S P E C I A L T R A N S P L A N T 2 0 0 1
`
`Inhibitors
`of mTOR and FTY 720
`
`
`
`Main Points
`■ Sirolimus : The first representative of the inhibitors
`of mTOR (rnammalian target of rapamycin), sirolimus
`or rapamycin has dose-dependent secondary effects
`which are usually controllable. Sirolimus and tacrolimus
`appear to be combinable at therapeutic doses; the
`same is true of sirolimus and cyclosporine at moderate
`doses. The useful plasma concentrations of sirolimus
`vary from 5 to 20 ng/ml depending on the
`immunosuppressor combinations used. An ability of
`sirolimus to inhibit tumor proliferation and metastatic
`diffusion of a renal adenocarcinoma in the mouse has
`been described. Its complex effects on angiogenesis,
`fibrosis processes, and chronic rejection are being
`analyzed.
`
`
`■ Everolimus: RAD or everolimus is a molecule with a
`short half-life, very close to sirolimus, but inducing
`fewer hematological effects. Regarding the therapeutic
`doses, it requires a circulating level of at least 3 ng/ml to
`prevent rejection; a level greater than 15 ng/ml
`increases the incidence of thrombopenia.
`■ FTY 720 : a new immunosuppressor agent, FTY 720
`does not belong to any known family. It has a mode of
`action totally different from the immunosuppressors
`thus far available: by increasing, on the surface of the
`lymphocytes, the expression of a receptor of the
`chemokins, it allows them to be captured in the
`ganglions and secondary lymphoid organs, rendering
`them unavailable to the rejection reaction. Its half-life is
`very long (108 hours). Due to the features of its hepatic
`metabolism, the risk of drug interactions is very low.
`
`
`Presse Med 2001 © 2001, Masson, Paris
`
`congress
`the
`of
`session
`One
`Transplantation 2001 was devoted to the
`use of sirolimus or rapamycin in kidney
`transplantation and another to that of new
`immunosuppressor agents
`
`Sirolimus
`Sirolimus is the premier representative of
`the inhibitors of mTOR (mammalian target
`Its secondary effects
`of
`rapamycin).
`(thrombopenia, leucopenia, modifications
`of the lipid metabolism, etc.) are dose-
`dependent and usually controllable. But it
`to
`define
`its modes of
`remains
`administration and combination with the
`classical immunosuppressors.
`Many therapy schemes have been
`tested, with or without calcineurin inhibitor
`(cyclosporine or tacrolimus). This latter
`combination seemed ill advised a priori on
`account of the fact that sirolimus and
`tacrolimus bind to the same intracellular
`protein, but with a risk of complications,
`something which has not been confirmed in
`the clinic at therapeutic doses.
`itself
`in
`is not
`Although sirolimus
`its
`combination with
`nephrotoxic,
`cyclosporine appears to increase the risk
`
`
`
`of nephrotoxicity associated with this anti-
`calcineurin. Yet it is important to note that,
`in the majority of these studies, the
`circulating levels of cyclosporine were very
`high (on the order of 300 to 400 ng/ml), in
`the 2 branches studied. These various
`clinical trials on the combination thus
`often lead to a conclusion in favor of the
`halting of cyclosporine for the purpose of
`recovery of a normal kidney function in the
`subject,
`although
`this
`transplanted
`conclusion does not appear to be formally
`validated. In fact, it seems quite illogical to
`sirolimus
`in
`combination with
`use
`cyclosporine or tacrolimus at high doses
`since these 2 types of immunosuppressors
`have totally synergic effects in regard to
`their mode of action. Their combination at
`moderate dose can only be beneficial in
`terms of tolerance. Yet the efficacy of
`these therapy schemes remains to be
`proven.
`One of the more interesting pieces of
`information during this session was given
`by Kahan [1] on the useful plasma levels of
`sirolimus, alone or in combination: he
`advises a target level of 15 ng/ml when
`sirolimus is used in monotherapy or at least
`
`without a calcineurin inhibitor, a level of 8
`to 10 ng/ml when it is combined with
`cyclosporine in low dose, and a level less
`than or equal to 5 ng/ml in combination
`with high doses of cyclosporine. The useful
`plasma concentrations of rapamycin thus
`vary from 5 to 20 ng/ml depending on the
`immunosuppressor combinations used.
