6%
`
`Molecular Psychiatry (2004) 9, 442-473
`© 2004 Nature Publishing Group All rights reserved 1359-4184/04 $25.00
`www_nature_com/mp
`
`FEATURE REVIEW
`
`Pharmacogenetics of antidepressants and antipsychotics:
`the contribution of allelic variations to the phenotype of
`drug response
`
`J Kirchheiner‘, K Nickchen‘, M Bauer2, M—L Wong‘, J Licinio3,
`
`I Roots‘ and J Brockm'c'>||er4
`
`‘Institute of Clinical Pharmacology, Campus Charité Mitte, University Medicine Berlin, Berlin, Germany; 2Department of
`Psychiatry and Psychotherapy, Campus Charité Mitte, University Medicine Berlin, Berlin, Germany; 3Center for
`Pharmacogenomics and Interdepartmental Clinical Pharmacology Center, Neuropsychiatric Institute, David Geffen
`School of Medicine at UCLA, Los Angeles, CA, USA; 4Department of Clinical Pharmacology, Georg August University,
`Gdttingen, Germany
`
`Genetic factors contribute to the phenotype of drug response. We systematically analyzed all
`available pharmacogenetic data from Medline databases (1970-2003) on the impact that
`genetic polymorphisms have on positive and adverse reactions to antidepressants and
`antipsychotics. Additionally, dose adjustments that would compensate for genetically caused
`differences in blood concentrations were calculated. To study pharmacokinetic effects, data
`for 36 antidepressants were screened. We found that for 20 of those, data on polymorphic
`CYPZD6 or CYP2C19 were found and that in 14 drugs such genetic variation would require at
`least doubling of the close in extensive metabolizers in comparison to poor metabolizers. Data
`for 38 antipsychotics were examined: for 13 of those CYP2D6 and CYP2C19 genotype was of
`relevance. To study the effects of genetic variability on pharmacodynamic pathways, we
`reviewed 80 clinical studies on polymorphisms in candidate genes, but those did not for the
`most part reveal significant associations between neurotransmitter receptor and transporter
`genotypes and therapy response or adverse drug reactions. In addition associations found in
`one study could not be replicated in other studies. For this reason, it is not yet possible to
`translate pharmacogenetic parameters fully into therapeutic recommendations. At present,
`an
`outcome of complex systems that interact at multiple levels. In spite of these limitations,
`combinations of polymorphisms in pharmacokinetic and pharmacodynamic pathways of
`relevance might contribute to identify genotypes associated with best and worst responders
`and they may also identify susceptibility to adverse drug reactions.
`Molecular Psychiatry (2004) 9, 442-473. doi:10.1038/sj.mp.4001494
`Published online 23 March 2004
`
`Keywords: pharmacogenetics; pharmacogenomics; antidepressant; dose recommendation;
`antipsychotic; cytochrome P450
`
`The need for predictive pharmacogenetics-based
`therapeutic recommendations
`
`Major depressive disorder, schizophrenia, and related
`disorders are among the most important causes of
`death and disability worldwide? These disorders are
`highly prevalent, chronic or recurrent conditions with
`a substantial impact on public health. Antidepressant
`drugs are the standard of care for clinical depression;
`likewise, antipsychotics are the standard treatment for
`schizophrenia. Despite the availability of a wide range
`of different drug classes. about 30-50% of patients
`will not respond sufficiently to acute treatment.
`regardless of the initial choice of standard psychiatric
`
`I Kirchheiner, Department of Psychiatry,
`Correspondence: Dr
`University of Bonn, Sigmund—Freud—Strasse 25, 53105 Bonn,
`Germany. E-mail: julia.l<irchhoinor@gmx.do
` M
`February 2004
`
`medication? 5 For example, in randomized controlled
`trials in major depressive disorder, after 6-8 weeks,
`only 35-45% of the patients treated with standard
`doses of the most commonly prescribed antidepres-
`sants return to premorbid levels of functioning with-
`out any significant depressive symptoms.“ There is
`consequently a considerable need to increase efforts
`i11 maximizing clinical outcomes i11 major psychiatric
`ef genetic facters under-
`lying drug response is among the most promising
`areas of research in molecular medicine.
`
`Large genetic variability has been described in drug
`metabolism, in drug effects, and genetic modulators
`of the response to drug treatment. However, it is not
`yet possible to use genetic tools to identify an
`individual’s likelihood of responding to a treatment
`and thereby to individualize drug therapy by choos-
`ing the best medication and dosage. While faster and
`more effective methods for genetic testing are being
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`developed, the co11cept of for111ally using pl1ar111aco-
`ge11etics
`to guide therapy ca11
`o11ly be cli11ical
`applicable when there is reliable ability to predict
`cliniealeutce1nes.Bleedtypingferth(+A,B,OJ_,ystem
`may serve as an analogy of how specific therapeutic
`products are administered after being specifically
`guided by a laboratory genetic test. Similarly, specific
`clinical guidelines in psychopharmacology have to be
`developed to clarify in which situations and with
`which consequences the results of individual phar-
`macogenetic tests may be applicable for therapy.
