UlllVElfl'|'Y OF IOWA
`
`rmlmnvm ll mmnumm mm
`
`3
`
`037 001 306
`
`Roxane Labs., Inc.
`Exhibit 1007
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`Roxane Labs., Inc.
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`JOINT EDITORS
`
`Professor Stuart A Montgomery
`StMary's Hospital Medical School
`London UK
`
`Professor Martin B Keller
`Brown University
`Providence USA
`
`FOUNDING EDITOR
`Professor Trevor Silverstone
`University of Otago
`Dunedin New Zealand
`
`MANAGING EDITOR
`
`Deirdre Montgomery
`StMary's Hospital Medical School
`London UK
`
`ADDRESS ALL
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`
`Professor SA Montgomery
`International Clinical
`Psychopharmacology
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`AIMS AND SCOPE
`
`International Clinical Psychopharmacol(cid:173)
`ogy provides an essential link between re(cid:173)
`search and clinical practice throughout
`psychopharmacology. It reports on stud(cid:173)
`ies in human subjects, both healthy vol(cid:173)
`unteers and patients, which relate the ef(cid:173)
`fects of drugs on psychological processes.
`A major objective of the journal is to
`publish fully refereed papers which throw
`light on the ways in which the study of
`psychotropic drugs in health and disease
`can increase our understanding of
`psychopharmacology. To this end the
`journal publishes the results of early Phase
`I and II studies, as well as those of
`controlled clinical trials of psychotropic
`drugs in Phase III and IV. Other topics
`covered include the epidemiology of
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`taking, the sociology of psychotropic
`drugs including compliance, and research
`into the safety of and adverse effects of
`these compounds.
`
`International Clinical
`Psychopharmacology
`
`An International Journal for Collaboration between Research and
`Clinical Practice
`
`EDITORIAL BOARD
`
`C Altamura, University of Milan, Italy
`
`T Barnes, Imperial College School of Medicine, London, UK
`
`M Bourin, Universite de Names, France
`
`G D Burrows, University of Melboume, Victoria, Australia
`
`G B Cassano, University of Pisa, Italy
`
`E F Coccaro, Medical College of Pennsylvania, Philadelphia, USA
`
`J C Cookson, Royal London Hospital, London, UK
`
`P Deniker, Universite de Sainte Anne, Paris, France
`
`H Dufour, Clinique Psychiatrique Universitaire, Lausanne, Switzerland
`
`H Emrich, Max Planck Institute, Miinchen, Germany
`
`J P Feighner, Feighner Research Institute, Poway, Cal(fornia, USA
`
`S Garattini, Instituto di Richerche Farmacologiche, Milan, Italy
`
`C-G Gottfries, Saint Jorgen 's Hospital, Hisings-Backa, Sweden
`
`P Grof, Royal Ottawa Hospital, Ottawa, Ontario, Canada
`
`I Hindmarch, University of Surrey, Guildford, UK
`
`L Hollister, University ofTexas, Houston, Texas, USA
`
`T Itil, New York University Medical Cellter, New York, USA
`
`D King, The Queen's University of Belfast, Northern Ireland
`
`B Leonard, University College, Galway, Ireland
`
`0 Lingjaerde, Gaustad Hospital, Gaustad, Oslo, Norway
`
`J J L6pez-Ibor, Universidad Complutense, Madrid, Spain
`
`J Mendlewicz, Erasme Hospital, Brussels, Belgium
`
`R M Post, National Institute of Mental Health, Bethesda, M(//)'land, USA
`
`T Shibuya, Tokyo Medical College, Japan
`
`M Versiani, Universidade Federal do Rio de Janeiro, Brazil
`
`H Westenberg, Academic Hospital, Utrecht, The Netherlands
`
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`!llternational Clinical Psychopharmacology is
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`ISSN: 0268-1315
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`SUPPLEMENT 5 SEPTEMBER 1998
`
`Care of Depression in Older Patients
`
`1 . . . -
`
`Proceedings of a Lundbeck symposium held in Copenhagen,
`7-8 Novemberl998
`·
`
`GUEST EDITORS:
`C. G. Gottfries, J. Mendlewicz and S.A. Montgomery
`
`Supported by an educational grant from H. L~ndbeck A/S
`
`CONTENTS
`
`S 1
`
`S3
`
`. Introduction
`J. Mendlewicz
`
`Is depression under-recognised and undertreated? ·
`Y. Lecrubier
`
`S7 Epidemiology of depression in the elderly
`J.P. Lepine and S. Bouchez
`
`S 13 Is there a difference between elderly and younger patients with regard to
`·
`-
`the symptomatology and aetiology of depression?
