• Princtple metabolites· activtty comparable to that ot the parent drug
`
`intermediate
`based on phenotypically identified
`sparteine or
`metabolizers with debrisoquine,
`dextrometho rphan for C YP2D6 or the mepheny(cid:173)
`toin test for CYP2C l 9. We a lso
`included one
`study usi ng quinidine as an inhibitor of CYP2D 6
`to mimic the poor metabolizer status.
`
`Consideration of active metabolites for genotype-based
`dose-recommendations
`Antidepressants undergo multiple biotransforma(cid:173)
`tions in the liver. producing progressively more
`polar metabolites which can be eliminated more
`the kidneys. Jf the
`readily by
`the
`liver or
`antidepressant activity of a metabolite is compar(cid:173)
`able to that of the parent drug (usually demon(cid:173)
`strated only in vitro) and if the metabolite exists in
`considerable concentrations in plasma. it was
`considered as a principle metabolite (27). Such
`metabolites were taken into account in the dose
`recommendations by adding their plasma concen(cid:173)
`trations to those of the parent drug. We did not
`consider active metabolites wh ich are formed in
`minor quantities, have short half-lives, or are
`subs tantially
`less active than
`the parent drug
`(Table 1 ). Our classification is not com plete, but
`includes the relevant metabolites which have been
`studied clinically in this context. T hese classifica(cid:173)
`tions are of a preliminary nature. as they are based
`
`176
`
`Roxane Labs., Inc.
`Exhibit 1019
`Page 007
`
`

`
`fllliCOkrnetrc p~rameters conr.ernrng CYP2D6
`J Pflar
`;_--
`
`Par am.
`
`UM
`
`EM
`
`Ill! II! -----
`
`ll)IYIII(I!
`
`, cMI
`, CMI
`"'""'e
`
`~t:tlflt!
`
`Nor.fXT
`, Nor·FXT
`ru1.1morre
`
`1111mrne
`
`-DMI
`llol~olollne
`
`Maorserin
`
`./,l.d~senn
`
`RIMianserin
`~MtO·MIA
`SlMIA+D·MIA
`1 n111aplne
`kobemlde
`
`'O'tliOdone
`
`mriptvlme
`
`rn•e110e
`
`:mehne
`ilOdone
`vramrne
`
`·rotax•~e
`
`AUC
`AUC
`Css
`AUG
`Css
`AlJC
`Css
`AlJC
`Css
`Css
`AUC
`Css
`AUG
`AUG
`AUG
`Css
`Css
`AlJG
`AUG
`AUG
`AUG
`AUG
`AlJC
`AUG
`AlJC
`AlJC
`Css
`Css
`AUG
`Css
`Css
`Css
`Css
`AUG
`Css
`AUC
`AUC
`Css
`AUC
`AUG
`AUC
`AUC
`Gss
`AUC
`AUG
`AUG
`AUC
`AUC
`AUC
`Css
`AUC
`Css
`AUC
`AUC
`AUC
`
`10
`
`0.18
`
`0,23
`
`08
`
`19
`1 7
`1154
`3.7
`0.13
`46
`020
`32
`0.69
`0.63
`LO
`021
`15
`1.0
`3.8
`0.30
`118
`5.3
`1.6
`25.8
`6.8
`100
`1.4
`2.5
`2.3
`2.3
`0 38
`0 42
`83
`0.09
`0.03
`0.16
`0.05
`0.56
`028
`0 64
`LO
`86
`110 1
`2.6
`13.6
`18
`0.39
`1.3
`22
`1 7
`0,55
`2,6
`1.4
`1.5
`12
`39
`12
`07
`64
`
`CYP206 and -2C l9-based dose recommendations
`
`PM
`
`Dose lmg)
`
`MfS
`
`Nromber tEMfiMfPM)
`
`Reference
`
`4 1
`3.0
`1 3
`5.6
`0 15
`4.7
`0.57
`5.7
`2 1
`1.25
`
`1.4
`66
`8.0
`33.0
`0.90
`
`38.5
`6.1
`536
`8.6
`1.3
`5.3
`2.1
`4.4
`43
`18
`04
`29 0
`0.05
`
`0.24
`
`0.94
`044
`11
`1.9
`65
`84.1
`2.5
`15.9
`3.9
`0.96
`4.3
`
`4.2
`3.9
`44
`1 5
`
`3.6
`41
`
`2,9
`476
`
`50
`50
`150
`75
`300
`40
`150
`100
`150
`125
`100
`100
`25
`25
`100
`100
`100
`60
`20
`60
`20
`50
`50
`(00
`100
`100
`100
`150
`100
`67
`30
`67
`30
`30
`67
`30
`15
`450
`600
`200
`400
`28.5
`150
`25
`25
`285
`30
`30
`50
`150
`75
`300
`31
`19
`225
`
`s
`s
`M
`s
`M
`M
`M
`s
`M
`M
`s
`M
`s
`s
`s
`M
`M
`s
`s
`s
`s
`s
`s
`M
`s
`s
`M
`M
`M
`M
`M
`M
`M
`s
`M
`s
`s
`M
`M
`s
`M
`s
`M
`s
`s
`s
`s
`M
`s
`M
`s
`M
`s
`M
`M
`
`5/3/3
`2/4(3
`11/0/4
`4/0/3
`4/0(3
`10/0/8
`35/0/1
`15/0/10
`35/0/1
`15/0/5
`5/6/0/0
`28(0/2
`8/0/6
`5(0/4
`6/6/6
`29/0/2
`4/5/0
`6/ll/6
`9/0/10
`6/0/6
`9/0/10
`10/0/5
`10/0/4
`8/0/2
`6/6/6
`6/5/5
`28/0/2
`75/0/5
`6/0/6
`21/711
`14/1/0
`2ln/1
`14/1/0
`10/0/5
`21fl/l
`10/0/5
`7/0/7
`22/0/5
`2/0(2
`10(0/10
`10/0/10
`2/3/2