`This review covers methods for data extraction
`
`from pharmacogenetic studies and for aggregating
`such information into concise and usable therapeutic
`recommendations. This concept is nearly established
`with respect to polymorphisms in pharmacokinetic
`pathways, but use of genetic testing of neurotrans-
`mitter transporter and receptor variants for therapeu-
`tic decisions,
`is still incipient. Rapid advances in
`molecular analytical tools will soon allow very rapid
`and inexpensive genotyping; however, pharmacoge-
`netics will only be used as a diagnostic tool in clinical
` mfl
`guidelines based on genetic testing can be provided.
`
`Methods of pharmacogenetics data extraction and
`dose calculation
`
`Literature research
`
`Data on antidepressant and antipsychotic genotype-
`dependent pharmacokinetics published in Medline and
`Embase databases were searched using word combina-
`tions of ‘cytochrome’, ‘debrisoquine’, ‘sparteine’, ‘dex-
`tromethorphan’, ‘mephenytoin’, ‘polymorph*’,
`‘meta-
`bolizer’, ‘ultrarapid’, ‘antidepressant’, ‘antipsychotic’ in
`combination with 36 generic names of commonly used
`antidepressants and 38 antipsychotics. Data on ther-
`apeutic response and adverse drug reactions of anti-
`depressants and antipsychotics in relation to genetic
`parameters were retrieved from current Medline using
`search combinations ‘antidepressant’, ‘polymorphism’,
`‘antipsychotic’, ‘genetic’, ‘response’, ‘tardive dysk1ne-
`sia’, and ‘adverse drug reactions’. Studies on inherited
`susceptibility factors for depression and schizophrenia
`were not included, because the focus of this work was
`on the phenotype of drug response, not on the
`elucidation of the genetic basis of disease susceptibility.
`Data were classified according to gene polymorphisms
`studied,
`sample size,
`time interval
`for
`response
`measurement, clinical outcome parameters, and surro-
` , decuinenta-
`tion of adverse drug reactions).
`“lith respect to pharmacokinetically relevant poly-
`morphisms, only data from human studies with
`healthy volunteers or patients were included. Data
`on the in Vitro biotransformation of antidepressants
`and antipsychotics have been reviewed elsewhere."’12
`Studies were restricted to those providing data on
`effects
`of genetic
`polymorphisms
`in CYPZD6,
`CYP2C19, or CYP2C9. The functional impact of other
`polymorphisms in drug-metabolizing enzymes includ-
`
`J Kirchheiner et al
`Therapeutic implications from pharmacogenetics
`
`i11g CYP1A2, CYPZA6, CYPZB6, CYP3A4, -5, a11d -7 or
`phase-II e11zy111es i11 psycl1opl1ar1nacology was co11-
`sidered to be either too moderate or controversial.
`
`m@
`
`443
`
`lyzes biotransformation of clozapine, olanzapine, and
`some other antipsychotics;‘” however,
`it
`remains
`questionable how much of the interindividual varia-
`bility in CYP1A2 activity is explained by genetic
`polymorphisms.13’15 Some data exist on higher drug
`concentrations and higher risks for tardive dyskinesia
`in schizophrenic patients who are smokers and carriers
`of CYP1A2 genotypes with reduced inducibility (C/A
`polymorphism at position 734 in intron 1 and G/A
`polymorphism at position -2964 in the 5’-flanking
`region of CYP1A2), but those results have not been
`fully replicated.“5’“’ Polymorphisms in CYPZB6 might
`be relevant for the antidepressant bupropion, but the
`differences due to genotype are small.” Polymorph-
`isms in the CYP3A enzyme family were not consid-
`ered, since CYP3A4 genetic variants have little effects
`on function or are rare in most populations.” Whether
`or not the polymorphisms in CYP3A5 and CYP3A7
`play a nredically
`expression levels are low and a psychotropic drug
`selectively metabolized by either CYP3A5 or CYP3A7,
`but not by CYP3A4, still remains to be identified.“
`Studies using CYP inhibiting substances such as
`quinidine to mimic poor metabolizer status were not
`included. Studies were classified based on whether
`
`they were conducted in patients or healthy volun-
`teers, single or multiple dosage, existence of data on
`am
`size, and available pharmacokinetic parameters. For
`dose adjustments, dose-related pharmacokinetic para-
`meters such as trough concentrations at steady state
`(Ctss), area under the concentration—time curve (AUC),
`or
`total drug clearance (Cl) were used. Data on
`metabolic ratios (MR) in urine or plasma could not
`be used since these parameters are not
`linearly
`correlated with dose.