`Some authors have used sirolimus in a
`secondary role, in order to diminish the
`nephrotoxic effects of cyclosporine, with
`not always convincing results. In fact, it
`appears that once the kidney function is
`deteriorated, with major histological lesions
`confirmed, the halting of cyclosporine and
`its replacement with sirolimus remains
`practically with no effect.
`Other studies have tested sirolimus
`against cyclosporine in equally very large
`serum concentrations and producing lipid
`anomalies and arterial hypertension. In
`these therapy schemes, the lipid anomalies
`secondary to the administering of sirolimus
`remain more pronounced than under
`cyclosporine, but with no major statistical
`difference.
`
`

`

`S P E C I A L T R A N S P L A N T 2 0 0 1 I n h i b i t o r s o f m T O R a n d F T Y 7 2 0
`
`An exciting abstract (Breitenbuch, abst 549,
`p 250) described the ability of
`sirolimus
`to
`inhibit
`tumor
`proliferation
`and metastatic
`diffusion
`of
`a
`renal
`adenocarcinoma in the mouse, as
`compared to a control, unlike the
`highly
`stimulative effect of
`cyclosporine on tumor diffusion.
`This effect is accompanied by a
`limitation of angiogenesis and a
`lowering of othe circulating level
`of VEGF. This notion should be
`confirmed for other types of
`tumor and in human trials, but as
`of now the preferential use of
`sirolimus
`in
`transplanted
`neoplasic patients is worthy of
`consideration.
`More generally, the complex
`effects
`of
`rapamycin
`on
`angiogenesis,
`fibrosis processes,
`and chronic rejection are being
`investigated.
`In an aortal graft
`model
`in the rat, at
`first
`in
`combination with cyclosporine, it
`limits the vascular lesions of chronic
`rejection
`but
`increases
`the
`expression of
`the
`genes of
`profibrotic
`cytokines, especially
`TGFß. In any case, it is not effective
`in rescue. On the other hand, it
`diminishes
`the proliferation of
`smooth muscle cells. This effect has
`already been utilized in cardiology,
`during the placement of stents
`coated with sirolimus, with very
`favorable
`results
`in
`terms of
`restenosis.
`Thus, there is still a broad field
`for exploration. The
`interest of
`sirolimus needs to be evaluated in
`the
`long
`term,
`in
`reasonable
`protocols in event of combination
`with the anticalcineurins.
`
`The new agents for maintenance of
`immunosuppression
`This session was dedicated in part
`to RAD or everolimus, a molecule
`with a very short half-life, very
`similar to sirolimus but having the
`advantage of
`inducing
`fewer
`hematological effects, and in part to
`an original molecule, FTY 720.
`
`Everolimus
`Everolimus was studied in particular
`in combination with cyclosporine
`
`(Neoral®). This study involved 3
`branches: the first with a dose of
`0.75 mg x 2/day of everolimus, the
`second with a dose of 1.5 mg x
`2/day of everolimus, the third with
`a dose of 2g/day of mycophenolate
`mofetil,
`all
`the
`patients
`furthermore receiving cyclosporine
`(Neoral®) in much more reasonable
`doses than
`in the trials with
`sirolimus
`[2]
`and
`corticoids.
`Everolimus has proven to be as
`effective as mycophenolate mofetil
`against acute rejection and graft
`loss, but at the price of
`lipid
`anomalies
`somewhat
`more
`pronounced and especially an
`increase in creatininemia at one
`year. Thus, everolimus may be
`viewed as a feasible alternative to
`sirolimus.
`Another study [3] was devoted to
`defining the therapeutic zone of
`everolimus based on titration of the
`residual plasma concentrations in
`treated
`patients
`receiving
`3
`different dosages of the product
`taken in fixed and regular manner.
