EXPERT
`OPHWON
`
`Introduction
`
`2.
`
`Cytochrome
`P450 family — metabolism of
`drugs
`
`3.
`
`Enzymes involved in SSRI
`
`metabolism
`CYP polymorphisms and 55m
`metabolism and action
`
`Expert Opinion
`
`4_
`
`5_
`
`hea|thCafe
`
`Review
`
`Effect of Cytochrome
`P450 polymorphism on the action
`and metabolism of selective
`serotonin reuptake inhibitors
`
`Kristina Probst-Schendzielorz, Roberto Vivi-ani 86 Julia C Stinglr
`TRemm‘/I Division, Fmlrm./' Imurirursfiir Drug:i1mI'.\[i-z/it‘iz/ [)(’L’iz‘f.f. Benn. Crmizz/1)’
`
`Introduction: The aim of this article is to review the field of clinically relevant
`pharmacogenetic effects of cytochrome P450 polymorphisms on metabolism,
`kinetics, and action of selective serotonin reuptake inhibitors (SSR|s).
`
`Areas covered: The relevant literature in humans on the implications of
`genetic variation on SSRI drug exposure, drug safety, and efficacy was system-
`atically evaluated. There is a large amount of evidence on the influences of
`CYP polymorphisms on the pharmacokinetics of SSRls. Regulatory agencies
`have issued warnings or advice considering dose adjustments in the presence
`of affected metabolic phenotypes for several SSRls. Evidence-based close
`adjustments for drugs dependent on CYP genotype are available to clinicians.
`However, few data on the relationship between genetically determined ele-
`vated plasma concentrations of SSRls and specific side effects or therapeutic
`failure are currently available.
`
`Expert opinion: Genetic polymorphisms in CYP2D6 and CYP2C19 exert large
`influences on the individual exposure to SSR|s, leading to the aim to achieve
`similar concentration time courses in different metabolizer phenotypes. The
`implementation of a stratified approach to medication with SSRIS in different
`
`metabolic phenotypes on a rational basis will require new studies assessing
`the association between clinical outcomes (such as adverse reactions) and
`genetically determined elevated plasma concentrations.
`
`Keywords: antidepressant/SSRI. Cytochrome P+§0/CYP. metabolism/response/side effectsl
`adverse reactions./outcome. pharmacogeneric, pharniacogenomics, pharmacokinetic
`
`Expert (J/ziiz, Drug .\r[mzl». Tu.\:ii‘o/.
`
`i._’()l5I
`
`I[i8.i.'I.»’1‘}—l_’_’3._’
`
`1. Introduction
`
`Therapy with selective serotonin reuptake inhibitors (SSRls) is at present the first
`choice in the pharmacological treatment of depressive disorders. Especially in the
`outpatient setting. SSRIS are widely prescribed. and are among the most common
`drugs to be found in long—term treatment prescriptions.
`Pharmacogenetic variability affects the action of‘SSRIs in three possible domains.
`First,
`there is
`the variability in drug metabolism caused by polymorphic drug
`metabolizing enzymes (DMEsl
`that lead to tremendous individual differences in
`drug exposure. The complexity of the effects of genetic polymorphisms on drug
`metabolism may affect
`the ease with which the individual safety and efficaqr of
`SSRls can be predicted on the basis of the genetic profile of the individual
`l-\. .\'ev—
`ertheless.
`there are several cases in which pharmacogenetic polymorphisms have
`clear and huge effects on drug exposure. For these cases, empirically based dose
`adjustments are available to offset the effect of polymorphisms. Because of the large
`size of these effects, and the availability of this information. if a patient is known to
`
`
`
`10 lSl7'l7~l2S253 20is.ios279i © 2015 inforrca ax, Lid ISSN 17425255 -;=—sssri 17444507
`All righ:s reserved reproduction in whole or in oar, not ;.3erm"eq
`
`1219
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`Vanda Exhibit 2023 - Page 1
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`Vanda Exhibit 2023 - Page 1
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`

`
`with clinical variables such as response or adverse effects report
`null findings with puzzling regularity rat», It should be noted
`that due to the relatively low frequency of phenotypes with
`large alterations of metabolic activity,
`large clinical samples
`ar'e required to assess the effect of these polymorphisms on
`clinical measures of outcome accurately. However. patients
`in these extreme phenotype groups are those concerned most
`specifically by the warnings issued by regulatory agencies.