`
`As many psychotropic drugs are metabolized to
`equally active metabolites,
`some studies provide
`data on both metabolite and parent drug, and thus the
`whole active moiety was taken into consideration. In
`Tables 2 and 3, data of all studies are shown and the
`substances measured in the respective studies are
`indicated. In Figures 2-4, dose adjustments calcu-
`lated as the weighted mean from the single studies
`were depicted for each substance and data of the
`active moiety were taken if available.
`
`Metabolic polymorphisms
`
`Classification of metabolizer groups The homo-
`zygous
`carriers
`of
`two CYPZD6 genes
`coding
`for
`functional
`enzymes
`are
`termed
`extensive
`metabolizers (EM; genotypes: *1/*1, *1/*2, *2/*2)
`and carriers of one duplication allele (*2 X 2 or *1 X 2)
`plus one deficient allele (eg *3, *4; *5, *6) were also
`classified as extensive metabolizers. Heterozygous
`carriers of only one active allele were termed
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`be regarded as
`
`Dav = 0.1Dp1V[+ 0.4D1M + 0.5DEM
`
`(1)
`
`where DEM, DIM and DEM represent the optimal dose
`for the groups of poor metabolizers,
`intermediate
`metabolizers,
`and
`extensive metabolizers. The
`empirically gained average dose (Dav) can be set as
`100%. Then,
`percentages
`of dose
`adaptations
`(reductions or elevations)
`for each genotype are
`obtained. The genotype-specific dose differences can
`be expressed by pharmacokinetic parameters from the
`patient
`or volunteer pharmacokinetic/pharmaco-
`genetic studies analyzed here (Tables 1 and 2):
`
`and
`
`DPM/DEM = C1PM/CIEM
`
`DIM/DEM = C11M/C1EM
`
`(2)
`
`(3)
`
`Then, Equations (2) and (3) can be substituted into
`(1):
`
`DEM(%) =100/(0.1C1pM /c1EM + o.4c11M/c1EM
`
`+ 0.5)
`
`When DEM is obtained, DPM and DIM can be calculated
`from (2)
`and (3).
`If no data on intermediate
`metabolizer are available,
`linear gene—dose effects
`were
`assumed and CIIM was estimated as 0.5
`(CIPM + CIE-M).
`For CYPZD6, gene duplications lead to the so-called
`ultrarapid metabolizer type (UM). Only few studies
`were found concerning UMs and these were mostly
`single case reports. We usually assumed a linear
`gem—do%efied.Thus,meHM
`active alleles would be correctly dosed with the EM-
`dose plus (difference between EM and IM doses):
`
`DUM = DEM + (DEM — DIM) = ZDEM — DIM
`
`(4)
`
`in most studies from Asiatic
`As explained above,
`populations only data on CYP2D6 EMs and IMs are
`available. For calculation of dose recommendations, a
`linear gene—dose effect was assumed and the AUC in
`PMs was estimated as follows:
`
`= AUCIM
`(AUCPM -i-
`AUCPM = ZAUCIM — AUCEM
`
`For CYP2C19, genotype frequencies of approximately
`3% PM, 27% IM and 70% EM as known in Caucasian
`populations were used.” The equation for CYP2C19
`corresponding to Equation (1) would be
`
`Therapeutic implications from pharmacogenetics
`J Kirchheiner et al
`
`i11ter1nediate 111etabolizers a11d homozygous or co1n-
`pound l1o111ozygous carriers of two deficie11t alleles
`were termed poor metabolizers. Ultrarapid meta-
`I
`1.
`.1 EH
`Gfany
`combination of one CYP2D6*1 or one CYP2D6*2 gene
`duplication in combination with another active allele
`(genotypes: *2 X 2/*1, *1 X 2/*1).23’24 CYP2D6 alleles
`*9, *10, *17, and *41 were also classified as active
`alleles but with intermediate to low activity.” In
`Africans, the CYP2D6*1 7 allele is frequent and causes
`greatly decreased (but not deficient) enzyme activity.
`This has to be considered if genotyping is used to
`predict
`metabolic
`phenotype
`in
`African
`populations.“ In Orientals,
`the CYP2D6*10 allele
`causing decreased (but not deficient) enzyme activity
`is prevalent with an allele frequency of about 50%.
`Heterozygous carriers of *10 may be in the higher
`activity range of
`the IM group and homozygous
`carriers
`(CYP2D6*10/*10) may be
`at
`the lower
`activity range.“ The poor metabolizer genotype
`with two deficient alleles is very rarely found in
`Orientals
`(<1%);
`therefore,
`studies in Iapanese,
`Chinese or Ixorean irrdivrdtrals are Irrostly focused
`on intermediate and extensive metabolizers of sub-
`
`strates of CYP2D6. Studies analyzing the impact
`of
`the CYP2D6*10 genotypes
`are marked by
`a number sign (#) in Table 2, and for these studies
`PM genotype data are extrapolated from data in IMs
`and EMS.