`The effective and non-toxic doses of
`everolimus were thus determined,
`after a treatment of 6 months, as a
`function of the residual levels and
`their
`correlations with
`the
`immunosuppressive efficacy and
`the secondary effects. It is also
`known that it requires a circulating
`level of at least 3 ng/ml of everoli-
`mus to prevent rejection and that a
`level greater
`than 15 ng/ml
`increases
`the
`incidence
`of
`thrombopenia.
`
`FTY 720
`This is a new immunosuppressor
`agent not belonging to any known
`family and having a totally different
`mode
`of
`action
`from
`the
`immunosuppressors available thus
`far. FTY 720 decreases the number of
`peripheral lymphocytes in reversible
`manner. It has no effect on apoptosis
`but increases, on the surface of the
`lymphocytes, the expression of a
`receptor of chemokins (CCR5) which
`allows
`a
`“capture”
`of
`the
`lymphocytes in the ganglions and
`secondary
`lymphoid
`organs,
`modifying the “homing” of the
`lymphocytes and thus rendering
`them unavailable
`in
`triggering
`
`rejection.
`The pharmacokinetics of FTY 720
`has been tested in 16 patients with
`liver failure and an equal number of
`healthy volunteers [4]. FTY 720
`administered orally has a very good
`digestive
`absorption with
`a
`concentration peak greatly spread
`out over time (on the order of 40
`hours). Its half-life is very long, on the
`order of 108 hours, and its hepatic
`metabolism utilizes a subclass of
`cytochrome P 450 very seldom
`employed by known drugs, which
`gives it a very low risk of drug
`interactions. The elimination of the
`metabolites, which are biologically
`inactive, occurs principally by the
`urine. This molecule is used in a
`single dose with cyclosporine A. □
`Text drafted by Marie Solignac based
`on information gathered from D.
`Morel, Hôpital Pellegrin, Bordeaux.
`
`[References]
`1. Kahan BO, Katz SM, Knight RJ.
`Outcome of 300 renal
`transplant recipients treated de nova
`with
`sirolimus
`cyclosporine
`a
`regimen at a single center. AJT 2001
`1 (supp l):abstract 145.
`2. Vrtko R, Margreiter R, Weimar W
`et al The Rad 201
`Study Group International, double-
`blind, parallel group
`study of the safety and efficacy of
`Certican TM(RAD)
`versus myocphenolate mofetil in
`combination with
`Neoral® and steroids. AJT 2001 1
`(suppl) :abstract 1337.
`3. Kovarik JM, Rordorf C, McMahon
`L, Berthier S, Boger R
`Exposure-response relationship for
`everolimus in
`de novo
`renal
`towards defning
`a therapeutic range~ AJT 200 I
`1(supp1 ):abstract 1336.
`4. Barilla D, Choudhury S, Ledford P,
`Figueiredo J,
`Schmauder R Effect of impaired
`hepatic function
`on the systemic exposure of FTY
`720 . AJT 200 l
`l(suppl):abstract 1342.
`
`transplantation:
`
`

`

`M A I N P O I N T S
`
`Inhibitors of mammalian target of rapamycin (mTOR)
`
`■ Sirolimus: The leading member of the mTOR inhibitor family, sirolimus or rapamycin, has dose-dependent side effects
`that can generally be well controlled. Sirolimus can be combined with tacrolimus at therapeutic doses ; likewise for the
`sirolimus-cyclosporine combination at moderate dosage. Effective plasma concentrations of sirolimus vary from 5 to
`20 ng/ml depending on the combination of immunosuppressant agents used. Sirolimus has been shown to inhibit metastatic
`diffusion of renal adenocarcinoma in the mouse. Its complex side effects on angiogenesis, fibro- sis processes and chronic
`rejection are still being investigated.
`
`■ Everolimus: Everolimus, or RAD, has a very short half-life, but induces fewer hematology effects. The therapeutic dose
`must reach at least 3 ng/ml to prevent rejection. Doses above 15 ng/ml increase the risk of thrombocytopenia.
`
`■ FTY 720: A new immunosuppressant agent, FTY 720, does not belong to any known family. It has a totally different
`mechanism of action compared with currently available immunosuppressants. FTY 720 increases the expression of chemokin
`receptors on the surface of T cells making them unavailable for the rejection reaction. FTY 720 has a very long half-life (108
`hours). Due to its particular liver metabolism, there is a very low risk of drug interactions.