`In this review. we focus on the effects of CW’ polymor-
`phisms on SSRI action in the first domain described above.
`summarizing the current level of evidence on their influence
`on SSRI metabolism and clearance.
`their safety, and their
`therapeutic efficacy.
`
`2. Cytochrome P450 family — metabolism of
`drugs
`
`Of relevance to SSRI metabolism are functional poly-'mor~
`phisms in CYPZDG. CYPZC9. and CYPZCI9 due to duplica-
`tions. Dene insertions, base pair deletions. gene deletions, copy
`number variations. as well as single nucleotide polymorphisms
`lSf\'l’s). These polymorphisms underlie differences in enzyme
`activity that range from no enzyme activity (poor metaboliz—
`decreased
`(intermediate metabolizers.
`ers,
`l’.\lsl.
`I.\ls‘),
`
`normal (extensive metabolizers/wild type. EMs) to increased
`lultra—rapid metabolizers. Ur\lsl enzyme activity (Table ll.
`A common consequence of these different phenotypes is
`therapeutic resistance or inefficacy due to insufficient plasma
`levels‘ of drugs metabolized by polymorphic Dr\lEs in U.\l
`phenotypes.
`In contrast, slow metabolism (Pr\ls) may lead
`to elevated plasma levels and toxicity.
`Scoring algorithms have been developed to provide quanti-
`tative predictions of CYPZDO enzyme activity based on the
`genotype Ts. Alleles with normal function (wild type) are
`assigned a score of 0.3. while alleles with decreased or no
`functionality are given a score of 0. The sum of the scores
`for the two alleles gives the activity score of the individual.
`Patients with an activity score ranging between 1.0 and
`2.0 are categorized as extensive metabolizers (E.\ls_l,
`those
`with a score of 0.3 are intermediate metabolizers ll.\ls). a
`
`score of 0 is assigned to poor metabolizers (l’.\lsl, and those
`with a score greater than 2.0 are U.\ls ".54. Although this
`classification scheme is the most frequently used. sortie varia—
`tion in the liter'attrr'e is present especially when concerning the
`[M phenotype "—l
`‘»
`. Individuals with only one active allele are
`classified by some as
`l.\l. but considered E.\l by others
`(Table 1)
`li.
`
`Similar‘ rules apply to assign a phenotype based on numbers
`of active alleles in CYPZCI‘).
`lndividuals with two normally
`functional alleles are classified as E.\ls,
`those with one func-
`tional allele and one allele with no function are classified as
`
`l.\ls. and individuals carrying two alleles without activity are
`considered as
`l’.\ls. Subjects with two lriglt—acti\=it_\' alleles
`are categorized as U.\'ls.
`
`K. Probst Schendzielorz et al.
`
`
`
`Article highlights.
`
`- Polymorphic cytochrome P450 enzymes are major
`enzymes involved in SSRI metabolism
`- Polymorphisms of CYPZD6 and CYP2Cl9 lead to large
`variaoility in plasma concentrations of SSRls.
`- Dose adjustments are based on the pharmacokinetic
`influences of the polymorphism taking into account the
`active drug moiety.
`- Warnings or dose reductions in poor metabolizer
`phenotypes are issued in patients with conditions that
`predispose to adverse effects under increased SSRI
`exposure
`- Dose increases for ultrarapid metabolizer phenotypes to
`avoid therapeutic failure at standard closes
`~ Few studies systematically investigate the impact in the
`clinical settings of phenotypes that are relatively rare,
`but have large effects on pharmacokinetics
`
`
`
`This TICK SLil"‘F"3l'?:-3’ key‘ poin‘s contained in the 5l'TlCl-3
`
`to
`
`is rational
`it
`belong to one of these phenotype groups.