`
`the following classifications of
`For CYP2C19,
`metabolic phenotype based on genotype were made:
`
`heterozygous carrier of one inactive CYPZCIQ allele
`(*2, *3) and poor metabolizer as homozygous combi-
`nation of two deficient CYPZCIQ alleles. Most studies
`
`did not provide data on intermediate metabolizers. In
`these cases,
`a linear gene—dose relationship was
`assumed and a mean AUC of those of the PMs and
`
`EMs was used to calculate dose adjustments for
`heterozygous carriers of deficient alleles.
`Phenotyping with debrisoquine or dextromethor-
`phan for CYP2D6 and_S-mephenytoin for CYP2C19
`was considered equivalent to genotyping. Classifica-
`tion by phenotype was based on the usual urinary
`metabolic ratio antimodes of 12.6 for testing with
`debrisoquine and 0.3 for testing with dextromethor-
`phan."“"“’
`
`@ 4
`
`44
`
`Data Calculation for dose adjustment To adapt doses
`according to genotypes. data on clearance (Cl). area
` HmecuWe&A%C)mE%gh
`concentrations at steady state (Cm) in the respective
`genotype groups were used to calculate i11ter11al
`and Equations (2) and (3) from above were applied
`exposure to the drugs.
`It was assumed that
`the
`accordingly.
`In the tables,
`tentative therapeutic
`average dose recommended for the whole popula-
`recommendations are given as percentual adjust-
`tion can be regarded as
`the weighted mean of
`ments from the standard dose.
`Intentionally, no
`subpopulation-specific doses.” For CYP2D6 about
`milligram-doses were given since the standard dose
`7—10% of Caucasians are poor metabolizers, 40% are
`may differ depending on factors such as disease
`intermediate (heterozygous carriers), and 50% are
`extensive metabolizers.“ Thus, the average dose (Dav)
`severity, age, gender, body weight, and ethnicity.
`usually recommended in Caucasian populations can When applying our dose recommendation tables in
`
`Dav : (0.03DpM -i- 0.27D1M -i- 0.7DEM)
`
`(5)
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`45
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`Therapeutic implications from pharmacogenetics
`J Kirchheiner et al
`
`the respective size]. Efiect ratio was the ratio of
`ethnic groups other than Caucasians, it is advisible to
`the response criterion i11 the group with the varia11t at
`calculate the dose adjust111e11ts based o11 the standard
`risk divided by the response
`criterion in the
`dose used in that population. Ethnic differences in
` adrug%%Hm%h7du&m
`in the frequencies of drug metabolic enzyme poly-
`assess for possible publication bias (Figures 5-7).“
`morphisms, but also due to differences in nutrition,
`Such funnel plots illustrate the relationship between
`other lifestyle factors, and the effects of various other
`sample size of clinical trials and the study outcome.
`genotypes on the pharmacodynamic site of drug
`From statistical theory, it is expected that the odds
`action.
`ratio or the effect ratio converging to the true values if
`sample size of studies becomes larger and individual
`study data should scatter
`randomly around the
`overall mean of all studies, unless there is selective
`publication.
`
`Limitations of dose adjustments based on CYPZD6 or
`CYP2C19
`genotype An
`approach
`using
`the
`principles of bioequivalence has been described
`above. However, drug concentration differences due
`to genotype are not exactly the same as drug
`concentration
`differences
`due
`to
`different
`
`active
`the
`because
`drug
`a
`of
`preparations
`metabolites also contribute to the overall drug effect
`or are responsible for adverse drug reactions.“'33
`Whenever possible, we based dose adjustments on
`the active moiety of drug exposure consisting of
`parent drug and active metabolites if prevalent in
`considerable concentrations.
`
`Pharmacokinetic phase: dose adjustments based on
`polymorphisms in cytochrome P450 enzymes
`Examination of research on metabolism of 36 anti-
`
`depressants and 38 antipsychotics was conducted
`(Table 1]. For 20 antidepressants, data on CYPZD6 or
`CYP2C19 polymorphisms from pharmacokinetic stu-
`dies in humans were found.
`
`and vilox-
`For
`azine, no data on polymorphic drug metabolism were
`found. Elimination mainly via conjugation reactions
`(glucuronidation, acetylation, sulfatation] and subse-
`quent renal excretion was described for phenelzine
`and tranylcypromine,
`and elimination via renal
`excretion of the unchanged compound was described
`for milnacipran.
`For several tricyclic antidepressants, no data on the
`I ‘
`‘ I
`II ‘
`I
`I
`‘ I.
`I
`I
`I.
`I .
`u
`I I
`I
`I. -
`
`
`
`Tianeptine as well as reboxetine seem to be mainly
`metabolized by CYP3A4 in humans and genetic
`polymorphisms of CYPZDB, CYP2C19 and CYP1A2
`enzymes are unlikely to cause relevant pharmacoki-
`netic variability of these antidepressants.”