`
`Presse Med 2001 © 2001, Masson, Paris
`
`D. Morel
`
`
`
`
`
`
`
`
`
`

`

`PARK·
`
`IP TRA SLATIONS
`~
`..,.2.
`
`May 17. 2017
`
`Cerfificaffon
`
`Pork IP Translations
`
`TRANSLATOR'S DECLARATION:
`
`L Ron Radzrn, hereby declare:
`
`That I p ossess advanced knowledge of the French and English languages. The
`attached French into English translation has been translated by me and to the
`best of my knowledge and belief. it is a true and accurate translation of: Les
`inhibiteurs de la. mTOR et le FTY 720
`
`[translator name)
`
`Project Number. M EGOP _ 1705_006
`
`15 W. 37th Street 8th Floor
`New Yoo, NY 10018
`212.581.8870
`PorklP.com
`
`
`
`

`

`~ l ____,....-,----,..,...,...,.,,,...,~......,_..,..._
`I . '''.'.;f,['.~;S}if://}J\f;
`
`Tome 30 / n° 24 - Cahier 2 / 1 er septembre 2001
`
`CONGRES TRANSPLANT 2001
`Chicago, 11 au 16 mai
`
`SOM MAIRE
`
`Editorial
`Y. Lebranchu ................................................................................................................................................. 3
`Quoi de neuf en transplantation en 2001 7
`E. Thervet ...................................................................................................................................................... 5
`Les complications en transplaJ1tation cardiaque
`S. Bangratz .................................................................................................................................................... 8
`Les complications en transplantation renale
`N. Ouali ....................................................................................................................................................... 13
`Les infections virales en transplantation renale
`B. Hurault de Ligny ..................................................................................................................................... 16
`Le point sur les transplantations d'ilots de Langerhans
`F. Bayle ........................................................................................................................................................ 19
`Prevention et traitement du diabete de type 1
`G. Choukroun .............................................................................................................................................. 21
`Transplantation hepatique et d9nneur vivant
`P. Campan ................................................................................................................................................... 24
`Des specificites a connaitre chez les femmes ayant re~u
`une transplantation d'organe
`S. di Filippo ................................................................................................................................................. 27
`lschemie-reperfusion
`R. Cursio .......... ; .......................................................................................................................................... 29
`Alloreconnaissance
`Y. Lebranchu ............................................................................................................................................... 31
`Les inhibiteurs de la mTor et le FTV 720
`D. Morel .............................................................................................. : ....................................................... 35
`lmmunosuppression, les essais cliniques en cours
`l Riva/an ..................................... ~ ............................................................................................................... 38
`Anticorps et immunomodulation
`F. Berthoux .................................................................................................................................................. 41
`Minimisation de l'immunosuppression
`E. Thervet .................................................................................................................................................... 44
`
`Textes rediges par Marie Solignac et Delphine Olivier d'apres !es informations recueillies
`aupres de /eurs auteurs /ors du congres TRANSPLANT 2001, qui s'est tenu a Chicago
`du 17 au 16 mai 2001.
`
`...
`
`: M((:.
`, nr; '.:;:fY .
`
`·?'='·
`
`Photo de couverture: © SCOPE. Chicago
`
`lndexe dans/lndexed in :
`i Current Conten1s/Clinical Medicine, Life Sciences ; EMBASE (Excerpt.a Medica) ; Medline (Index Medicus) ; Pascal
`· {INIST/CNRS); Research Alert; Science Citation Index; SCI Search.
`
`'
`• 1er ,PntPmhrP ?()nl / -i;n In° ?4 -
`
`r;:ihiPr?
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`
`Les inhibiteurs
`de la mTOR et le FTY 720
`
`CfESSENTIEL
`
`111 Le sirolimus: Premier representant des inhibiteurs de la mTOR (mam(cid:173)
`malian target of rapamycin), le sirolimus ou rapamycine a des effets
`secondaires dose-dependants habituellement maitrisables. Le sirolimus
`et le tacrolimus semblent pouvoir etre associes a doses therapeutiques ;
`ii en est de meme pour le sirolimus et la ciclosporine a doses moderees.