`attempt to equalize exposure through dose adjustments.
`By affecting the relative concentration of the parent drug
`and its active metabolites. genetic polymorphisms also modify
`the risk profile for side effects and the overall efficacy of the
`medication. The second domain we consider is dealing with
`serious adverse effects that, even though rarely occurring,
`have potential
`serious clinical consequences. This
`is
`the
`domain where regulatory agencies have been issuing warnings
`for specific side effects in specific compounds. These warnings
`constrain the use ofSSRls or limit the dosage to minimize the
`consequences of individual variability in SSRI exposure. For
`example. warnings of increased suicide risk in adolescents
`have been issued by the FDA. Reports about bleeding inci—
`dents due to the inhibition of the peripheral serotonin uptake
`in platelets have led to warnings about drug interactions and
`advise considering individual
`risk factors for bleeding. QT
`prolongation and cases of severe arrhythmia have led to dose
`restrictions and warnings about drug e_‘<posure—i'elated harm.
`Genetic vziri-ability may also affect drug response and adverse
`effects through mechanisms other than unanticipated changes
`in plasma concentrations le.g. pharmacodynamic mechanisms‘
`or mechanisms invol\'ed in the pathogenesis of side effects).
`These aspects of the pharmacogenetics of SSRls have been
`reviewed extensively elsewhere 9
`.
`Third. pharmacogenetic variation in the population raises
`the issue of the rationality and feasibility of genetic testing to
`optimize treatment (‘preemptive testing). Note that the ratio»
`nality of preemptive testing (whether or not to genotype an
`individual patient) differs from the rational course of action
`to take ifthe genotype is known (covered in the first domain).
`The rationality of genetic testing depends’ on the empirical
`demonstration of an effect ofpharmacogenetic polymorphism
`on clinical measures of outcome. However. while the effects of
`
`CYP genotypes on plasma concentrations of drugs are well
`established. studies attempting to demonstrate an association
`
`1220
`
`T’.‘«'f"~
`
`LL‘-3 113
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`Vanda Exhibit 2023 - Page 2
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`

`
`Effect of Cytochrome P450 polymorphism on the action and metabolism of selective serotonin reuptake inhibitors
`
`Table 1. Phenotypes, as predicted from genotypes.
`
`Genotype
`
`Other classifications
`
`UM: ultra-rapid
`metabolizer
`
`EM: extensive
`metabolizer
`IM: intermediate
`metabolizer
`
`Phenotype
`(metabolizer
`status)
`
`More than two
`copies of active
`(wild~ty_oe) alleles
`Two copies of active Zero variant/mutated
`(wi|d—type) alleles
`alleles
`One inactive and
`One or Two variant]
`one reduced activity mutated alleles
`allele or two reduced
`activity alleles
`Two copies of
`inactive alleles
`
`PM: poor
`metabolizer
`
`Two variant/mutated
`alleles without activity
`
`CYPs have overlapping substrate specificity. Some SSRIs
`are at
`the same time substrate and inhibitor of the same
`
`CYP enzyme. This is for example the case of paroxetine.
`fluvoxamine.
`and fluoxetine with respect of CYPZDG.
`Individuals with a normal metabolizing status can therefore
`switch into the poor metabolizer group through inhibition
`(a phenomenon called phenoconversion) lisg. These drugs dis-
`play non—linear kinetics in which genetic differences in phar-
`macolcinetic parameters gradually lessen at increasing doses.
`The capacity to inhibit D.\lEs also underlies differences
`among the SSRls in their potential for drug—drug interac-
`tions. Paroxetine, fluoxetine. and its active metabolite nor-
`
`fluoxetine are potent inhibitors of CYPZDG: fluvoxamine is
`a potent
`inhibitor of CYP1A2. CYP2Cl9, CYP3A4. and
`CYPZD6 !i<.,.
`
`3. Enzymes involved in SSRI metabolism
`
`CYPZD6 activity scores previously mentioned Isl
`mwv.cypalleles.ki.se/CYP2D6.htm).