`The new atypical antidepressant duloxetine is a
`potent inhibitor of CYPZD6 in Vivo and a CYPZD6
`substrate in Vivo.“ It therefore seems probable that
`CYPZD6 genetic polymorphisms have a major impact
`on elimination of this drug. but this has not yet been
`studied in detail.
`
`were studied
`CYPZB6‘ er CY1l2C}9
`for the metabolism of 13 a11tipsycl1otic drugs (Table
`1]. Other elimination pathways than cytochrome P450
`enzymes are important for following antipsychotics:
`sulpiride and amisulpride (renal excretion], raclo-
`pride (glucuronidation, sulfatation], zotepine (flavin-
`mono-oxygenases involved). CYP3A4 is the main
`enzyme involved in the metabolism of bromperidole,
`iloperidone, perospirone, quetiapine, and ziprasi-
`done.""” For chlorpromazine, remoxipride, and ser-
`tindole, only in Vitro data exist on involvement of
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`methylation reactions were available, and apparently
`the impact of genetic polymorphisms for biotransfor-
`mation of these drugs has not been studied. However,
`structural
`similarity to other
`tricyclics
`such as
`imipramine implicates that CYPZDB and CYP2C19
`might be involved in metabolism of these tricyclics,
`as well.
`
`Many psychotropic drugs are administered as
`racemates and the enantiomers may undergo differ-
`ential biotransformation, have different
`receptor
`binding profiles and different side effects,3“’35 but
`pharmacologic activities of the specific enantiomers
`are frequently unknown in humans: enantiomers
`have been in most cases only tested in animals or in
`Vitro. Therefore, dose recommendations might not be
`seen...
`gen: sue.
`
`into account.
`
`Some psychotropic drugs show saturation kinetics
`in the common dose-range. For clomipramine, desi-
`pramine, fluvoxamine, haloperidol, paroxetine, trimi-
`pramine, dose adjustments are only applicable in the
`dose ranges used in research studies, which is often
`much lower than clinical dosages.
`Data from single dose experiments cannot be
`extrapolated to long-term drug therapy as saturation
`pharmacokinetics, irreversible enzyme blockade, or
`enzyme up- or downregulation might change the
`outcome under multiple dosing.35’3" Enzyme inhibi-
`tion by the substrate itself was described to convert
`genotypic extensive metabolizers of CYPZD6 sub-
`strates to phenotypically poor metabolizers in anti-
`depressant drug therapy.3"’“
`
`Drug target polymorphisms
`
`Data analysis We included all available studies
`concerning response to therapy a11d adverse drug
`reactions. We did 11ot include studies o11 genetic
`polymorphisms
`as
`risk factors
`for
`the genetic
`susceptibility to mental illness. Essential parameters
`in this meta-analysis were sample size (power of the
`study], effect size and statistical significance. Effect
`size was either the odds ratio (if therapy response or
`adverse events were dichotomized] or the effect ratio
`(if response was presented on a continuous scale in
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`
`Table 1 List of antidepressant and anlipsycholic drugs screened for polymorphic metabolism
`
`Not any data
`
`In Vitro
`
`data only
`
`Renal
`excretion,
`mainly
`
`Phase-ll
`enzymes,
`mainly
`
`CYP1A2,
`CYPZB6 or
`CYP3A4,
`mainly
`
`In ViVo studies on
`
`polymorphic
`enzymes CYPZD6,
`CYP2C1 9, CYP2C9
`
`Antidepressant
`drugs
`
`Iprindole
`Isocarboxacid
`
`Setiptiline
`Viloxazine
`
`Amineptine
`Amoxapine
`Dibenzipine
`Doslepine
`Dothiepin
`Lofepramine
`Protriptyline
`
`Milnacipran
`
`Bupropion
`Phenelzine
`Tranylcypromine Tianeptine
`Reboxetine
`
`Amitriptyline
`Citalopram
`Desipramine
`Doxepin
`Duloxetine
`Fluoxetine
`Fluvoxamine
`Imipramine
`Maprotiline
`Mianserin
`Mirtazapine
`Moclobemide
`Nefazodone“
`
`Chlorpromazine
`Remoxipride
`Sertindole
`
`Amisulpride
`Sulpiride
`
`Raclopride
`
`Melperone
`
`Antipsychotic
`drugs
`
`Benperidol
`Chlorprotixen
`Fluphenazine
`Flnspirilen
`Mazapertine
`Nemonapride
`Pipamperon
` p
`
`Prothipendyl
`Trifluperidol
`Triflupromazine
`
`Nortriptyline
`Paroxetine
`Sertraline
`Trazodone
`Hmnm
`Venlafaxine
`
`Bromperidol
`Iloperidone
`Perospirone
`Quetiapine
`Ziprasidone
`Clozapine
`
`Aripiprazole
`Clopenthixol
`Clozapine“
`Flupenthixol
`Haloperidol
`Levomepromazine“
`Olanzapine
`B
`
`Perphenazine
`Pimozidea
`Risperidone
`Thioridazine
`Zotepine
`Zuclopenthixol
`
`aDrngs that are minor substrates of CYPZDB or L‘YP2L‘19 according to in Vivo studies.