`C.G. Gottfries
`
`S 19 Quality of life and social issues in older depressed patients
`J.P. Warner
`
`S25 Cardiovascular effects of antidepressant drugs: updated
`A.H. Glassman
`
`S31 Simple steps to diagnosis at primary care centres
`S. Noltorp, C.G. Gottfries and N. Norgaard
`
`S35 Care of depression in the elderly: comparative pharmacokinetics of SSRis
`P.Baumann
`
`S45 Differences in interactions of SSRis
`K. Br0sen
`
`S49 Efficacy and safety of the selective serotonin reuptake inhibitors in treating
`depression in elderly patients
`S.A. Montgomery
`
`(contents continued overleaf)
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`ISSN: 0268-1315/98
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`/
`
`·International Clinical
`Psychopharmacology
`
`An International Journal for Collaboration between Research and
`Clinical Practice
`
`~VOLUME 13 SUPPLEMENT 5 SEPTEMBER 1998
`
`. CONTENTS (CONTINUED)
`
`S55 DepRelief: training programme for primary care
`L Philp
`
`S59 Conclusions
`C.G. Gottfries
`
`:r;,-
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`lnteriwtional Clinical Psychopharmacology is col'ered in Index Medicus/MEDUNE,
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`International Clinical Psychopharmacology 1998, 13 (suppl 5):S45-S47
`
`Differences in interactions of SSRis
`
`K. Bmsen
`
`Department of Clinical Pharmacology, Institute of Medical Biology, Odense University,
`Winslowsparken 19, DK-5000 Odense, Denmark.
`
`The SSRis differ fmm each other with regard to their chemical structure, their pharmacokinetics and their potential for
`causing pharmacokinctic interactions through inhibition of species of the cytochrome P450 enzyme system. Cytochrome
`P-t50 (C\'P) is a gnmp of more than 30 different heme containing proteins in humans, some of which play a key role in the
`oxidation and hence the elimination of numerous drugs, including the SSRis. Thus tlumxamine, but not citalopram, tluoxetine,
`paroxctinc and scrtralinc is a potent inhbitor of CYPIA2. Accordingly tluvoxamine has interactions with other drugs elimi(cid:173)
`nated by CYP 1A2 including caffeine, clozapine, olanzapine, theophylline, propranolol and tacrine. CYP2Cl9 is the source of
`the S-mcphcnytoin oxidation polymorphism. About 2% of whites are poor metabolizers in whom CYP2C19 is not expressed.
`Poor mctaholizcrs have an impaired elimination of among other drugs citalopram.Aithough not metabolized by CYP2C19,
`llumxaminc is still a potent inhibitor of the enzyme. The same applies to tluoxetine. CYP2D6 only makes up about 2-5% of
`the total P-150 in the human liver, hut anyway is the major enzyme catalyzing more than 30 clinically used drugs including all
`of the tric)-clic antidepressants, several neuroleptics, opiates, betablockers, antiarrhythmics and among the SSRis N(cid:173)
`desmcth)·Icitalopram, fluvoxamine, tluoxetine and paroxetine but not sertraline.AII of the SSRis inhibit CYP2D6 but tluoxetine,
`norlluoxctinc and pamxctinc arc particularly potent inhibitors. CYP3A4 is the most abundant human cytochrome P450, but
`most of the SSRis with the exception of nortluoxetine do not inhibit this enzyme, and interactions with SSRis and CYP3A4
`appear not to IJC a significant. lnt Clin p,)ch<>pharmacol 13 ('uppl5t:S.J5-S.J7 <D 1998 Lippincott William' & Wilkin'
`
`Keywords: cytochrome P450. drug-drug interactions, CYP1A2, CYP2C9, CYP2Cl9, CYP2D6, CYP2El, CYP3A4
`
`An interaction is defined as an unwanted change in the
`action of a drug on the organism (pharmacodynamics)
`and/or an unwanted change in the action of the organ(cid:173)
`ism on a drug (pharmacokinetics) due to the previous
`or concomitant intake of another drug. The true inci(cid:173)
`dence of interactions in the population is not known,
`but based on data from studies of drug related hospi(cid:173)
`tal admissions it is reasonable to assume, that the fig(cid:173)
`ure is low (Hallas, 1995). Hence interactions are prob(cid:173)
`ably not a major health problem, although the
`importance in individual patients can be great.