`CYPZD6 is the main enzyme responsible for the metabo—
`lisms of paroxetine. fluoxetine, and fluvoxamine, and plays a
`role in sertraline metabolism. In addition,
`it can in turn be
`
`(htrp://
`
`inhibited b_v SSRIS, with the consequence of a change in
`metabolizing status.
`Ethnicity plays an important role in the distribution of the
`genetic variability of CYPZDG in different populations (for a
`comprehensive listing. see Hi). W/hile rare in Asiatic popula~
`tions. the complete loss ofenzyme activity of the PM pheno-
`type is found in around 10% of the Caucasian. Hispanic. and
`African populations. The ultrarapid metabolizer phenotype
`(UM) is found in less than 396 of Caucasians and African
`
`in up to 50% of Ethiopians and Saudi
`
`Americans, but
`Arabians 'l‘).l()l.
`
`3.3 CYP2C19
`
`CYP2C19 is involved in metabolism of citalopram, escitalo—
`pram. and sertraline. Similar to CYPZDG.
`the CYl’2Cl9
`enzyme is highly polymorphic. To date. more than 50 allelic
`variants and subvariants have been identified. Three variant
`
`IM.
`the common PM.
`alleles are mainly responsible for
`EM. and UM phenotypes: CYPZCI9 ‘I has normal enzyme
`activity (wild type),
`'17allele carriers have increased enzyme
`activity. and '2 is the most frequent non—function allele, fol-
`lowed by ‘3 .21} (http://wwwcypalleles.l<i.se/CYPZCl9.htm).
`The occurrence ofthese alleles differs among ethnic groups.
`The allelic frequency of CYP2C19‘2 has been shown to be
`around 15% in Caucasians and Africans. but doubles (30%)
`in Asians. The CYP2C19'3 allele is mainly found in Asians
`(5 — 9%; while is found in less than 0.3% of Caucasians).
`The frequency of Ci'7’2C19‘17' (UMS) is 16 — 21% among
`and Africans, but
`rare
`(5
`- 6%)
`CRLICHSTRHS
`ZlTI10l1g
`Asians ;22.:3|.
`
`3.1 CYP1A2
`
`3.4 CYP2C9
`
`CYP1A2 plays a minor role in the biotransformation of flu-
`voxamine and paroxetine. The genetic component of varia-
`tion in CYP1A2 activity is thought to be small, with little
`room for effects on the pharmacokinetics of these SSRIs. In
`contrast. environmental factors such as smoking (induction)
`and oral contraceptive use in women (inhibition) explain
`most of the individual variation in CYP1A2 activity iii.
`Remarkably, genetic variants have recently been described
`that neutralize the effect of inducers, showing that genetic
`polymorphism may affect
`the activity of this enzyme indi-
`rectly at this step its .
`
`3.2 CYP2D6
`
`The CYPZDG gene is highly polymorphic, resulting in very
`large variations in enzyme activity. More than 100 allelic var«
`iants contribute to the variability in enzyme activity that leads
`to the four phenotypes of PM. IM. EM. and UM. or the
`
`CYPZC9 is characterized by a genetic polymorphism in which
`two alleles
`(alleles
`‘.2 and '3)
`lead to reduced enzyme
`activity tar. \‘</hile relatively rare in Asian and African popula
`tions.
`these alleles are carried by approximately 35°.-‘o of
`Caucasians 24:. The CYPZC9 polymorphism may influence
`the metabolism of fluoxetine and sertraline.
`
`3.5 CYP3A4
`
`\‘(7ith only few single nucleotide polymorphisms lS.\'l’s) that
`are known to influence enzyme expression or
`function.
`CYP3A4 has not been traditionally considered a polymorphic
`DME. However,
`a variant
`leading to the complete loss
`of CYP5A4
`activity has been
`recently identified
`525».