`
`CYP2D6.’3 Remoxipride and sertmdole were with-
`drawn from the market due to adverse drug reactions
`(aplastic anemia and arrhythmia]. Melperone is
`described as potent inhibitor of CYPZD6 but studies
`on impact of CYPZD6 polymorphisms on melperone
`metabolism are not yet available.“
`
`Studies on polymorphic metabolism by CYPZD6
`Table 2 summarizes all human studies found for
`
`information on
`antidepressants and antipsvchotics:
`poor and extensive metabolizers of CYPZDB are shown
`and percents of dose adjustments were calculated from
`AUC, Cl, or C133 as described above. There is good
`concordance of the quantitative effects on pharmaco-
`kinetic parameters among various studies.
`
`Impact of (,'YP2D6 polymorphisms on dosing of
`antidepressants
`
`tricyclic
`Tricyclic antidepressants The group of
`antidepressants undergoes
`similar biotransforma-
`
`in the liver with CYPZD6 catalyz-
`t1on actions
`ing hydroxylation reactions,“ 51’‘”’1'“’122 whereas
`demethylation of the parent drug is mediated by
`CYP2C19. Both metabolites
`are
`pharmacologi-
`cally active and the demethylated metabolites are
`partially tricyclic drugs by themselves
`such as
`nortriptyline and desipramine, which are desmethyl-
`metabolites of a1nitriptyli11e a11d i111ipra1ni11e, respec-
`tively. For dose adjustments, the active drug moiety
`c ef the suin ef parent drug :d
`metabolite was used if available from the studies.
`
`The desmethyl-metabolite-drugs nortriptyline and
`desipramine are mainly hydroxylated to less active
`or
`inactive metabolites,‘“’‘'“ in consequence, dose
`adjustments were calculated taking the parent drug
`alone.
`
`Differences in the internal exposure to the drug
`(AUG)
`due
`to genotypes were mostly similar
`when comparing single-dose or multiple-dose studies
`(Table 2].
`
`Molecular Psychiatry
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`@ 4
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`47
`
`Therapeutic implications from pharmacogenetics
`J Kirchheiner et al
`
`Stereoselective 111etabolis1n by CYP2D6 was re-
`ported i11 tri111ipra1ni11e metabolism towards the less
`
`Bupropion is a substrate of CYPZB6 a11d appa-
`rently 11ot influenced by CYPZD6 polymorphisms.7€’
`
`
`
`
`identified.”
`the less active E-isomer.“ For these two tricyclics,
`dose adjustments should be based on the active drug
`compound (active enantiomers or isomer plus de-
`methylated metabolite].
`An extremely high clearance was described for a
`few CYPZDG ultrarapid metabolizers from studies
`with nortriptyline and desipramine. For nortriptyline,
`one ultrarapid metabolizer carrying 13 active CYPZD6
`genes was included, which caused the very high
`mean of clearance in this group.‘“’123 However, the 1-
`10% carriers of a CYPZD6 gene-amplification allele
`found in Caucasian populations usually carry only
`one gene duplication and should get moderately
`higher doses as calculated above and as illustrated
`in Figures 2 and 3.
`In Figure 1, dose adjustments calculated from the
`data of Table 2 of all studies on tricyclic antidepres-
`sants and CYPZD6 polymorphisms are depicted in
` EMsmPMsfiudmd.A§cm
`
`There are contradictory data regarding the effects
`of CYPZDG polymorphisms on metabolism of the
`tetracyclic antidepressant maprotiline: while in a
`patient group receiving monotherapy with 150 mg
`maprotiline, no differences in steady-state concen-
`trations were
`detected
`due
`to
`the
`debriso-
`
`quine metabolizer status," a study with healthy
`Volunteers receiving 100 mg maprotiline over 7 days,
`revealed differences similar to those detected in
`
`tricyclics.7"
`For mianserin, CYPZDG mediates enantioselec-
`tive hydroxylation of the more active S—( +] mianser-
`in. For dose adjustments,
`the sum of S—(+]—mian—
`serin and the active desmethylmianserin was taken
`(Table 2].
`For the racemic drug mirtazapine, S—(-l—]—mirtaza—
`pine clearance significantly depends from CYPZD6
`
`clearance was found?” Achiral analysis did not
`reveal
`CYPZD6
`genotype-related
`differences.“
`Further
`clinical
`studies
`are warranted on the
`
`be seen in the figure, despite small sample sizes,
`different studies come to very similar results for dose
`adjustments. CYP2D6 PMs seem to be dosed correctly
`with approximately half of an average dose of tricyclic
`antidepressants.