`By tradition, interactions are classified according to
`their mechanism into pharmacodynamic, pharmaco(cid:173)
`kinetic and pharmaceutical. A pharmacodynamic in(cid:173)
`teraction may arise from the concomitant administra(cid:173)
`tion of two drugs that affect the same receptor,
`neurotransmittor or physiological system. For instance
`the SSRis all share the same important pharmacody(cid:173)
`namic property, the inhibition of the serotonin trans(cid:173)
`porter. Thereby, the concentration of serotonin is el(cid:173)
`evated in the synaptic cleft. The so-called serotonin
`syndrome may occur if an SSRI is administered to(cid:173)
`gether with a drug that either via the same or a differ(cid:173)
`ent mechanism also increases the serotonin concentra-
`
`tion. A pharmacokinetic interaction is an interaction
`where the plasma concentration of one drug is changed
`without change of dose because another drug is given
`simultaneously. The plasma concentration may in(cid:173)
`crease due to an increase in the absorption fraction,
`inhibition of the biotransformation, impairment of the
`renal excretion or disappearance of induction. Con(cid:173)
`versely, the plasma concentration may decrease be(cid:173)
`cause of a decrease in the absorption fraction, induc(cid:173)
`tion of the biotransformation, enhancement of the re(cid:173)
`nal excretion or the disappearance of impairment of
`the elimination.
`The clinical relevance of an interaction is deter(cid:173)
`mined by several factors: (1) The frequency and rel(cid:173)
`evance of the combination of the two drugs. (2) The
`frequency of the interaction during combined intake
`of the two drugs. (3) The therapeutic index which
`means the ratio between the lower toxic and the lower
`therapeutic level is low. ( 4) Clinical dose titration is
`not feasible. (5) The patient population.
`The clinical consequence of an interaction may ei(cid:173)
`ther be an enhancement of an adverse effect or an en(cid:173)
`hancement of the drug's desired effect. Alternatively
`the consequence may be a weakening of the desired
`
`0268-1315 ([) 1998 Lippincott Williams & Wilkins
`
`International Clinical Psychopharmacology 1998, Vol 13 (suppl 5) S45
`
`Roxane Labs., Inc.
`Exhibit 1007
`Page 005
`
`

`
`effect but only very rarely an interaction shows a quali(cid:173)
`tative change in the known effects of a drug. Hence
`interactions can nearly always be predicted and avoided
`by rational use of the drugs known pharmacological
`characteristics. An interaction observed in one patient
`does not necessarily mean that all patients will suffer
`from the interaction when treated with the combina(cid:173)
`tion of the two drugs. Likewise, it is difficult to ex(cid:173)
`trapolate from animals to humans and as clearly illus(cid:173)
`trated by the SSRis an interaction caused by one drug
`does not mean, that all drugs from the same class share
`the interaction.
`When the SSRis were introduced about 10 years
`ago, very little was known about their interaction pro(cid:173)
`file. During the postmarketing surveillance this turned
`out to be a major feature distinguishing the SSRis.
`Hence at clinically equivalent doses, their efficacy and
`adverse effect profile show no clinically relevant dif(cid:173)
`ferences. The SSRis clearly differ in 3 ways, and that
`is with regard to their chemical structure, their phar(cid:173)
`macokinetics and their potential for drug-drug inter(cid:173)
`actions. The two former aspects are only of marginal
`clinical relevance. Here focus will be on the interac(cid:173)
`tions.