`CYT‘3r\-/i plays a minor role in the metabolism of SSRls,
`where it is involved in the biotransformation of sertraline. cit-
`
`alopram. and escitalopram. Therefore. genetic variants in the
`CYT3A4 gene are almost certainly of negligible clinical
`importance in the therapy with SSRls.
`
`Expert Opin Drug 4‘-/terao Toxicol v2-O15: 11:8?
`
`1221
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`Vanda Exhibit 2023 - Page 3
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`Vanda Exhibit 2023 - Page 3
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`K. Probst Schendzielorz et al.
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`1222
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`Vanda Exhi
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`it 2023 - Page 4
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`Vanda Exhibit 2023 - Page 4
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`Effect of Cytochrome P450 polymorphism on the action and metabolism of selective serotonin reuptake inhibitors
`
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`1223
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`Vanda Exhi
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`it 2023 - Page 5
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`Vanda Exhibit 2023 - Page 5
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`

`
`K. Probst Schendzielorz et al.
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`1224
`
`Vanda Exhi
`
`it 2023 - Page 6
`
`Vanda Exhibit 2023 - Page 6
`
`
`

`
`Effect of Cytochrome P450 polymorphism on the action and metabolism of selective serotonin reuptake inhibitors
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`1225
`
`Vanda Exhi
`
`it 2023 - Page 7
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`
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`
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`
`Vanda Exhibit 2023 - Page 7
`
`
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`

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`K. Probst Schendzielorz et al.
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`Vanda Exhi
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`it 2023 - Page 8
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`Vanda Exhibit 2023 - Page 8
`
`
`

`
`Effect of Cytochrome P450 polymorphism on the action and metabolism of selective serotonin reuptake inhibitors
`
`Also CYT’2D6 was found to influence the plasma concen-
`trations of escitalopram. Plasma concentrations in PMs were
`twice as high as in EMs ($8.413. CYP1A2 was not found to
`have an effect on escitalopram plasma levels mi.
`Due to the influence ofCYP2Cl9 on escitalopram plasma
`levels, adjustments to 130% of standard doses may be recom-
`mended in CYPZCI9 U.\/‘ls.
`In CYPZCI9 PMS. a lower
`
`initial dosage (50%) or alternative drugs not metabolized
`by CYP2Cl9 may be considered 11. At present. data are
`too
`sparse
`to
`issue
`dose
`adjustments depending on
`CYPZDG genotype. Currently, no FD.-\ warning for escitalo—
`pram comparable to the warning for Citalopram has been
`issued. even though the metabolism is the same. This might
`depend on the fact that,
`in contrast to citalopram, no influ-
`ence of CYPZC19 or CYPZDG on side effects (especially
`QTC prolongation) or on therapeutic response has been
`observed in several clinical studies 13(S._)9,-10.-ll.-l3.—l()j.
`
`4.3 Fluoxetine
`Fluoxetine is a racemic mixture of 3- and R—fluoxetine. Both
`
`enantiomers are approximately equipotent in inhibiting sero-
`tonin reuptake. Fluoxetine is metabolized primarily via
`[V-demethylation to norfluoxetine. whose S-enantiomer
`is
`20 times more potent than the R-enantiomer and the parent
`drug. Both metabolites significantly contribute to the thera-
`peutic effect 76,4‘). CYPZDG and CYPZC9 are the main
`metabolizing enzymes of fluoxetine and norfluoxetine, with
`minor
`contributions
`from CYPZCI9. CYP5A4,
`and
`CYP}.-\5 .1481. The metabolism of fluoxetine and its metabolite
`
`norfluoxetine is stereoselectively C;1E;.1l}Z€Cl. CYPEDG is selec-
`tive
`for
`the S-enantiomer. while both CYPZC9 and
`CYPZDG metabolize the R-enantiomer. The further metabo-
`
`4. CYP polymorphisms and SSRI metabolism
`and action (Table 2)
`
`4.1 Citalopram
`
`Citalopram is a racemic mixture ofa pharmacologically active
`S-enantiomer (marketed as escitalopram) and the R—enantio—
`mer, which is largely inactive. The primary metabolic path-
`way of citalopram is N—demeth__vlation by CYPZCI‘) with
`minor contributions of CYP5A4 and CYPZDG. The subse-
`
`quent N—demethylation to didesmethylcitalopr-am depends
`on CYPZD6 :20‘. Metabolites do not contribute to the overall
`
`pharmacological effect of citaloptam firs}.