`Les concentrations plasmatiques utiles du sirolimus varient de 5 a 20 ng/ml
`selon !es associations d'immunosuppresseurs utilisees. II a ete decrit
`une capacite du sirolimus a inhiber la proliferation tumorale et la diffusion
`metastatique d' un adenocartinome renal chez la souris. Ses effets
`complexes sur I' angiogenese, les processus fibrotiques et le rejet
`chronique sont en cours d'analyse.
`m L'everolimus: Le RAD ou everolimus est une molecule a demi-vie
`tres courte, tres proche du sirolimus, mais induisant moins d'effets
`
`hematologiques. Concernant !es doses therapeutiques, ii faut un taux
`circulant d'au moins 3 ng/ml pour eviter le rejet; un taux superieur
`a 15 ng/ml augmente !'incidence des thrombopenies.
`11 Le. FTY no : Nouvel agent immunosuppresseur, le FTY 720
`n'appartient a aucune famille connue.11 a un mode d'action totalement
`different des immunosuppresseurs disponibles jusqu' alors :
`en augmentant a la surface des lymphocytes, !'expression d'un recepteur
`des chemokines, ii permet leur capture dans les ganglions et organes
`lympho"ides secondaires, ce qui les rend indisponibles pour la reaction
`de rejet. Sa demi-vie est tres longue ( 108 heures). Du fait des particularites
`de son metabolisme hepatique, le risque d'interactions medicamenteuses
`est tres faible.
`
`Presse Med 2001 C 200 l, Masson, Paris
`
`U ne session du congres Transplantation
`2001 a ete consacree a !'utilisation du
`sirolimus ou rapamycine en transplantation
`renale et une autre a celle de nouveaux
`agents immunosupresseurs
`
`Le sirolimus
`1 Le sirolimus est le premier representant des
`-~lnhibiteurs de la mTOR (mammalian target of
`! ropamycin). Ses effets secondaires (thrombo-
`1 penies, leucopenies, modifications du meta-
`1 bolisme lipidique ... ) sont dose-dependants et
`habituellement maitrisables. Mais ii reste a
`definir ses modalites d'administration et d'as(cid:173)
`sociation aux irnmunosuppresseurs classiques. ·
`.De nombreux s~hemas therapeutiques ont
`ete testes, avec ou sans inhibiteur de I.a calci-
`1 neurine ( ciclosporine ou tacrolimus ). Cette
`1 derniere association semblait a priori decon(cid:173)
`seillee compte tenu du fait que le sirolimus
`1 et le tacrolimus se lient a la meme proteine
`intra-cellulaire, done avec un risque de com(cid:173)
`plications, ce qui n'a pas ete confirme en cli(cid:173)
`nique aux doses therapeutiques.
`Bien que le sirolimus ne soit pas par lui-
`1 meme nephrotoxique, son association a_ la
`ciclosporine semble augmenter le risque de
`
`rd:
`
`l er septembre 2001 / 30 / n° 24 - G:ahier 2
`
`nephrotoxicite lie a cet anti-calcineurine.
`Mais il est important de noter que, dans la
`plupart de ces etudes, les taux circulants de
`ciclosporine etaient tres eleves ( de l'ordre
`de 300 a 400 ng/ml), dans les 2 bras etu(cid:173)
`dies. Ces differents essais cliniques d'asso(cid:173)
`ciation debouchent done souvent sur une
`conclusion en faveur de l'arret de la ciclo(cid:173)
`sporine dans l'objectif de faire recuperer
`une fonction renale normale au sujet trans(cid:173)
`plante, conclusion qui cependant n'apparait
`pas fonnellement validee. En fait, ii semble
`parfaitement illogique d'utiliser le sirolimus
`en association a la ciclosporine ou au tacro(cid:173)
`limus a des doses elevees puisque ces 2
`types d'immunosuppresseurs ont des effets
`tout a fait synergiques quanta leur mode
`d' action. Leur association a dose moderee
`ne peut qu, etre benefique quant a la tole(cid:173)
`rance. Mais l 'efficacite de ces schemas the(cid:173)
`rapeutiques reste a prouver.