`In this context, the cytochrome P450 enzyme sys(cid:173)
`tem in the liver plays a key role. Oxidation by cyto(cid:173)
`chrome P450 is the major route of elimination for
`drugs. By oxidation, drugs are usually made less ac(cid:173)
`tive, more water soluble and most importantly, they are
`prepared for the attack by so-called phase 2 or conju(cid:173)
`gation enzymes such as glucoronyl transferases and
`sulphate transferases. A conjugated metabolite is nearly
`always inactive and very polar and hence readily
`excretable via the kidneys. In this way, the cytochrome
`P450 becomes a key in regulating the elimination of
`the majority of drugs. In humans the number of cyto(cid:173)
`chrome P450 (CYP) genes and enzymes exceeds 30,
`but a major role in drug oxidation so far only has been
`demonstrated for about 6-8 species. The enzymes are
`heme proteins, and they are grouped in families and
`subfamilies according to their amino acid similarity.
`About 3.5 billion years ago there was only one P450
`gene, and it is beleived, that this gene in the course of
`the evolution underwent gene duplications and muta(cid:173)
`tions. Hence the cytochrome P450 gene loci is spread
`on at least 6 different human chromosomes.
`Each cytochrome P450 has a very broad substrate
`specificity, and co-administration of two substrates for
`the same enzyme is common in clinical practice. Due
`to competition for the active site this may lead to clini(cid:173)
`cally important interactions. A cytochrome P450 based
`interaction is likely to become important if a drugs,
`which is almost exclusively eliminated by a single cy(cid:173)
`tochrome P450 is co-administered with another drug
`
`BR0SEN
`
`which is a potent or an effective inhibitor of the P450
`in question. Besides, the therapeutic index of the
`substrate should be low, and clinical dose-titration
`should not be feasible.
`The cytochrome P450 I A2 (CYP I A2) is an induc(cid:173)
`ible P450 that on average makes up 10-15% of the
`total P450 in the human liver. CYP I A2 is induced by
`tobacco smoking and charcoalbroiled meat and very
`weakly by omeprazole. It oxidizes caffeine, theophyl(cid:173)
`line, tacrine, clozapine, olanzapine, propranolol, and
`it is partially involved in the oxidation of amitriptyl(cid:173)
`ine, clomipramine and imipramine. It is very potently
`inhibited by fluvoxamine and methoxsalen. Neither
`citalopram, fluoxetine, paroxetine or sertraline inhibit
`CYPlA2 to any important degree. Thus clinically im(cid:173)
`portant interactions have been reported between
`fluvoxamine and caffeine, clozapine, theophylline and
`tacrine. It is possible to co-administer fluvoxamine with
`these drugs provided that their dose is reduced to 10-
`30% of the normal. Whenever possible plasma levels
`should be monitored.
`CYP2C9 is another quantitatively important cyto(cid:173)
`chrome P450, although its role in the oxidation of psy(cid:173)
`chotropic drugs has not yet been established. So far
`systematic studies on the inhibition of CYP2C9 by
`SSRis have not been carried out. It is the main cyto(cid:173)
`chrome P450 oxidating S-warfarin, and there is a theo(cid:173)
`retical possibility, that the augmentation of anticoagu(cid:173)
`lant effect during warfarin treatment with concomitant
`fluvoxamine may be due to inhibition of CYP2C9.
`Other important substrates of CYP2C9 include pheny(cid:173)
`toin, tolbutamide, diclofenac and other non-steroidal
`anti-inflammatory drugs (NSAIDs). CYP2Cl9 is the
`source of the so-called S-mephenytoin oxidation poly(cid:173)
`morphism in humans. In whites, the enzyme is not ex(cid:173)
`pressed in 2-3% of the population, the so-called poor
`metabolizers. The frequency of poor metabolizers is
`much higher, 15-20% in Orientals. CYP2C 19 is an
`important enzyme catalyzing
`the oxidation of
`citalopram, clomipramine, diazepam, imipramine,
`moclobemide, proguanil and omeprazole. Interestingly,
`citalopram which is partially N-demethylated to
`desmethylcitalopram via CYP2C 19 does not inhibit the
`enzyme at clinical doses. However, fluvoxamine,
`which apparently is not metabolized by CYP2Cl9 but
`by CYPl A2 and CYP2D6 (see below) is a very po(cid:173)
`tent inhbitor of the enzyme. This may have a bearing
`on the combination of tluvoxamine and the antimalar(cid:173)
`ial drug proguanil. Proguanil is a prodrug that requires
`oxidation to the active metabolite cycloguanil. The for(cid:173)
`mation of cycloguanil is pre-dominatly catalyzed by
`CYP2C 19 (Jeppesen eta/., 1997). Hence cycloguanil
`formation is much slower in the poor metabolizers than
`in the extensive metabolizers, and in the latter it drops
`
`S46
`
`International Clinical Psychopharmacology 1998, Vol 13 (suppl 5)
`
`Roxane Labs., Inc.