`Several studies to date have investigated the effects of
`CYPZCI9 polymorphism on the pharmacokinetics ofcitalo—
`pram. CYPZCI9 l’.\/ls had higher Citalopram plasma levels
`and lower oral clearance in comparison to those with higher
`enzyme activity i1"—_=.=i.
`The effect of the CYPZDG polymorphism on the pharma—
`cokinetics of Citalopram is weak i3i>.:»_>= or below the signifi-
`cance threshold mi.
`
`The amount of data on the effects of CYP2Cl9 pol_vmor—
`phism on clinical variables is considerable. Two anal_vses in
`more than 1000 patients from the START) collective }..,5s,
`looked for pharmacogenetic effects on drug tolerance and
`clinical outcome (response, remission). The first analysis of
`1877' patients found no association between CYPZCI9 and
`side effects or drug response ass}. The second analysis, how-
`ever. looked more closely at drug tolerance and observed sig-
`nificantly lower odds of tolerance in CYPZCI9 P.\ls 134:.
`Although sample sizes are considerable, one should note that
`in the STAR‘D study. no measure ofdrug exposure was avail-
`able. Furthermore. side effects were recorded at a qualitative
`symptomatic level
`(e.g. dizziness)
`rather than documented
`with specific exams (such as EEG for QTc prolongation).
`A much smaller study observed a tendency toward QTC pro-
`longation in CYPZCI9 PMs
`35;.
`In CYPZCI9 PMs.
`the
`FDA recommends a maximum dose of 20 mg/day to mini—
`mize the risk oflonger QTC intervals. Drug monitoring may
`be advised :2‘
`(see http://wwwv.fda.gov/Drugs/DrugSafety/
`ucm29.759l.htm).
`
`4.2 Escitalopram
`
`lism ofS—norfluoxetine but not ofR—norfluoxetine is catalyzed
`by CYPZDG 13‘.r,q«>g.
`Fluoxetine is known for inhibiting its own metabolism by
`being a strong inhibitor of CYPZDG. Therefore, differences
`in pharmacogenetic parameters may substantially decrease
`under chronic treatment (32. As a consequence. at high doses
`or under prolonged treatment, the relative concentration of
`the parent drug and its metabolite norfluoxetine may change.
`Because both parent drug and metabolite have significant
`pharmacological effects,
`it
`is meaningful
`to consider
`the
`effects of pharmacogenetic polymorphisms on the moiety as
`The S—enanti0mer of Citalopram is pharmacologically active
`a whole. Pharmacokinetic studies revealed that the activity
`while R—citalopram appears to be largely pliarinacologically
`of the moiety (fluoxetine + norfluoxetine) did not differ
`inactive gs". Therefore. S—citalopram has been marketed since
`appreciably between subjects with different CYTZD6 geno-
`2002 as escitalopram.
`types .r..i<).sti:..
`interestingly.
`the CYPZCC) genotype affected
`The main metabolic step is :\"—demethylation to .\/—desme—
`the active moiety. and It\-‘ls/P.\'ls had l.3—fold higher active
`thylcitalopram by CYPZCI9. with minor contributions of
`drug fractions than E.\ls rs-‘)..
`CYP5A4 and CYP2D6. and the subsequent 1V—demethylation
`no close
`:2/..
`rt
`In
`the
`systematic
`review by Stingl
`to didesmethvlcitalopram by CYPJDG jzisj. Metabolites do
`adjustments were given because no differences between
`not
`contribute
`to
`overall
`pharmacological
`effect
`of
`CYPZDG or CYPZCI‘) metabolizer groups were detected
`escitalopram 16;.
`with regard to the active drug moiety 3.