`
`inhibitors Some
`reuptake
`serotonin
`Selective
`selective serotonin reuptake inhibitors (SSRISJ such
` ,mdpmmefimampomm
`inhibitors of CYP2D6 activity. Therefore, multiple
`Venlafaxine is a chiral drug with both enantiomers
`dosing
`causes
`decreased
`CYP2D6-mediated
`transformed by CYPZDB to the equipotent O-des-
`metabolism of the drugs themselves, and conversion
`from extensive to slow metabolizer phenotype and
`methyl-Venlafaxine.""’9°’131 Thus,
`the active drug
`moiety, sum of parent drug and metabolite is not
`from ultrarapid
`to
`extensive metabolism was
`much changed by the CYPZD6 genotype. However, a
`described.124’127 Unfortunately,
`these
`studies
`for
`higher risk for cardiotoxic events and severe arrhyth-
`fluoxetine and fluvoxamine describing conversion
`mia was reported in fo11r patients admitted to a
`from higher to lower enzyme activity have studied the
`cardiologic unit who all were PMs, according to
`effect of enzyme inhibition only in one genotype
`CYPZDB function.“ Dose adjustments based on
`groupmi
`and could therefore not be used in our dose
`parent drug alone would lead to 60% reduction of
`calculation approach.
`the average dose for PMs.
`Genotype-based dose adjustments might be neces-
`Figure 2 shows the differential doses of antide-
`sary for paroxetine (Table 2], but less for fluoxetine
`pressants needed because of polymorphisms of
`and fluvoxamine; moreover, caution has to be paid to
`CYPZD6 as the weighted mean (weighted according
`drug interactions. These drugs are strong inhibitors of
`to the sample sizes in the studies] of single-study
`CYP2D6, and therefore, differences in pharmacoge-
`data given in Table 2. Dose adjustments are given
`netic parameters are substantially decreasing under
`for poor,
`multiple dosing conditions72’75 (Table 2]. For parox-
`intermediate, extensive, and ultrarapid
`'efCY1lzD6.FertheUMgreup.
`
`
`
`extrapolation was 111ade assuming a li11ear ge11e—dose
`in one ultrarapid metabolizer carrying at least three
`functional CYPZD6 genes. For sertrali11e a11d citalo-
`effect according to the calculation methods given
`above.
`If possible, data on active moiety of
`the
`pram, no influence of CYPZD6 polymorphisms 011
`pharmacokinetic parameters was detected.
`drug (sum of parent drug and active metabolites]
`after multiple dosing were
`taken and if more
`studies exist, mean dose adjustments were calculated.
`The figure shows that the amount of dose adjust-
`ment varies for substrate to substrate, and that
`clinically relevant differences in dosages are sup-
`ported by existing data.
`
`
`
`Other antidepressants For other antidepressants
`(bupropion, maprotiline, mianserin, mirtazapine,
`moclobemide, nefazodone, reboxetine, venlafaxine],
`no
`general
`assessment
`on
`polymorphic
`drug
`metabolism can be made.
`
`impact of CYP2D6 on mirtazapine clinical effects
`and adverse events, which differ between both
`enantiomers.
`reboxetine, and
`For moclobemide, nefazodone,
`trazodone, CYPZD6 polymorphisms do not seem to
`have a major
`influence on metabolism 1D
`b11-
`manS.37,B3—B6,129,13O
`
`Molecular Psychiatry
`
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`
`@
`448
`
`J Kirchheineretal
`Therapeutic implications from pharmacogenetics
`.
`.