`Exhibit 1007
`Page 006
`
`

`
`DIFFERENCES IN INTERACTIONS OF SSRI
`
`to the poor metabolizer level during fluvoxamine in(cid:173)
`take (2). Accordingly the combination of the two drugs
`is not recommended.
`Although CYP2D6 only makes up about 2-5% of
`the total P450 in the human liver it is a major enzyme
`catalyzing the oxidation of more than 30 drugs. The
`list includes all of the tricyclic antidepressants, sev(cid:173)
`eral neuroleptics, beta-adrenoceptor blockers and many
`opioids including codeine and tramadol. It should now
`be clear, that CYP2D6 substrates either have the heart
`or the brain as their effector organs. However the as(cid:173)
`sociation between the mode and place of action and
`the affinity for CYP2D6 is not fully understood.
`CYP2D6 is not expressed in 7% of whites, and this is
`due to mutations in the CYP2D6 gene. Up to now at
`least 20 different mutations or gene deletions have been
`identified, some of which are more frequent than oth(cid:173)
`ers in the poor metabolizers. Another important char(cid:173)
`acteristic of CYP2D6 is, that the enzyme is the source
`of important drug-drug interactions. Thus quinidine,
`pro-pafenone, several neuroleptics and some SSRis are
`very potent inhibitors of CYP2D6. In fact, all SSRis
`inhbit CYP2D6, but fluoxetine, norfluoxetine and
`paroxetine are particularly potent. Thus at the usual
`therapeutic doses of citalopram, fluvoxamine and
`sertraline, it is unlikely that clinically important drug(cid:173)
`drug interactions occur in combination with CYP2D6
`substrates, but with fluoxetine and paroxetine is usu(cid:173)
`ally recommended that doses of the substrate are re(cid:173)
`duced to about 25-50% of the standard dose.
`
`CYP2El only has a marginal role for the oxidation
`of drugs, and in vitro studies have shown, that no SSRI
`inhibits the enzyme to any important degree. CYP3A4
`is quantitatively and probably also qualitatively the
`most important cytochrome P450 enzyme in humans.
`Interestingly the enzyme is expressed also in the gut
`mucosa. The enzyme is inhibited by ketoconazole,
`itraconazole, erythromycin and also by the protease
`inhibitors used in the treatment of AIDS.
`The SSRis have taught the pharmaceutical industry,
`the regulatory authorities and the prescribing physicians
`a lesson. The SSRis are probably (hopefully?) the last
`class of very important drugs that was not character(cid:173)
`ized with regard to CYP interactions by the time they
`were launched (Bn;;sen and Buur Rasmussen, 1996).
`
`REFERENCES
`Bnllsen K and Buur Rasmussen B (1996). Selective serot(cid:173)
`onin reuptake inhibitors: Pharmacokinetics and drug in(cid:173)
`teractions. In Selective serotonin re-uptake inhibitors.
`Advances in basic research and clinical practice, Second
`edition. (Feighner J and Boyer WP eds.) UK: John
`Wiley&Sons. pp. 87-108.
`Hallas J (1995). Drug related hospital admissions in
`subspecialities of internal medicine. Doctoral Thesis,
`Odense University, Denmark. La:geforeningens Forlag,
`Copenhagen, Denmark.
`Jeppesen U, Buur Rasmussen B and Brsz;sen K (1997).
`Fluvoxamine inhibits the CYP2Cl9 catalyzed
`bioactivation of proguanil. Clin Pharmacal Ther 62:279-
`86.
`
`International Clinical Psychopharmacology 1998, Vo\13 (supp\5) S47
`
`Roxane Labs., Inc.
`Exhibit 1007
`Page 007