`7/13/1
`6/5/5/5
`10/5/0
`2/4/2
`9/0/8
`9/018
`10/0/10
`46/8/0
`1/0/1
`25/0/1
`8/4/0
`8/0/6
`22/6/3
`
`(531'
`(51)'
`(521'
`(50)'
`(55)"
`(56)
`(57)
`(58)
`157)
`(59)
`(70)
`162)'
`(63)
`(64)
`(61)
`(69)'
`(71)'
`(73)'
`(721
`(73)'
`(72)
`(75)
`(74)
`(76)
`(61)
`(77)'
`(62)
`(83)
`(841
`(861
`(48\'
`(86)
`(48)'
`(85)
`1861
`185)
`(871
`188)
`(891'
`1911
`(91)
`(107)'
`(94)
`(95)'
`(49)'
`(92)'
`(96)
`(961
`(721
`(99)'
`(1001'
`(101)
`(47)'
`(102)
`(103)
`
`IM
`
`28
`28
`
`61
`
`530
`
`26
`2.5
`
`0.08
`om
`0.2
`0.14
`
`0 36
`
`3.1
`0.5
`3.6
`4,0
`30
`
`18
`
`4.6
`
`113
`
`"'COlumn Param · refers to the measured pharmacokinetic parameter. either the area under the curve (AUCI 1n )tM.h or the steady-stare trough conr.emration (Css) rn ~M
`values for ultra-raprd metabohzers (UM), extensrve metabolizers IEM). onlermedrate metabohzers liM I and poor metabolizers (PMI are goven in the respective columns
`' l;llfumn 'dose' refers to the dose tested in the respectrve studres.
`No•-FXT sum of Huoxetine and nortluoxetine: + D-MIA· sum of mianserin and desmethylmianserin: t D-CML sum of clom1pramme and desrnethylclornipranune: 1 NT: sum
`4111itrrp!VIIne and nortnp!VIine,
`COlumn MIS refers to the fact whether lire parameters were denved from multr~le·dose (MI or srngle·dose lSI studies
`l~na recalculatrorr, e.g data calculation from values presenred in figures
`
`177
`
`Roxane Labs., Inc.
`Exhibit 1019
`Page 008
`
`

`
`I .. .. . .
`I
`1
`
`Kirchhe incr c t a l.
`
`may not be valid far outside the dose range or the
`reviewed studies (104).
`Studies which provided only the ratios between
`the concentrations of the parent drug and its
`metabolite and not the actual plasma concentration
`data could not serve for quantitative dose adjust(cid:173)
`ments. Since such metabolic ratios provide informa(cid:173)
`tion about the cytochrome enzymes in' olved in the
`metabolism. we have included them in the qualita(cid:173)
`tive Table 2.
`recorded covariables such as
`Although we
`gender. age. ethnicity. dose level and tobacco
`smoking. the limited availability of such data
`made it impossible to consider these variables
`systematically in the dose recommendations.
`When the differences in pharmacokinetic data
`between PMs and EMs, or IMs and EMs. were
`statistically significant, dose recommendations were
`deduced by calculating the ratios of AUC or Cs
`between PMs and EMs and. if available, between
`IMs and EMs. lf severul studies were available for
`one drug, we summarized the AUCs or Css by
`calculating the weighted mean from the various
`studies. T his was the case for clomipramine (57. 59.
`104), desipramine studies with single-dose drug
`application (61 , 64. 105) and multiple-dosing (62.
`69). nuoxetine (studies providing data on F LU and
`NOR-FLU) (71. 73). fluvoxam ine (72 75), imipra(cid:173)
`mine concerning CYP2D6 (61. 77) and CYP2Cl9
`(82. 106). nortriptyline for !;ingle-dose drug applica(cid:173)
`tion (49, 92. 95, 107) an d venlafaxine ( 102, 103).
`Studies including only one poor metabolizer were
`also included. but dose recommendations must be
`considered with caution if these da ta are the only
`available fo r a particular substance.
`tudies from those
`We distinguished single-dose
`where steady-state plasma levels of a drug were
`achieveu. Dose rccommendutions were calculated
`the beginning of the treatment
`separately for
`(re~u lts of single-dose studie ) and ror multiple(cid:173)
`dose treatment (mainly but not alw:Jys at steady
`state). If data were not given in the texb or tables.
`but were possible to derive from table · or figures. or
`