`I\'evertheles.s,
`Higher escitalopram plasma levels were observed in subjects
`alertness when administering other CYP2D6 substrates was
`with lower CYPZCI9 enzyme activity .1s.=.sv4=;.
`recommended,
`as drug—drug interactions may occur
`1,.
`
`1227
`
`E;<per' Dom Drug Ve'ao Toxcor 42015‘ 11z8=
`
`Vanda Exhibit 2023 - Page 9
`
`Vanda Exhibit 2023 - Page 9
`
`

`
`K. Probst Schendzielorz et al.
`
`Further studies investigating the effect of CYI’2C9 polymor-
`phism are needed, especially with respect
`to the rare PM
`phenotype.
`Few data are available on the effects ofCYI’ polymorphisms
`on side effects of fluoxetine or response to treatment. The
`occurrence ofadverse reactions. discontinuations oftreatment.
`
`or response was not associated with the CYPZD6 polymor-
`phism in several observational studies ‘i~'&()5l.5ll.
`
`4.4 Fluvoxamine
`
`Fluvoxamine is metabolized by the isoenzymes CYPZD6 and
`CYP1A2.
`It has no pharmacologically important active
`metabolite is"). Fluvoxamine is also a potent
`inhibitor of
`CYP1A2, CYPZCI9. CYP3A4. and CYPZDG am. and conse-
`
`steady—state pharmacokinetics,
`quently displays nonlinear
`with disproportionally higher plasma concentrations at higher
`dosages L51.
`Although CYPIA2 is also involved in the metabolism of
`fluvoxamine.
`the existing studies have only considered the
`effects of polymorphisms in CYPZDG. One study found flu-
`voxamine plasma concentrations not
`to be affected by
`CYPZCI9 polymorphisms 63..
`Studies investigating whether the CYPZDG polymorphism
`correlates with the clearance of fluvoxamine showed confIict—
`
`ing results. These discrepancies. however. may be due to the
`nonlinear kinetics induced by phenoconversion. Two studies
`in patients at steady state with doses in the range from 50 to
`200 mg/d found that
`fluvoxamine concentrations were
`affected by CYPZDG genotype depending on dose 9.15.. The
`impact of CYPZDG genotype decreased with increasing doses.
`This pattern of results is consistent with the inhibitory effect
`of fluvoxamine on CYPZD6.
`
`and
`considered in poor
`adjustments may be
`Dose
`ultra—rapid metabolizers in the lower dose range. Doses of
`fluvoxamine may be adjusted to about 70% in PI\/IS, while
`in Ui\-"Is may be titrated up to about 150%; furthermore.
`drug monitoring may be indicated 12:.
`Few data are available on the effects of genetic polymor-
`phisms on side effects and the clinical outcome of flux-'o.\’—
`amine treatment. Two independent studies looking at side
`effects
`and
`found
`no
`response
`association
`between
`CYPZDG genotype and side effects (nausea) or clinical out—
`come iI!).+(>j. However. another study in Japanese patients
`reported a significantly higher risk of developing gastrointesti—
`nal side effects in CYPZDG low metabolism phenotypes ‘[15.
`
`4.5 Paroxetine
`
`is mainly responsible for the
`CYPZDG is the enzyme that
`metabolism of paroxetine. which is extensively metabolized
`by it. .-\t the same time, paroxetine is also a mechanism—based
`inhibitor ofCYPZD6. Paroxetine metabolites do not contrib-
`
`Besides CYI’2D6. CYI’3r\-/1. CYP1A2. and CYPZCI9
`
`a minor contribution to the metabolism of
`may give
`paroxetine [%:é.SS|.
`Considerable variations in paroxetine plasma concentra—
`tions have been reported depending on CYPZD6 enzyme
`activity. Subjects with decreased CYP2D6 enzyme activity
`had higher paroxetine plasma concentrations
`than those
`with normal activity 30-61;. In contrast, very low or undetect-
`able paroxetine plasma concentrations in CYPZDG UMS have
`been reported i(xZ~()4j.
`Since paroxetine is at the same time