`Table 2 Dose a(l]L1St1I1B11tS aooordnig to CYP2D6 genotype
`
`Drug
`
`Study conditions and parameters measured
`
`Numbers
`
`Extrapolated dose
`adjustments
`
`References
`
`Measured Parameter Dose Dosage Participants UM/EM/ UM EM
`{mg}
`TM/PM {%J
`[%J
`
`IM
`{%J
`
`PM
`[%J
`
`Tricyclic antidepressants
`Aniitriptyline
`P
`
`P —— DM
`
`Cloniipraniine
`
`P
`P —— DM
`
`Desipramine
`
`P
`
`CL
`CL
`AUC
`Css
`
`CL
`Css
`Css
`Css
`Css
`
`AUC
`AUC
`CL
`CL
`Css
`Css
`
`50
`50
`75
`150
`
`SD
`SD
`SD
`MD
`
`Volunteers
`Volunteers
`Volunteers
`Patients
`
`0/2/4/3
`0/5/3/3
`0/4/0/3
`0/11/0/4
`
`SD
`100
`150 MD
`200
`MD
`75
`MD
`125
`MD
`
`25
`25
`100
`100
`100
`100
`
`SD
`SD
`SD
`SD
`MD
`MD
`
`Volunteers
`Patients
`Patients
`Patients
`Patients
`
`Volunteers
`Volunteers
`Vo unteers
`Volunteers
`Patients
`Patients
`
`15/0/10
`0/35/0/1
`0/15/0/5
`0/19/0/3
`0/21/0/2
`
`0/5/0/4
`0/8/0/6
`0/6/6/6
`6/6/0/0
`0/29/0/2
`0/4/5/0
`
`Doxepin
`
`P —— DM
`
`75
`
`SD
`
`Vo unteers
`
`0/8/8/8
`
`Iniipraniine
`
`P
`P —— DM
`
`CL
`Css
`
`SD
`100
`100 MD
`
`Volunteers
`Patients
`
`0/6/6/6
`0/28/0/2
`
`Nortriptyline
`
`P
`
`Triniipraniine
`
`P + DM
`D-P + D-
`DM
`
`AUC
`AUC
`CL
`Css
`AUC
`Css
`
`Css
`
`SD
`25
`SD
`29
`SB
`29
`MD
`150
`SD
`25
`15-120 MD
`
`Vo unteers
`Volunteers
`Voltrrrteers
`Patients
`Volunteers
`Patients
`
`6/5/5/5
`0/2/3/2
`07’2+47’2
`0/7/13/1
`0/10/5/0
`0/7/6/0
`
`SD
`75
`300-400 MD
`
`Volunteers
`Patients
`
`0/8/7/6
`0/25/0/1
`
`124
`123
`120
`111
`
`115
`125
`112
`122
`118
`
`136
`130
`131
`130
`125
`166
`
`127
`
`110
`131
`
`149
`128
`B0
`119
`133
`138
`
`150
`131
`
`74
`85
`86
`92
`
`90
`83
`92
`85
`88
`
`76
`80
`106
`
`83
`37
`
`82
`
`108
`79
`
`50
`73
`7
`96
`72
`66
`
`60
`91
`
`67
`57
`52
`73
`
`65
`41
`72
`48
`59
`
`16
`29
`19
`
`42
`21”
`
`36
`
`64
`28
`
`42
`59
`54
`53
`49”
`435
`
`13
`51
`
`247
`
`254
`
`45
`47
`45
`45
`
`5"
`51
`52
`52
`52
`
`55
`54
`55
`55
`5
`55
`
`55
`
`55
`55
`
`51
`52
`55
`54
`55
`55
`
`57
`55
`
`SSRIS
`
`CitdlQpIdII1
`
`P
`
`Fluoxetine
`
`P + DM
`
`Fluvoxamine
`
`Paroxetine
`
`Sertraline
`
`P
`
`P
`
`P
`
`Other antidepressants
`Bupropion
`P
`
`Maprotiline
`
`P
`
`Mianserin
`
`S—P
`
`AUC
`
`AUC
`AUC
`
`AUC
`AUC
`AUC
`
`AUC
`
`AUC
`
`Css
`
`Css
`AUC
`
`Css
`
`40 MD
`
`VOlll[]tl;:fl[§‘
`
`[)1 l0/0/8
`
`60
`20
`20
`
`50
`50
`100
`
`SD
`SD
`MD
`
`SD
`SD
`MD
`
`Volunteers
`Volunteers
`Patients
`
`Volunteers
`Volunteers
`Volunteers
`
`0/6/0/6
`0/9/0/10
`0/8/0/3
`
`0/10/0/5
`0/10/0/4
`0/8/0/2
`
`30 MD
`
`Volunteers
`
`0/9/0/8
`
`50
`
`SD
`
`Volunteers
`
`0/10/0/10
`
`101
`
`119
`107
`[99
`
`108
`129
`[94
`
`114
`
`100
`
`100
`
`87
`96
`100
`
`95
`81
`104
`
`90
`
`100
`
`98
`
`56
`84
`101]
`
`82
`33
`113]
`
`66
`
`99
`
`300 MD
`
`Patients
`
`0/4/0/3
`
`150 MD
`100
`MD
`
`Patients
`Volunteers
`
`0/75/0/5
`0/6/0/6
`
`[104
`
`[100
`127
`
`97
`
`90]
`
`100
`82
`
`100]
`36
`
`30 MD
`
`Patients
`
`0/14/1/0
`
`153
`
`52
`
`31”
`
`59
`
`75
`71
`72
`
`75
`74
`75
`
`55
`
`71
`
`75
`
`77
`75
`
`7”
`
`Molecular Psychiatry
`
`ROXi|op00148134
`
`Vanda Exhibit 2013 - Page 7
`
`Vanda Exhibit 2013 - Page 7
`
`

`
`Table 2
`
`(Continued)
`
`Therapeutic implications from pharmacogenetics
`J Kirchheiner et al
`
`9
`
`449
`
`Drug
`
`Study conditions and parameters measured
`
`Numbers
`
`Extrapolated dose References
`adjustments
`
`Measured Parameter Dose D