`Une des informations les plus interes(cid:173)
`santes de cette session a ete donnee par
`Kahan [I] sur les taux plasmatiques utiles de
`sirolimus, seul ou en association : il
`conseille de viser un taux de 15 ng/ml
`lorsque le sirolimus est utilise en monothe-
`
`rapie ou du mains sans inhibiteur de la cal(cid:173)
`cineurine, un taux de 8 a 10 ng/ml lorsqu' i1
`est associe a la ciclosporine a faible dose et
`un taux inferieur OU egal a 5 ng/ml en asso(cid:173)
`ciation avec de fortes doses de ciclosporine.
`Les concentrations plasmatiques utiles de
`rapamycine varient done de 5 a 20 ng/ml
`selon les associations d'immunosuppresseurs
`utilisees.
`Certains auteurs ont utilise le sirolimus en
`seconde ligne, clans l'objectif de diminuer les
`effets nephrotoxiques de la ciclosporine,
`avec des resultats pas toujours probants. II
`semble en effet qu'une fois la fonction renale
`deterioree, avec des lesions histologiques
`importantes averees, l'arret de la ciclosporine
`et son remplacement par le s'irolimus restent .
`pratiquement sans effet.
`D'autres etudes ont teste le sirolimus
`contre la ciclosporine a des concentrations
`seriques aussi tres importantes et entrainant
`· des anomalies d'ordre lipidique et une
`hypertension arterielle. Dans ces sche(cid:173)
`mas therapeutiques, Jes anomalies lipidiques
`secondaires a la prise de sirolimus restent
`plus marquees que sous ciclosporine, mais
`sans difference statistique majeure.
`eoe
`
`La Presse Medicale-+ 15
`
`

`

`Un abstract passionnant (Breitenbuch,
`abst 549, p 250)·a decrit la capacite du siro(cid:173)
`limus a inhiber la proliferation tumorale et ·
`la diffusion metastatique d'un adenocarci(cid:173)
`nome renal chez la souris, par rapport au
`temoin, au contraire de l 'effet tres stimulant
`de la ciclosporine sur la diffusion tumorale.
`Cet effet s'accompagne d'une limitation de
`l'angiogenese et d'une baisse du taux circu(cid:173)
`lant de VEGF. Cette notion doit etre confir(cid:173)
`mee pour d'autres types de tumeurs et en cli(cid:173)
`nique humaine mais, d'ores et deja, !'utilisa(cid:173)
`tion preferentielle du sirolimus chez les
`patients transplantes neoplasiques merite
`d'etre consideree.
`D'une maniere plus generale, les effets
`complexes de la raparnycine sur l'angioge(cid:173)
`nese, les processus fibrotiques, done le rejet
`chronique sont en cours d'analyse. Dans un
`modele de greff e d' aorte chez le rat, en
`association d'emblee avec la ciclosporine,
`elle limite les lesions vasculaires de rejet
`chronique, mais augmente l'expression des
`genes de cytokines profibrotiques, en parli(cid:173)
`culier le TGF~. De toute favon, elle n'est
`pas efficace en rescue. Par contre, elle dimi(cid:173)
`nue la proliferation des cellules musculaires
`lisses. Cet effet a deja ete utilise en cardio(cid:173)
`logie, lors de la pose de stents recouverts de
`sirolimus, avec des resultats tres favorables
`en termes de restenose.
`II y a done, la encore, tout un champ
`d'exploration. L'interet du sirolimus doit
`etre apprecie a long terme, .dans des proto-
`
`coles raisonnables en cas d'association avec
`les anticalcineurines.
`
`Les nouveaux agents
`de maintenance
`de l'immunosuppression
`Cette session etait dediee pour moitie au
`RAD ou everolimus, molecule a demi-vie
`tres courte, tres proche du sirolimus mais
`ayant l'avantage d'induire moins d'effets
`hematologiques et, pour l'autre moitie, a une
`molecule originate, le FTY 720.
`
`Everolimus
`L'everolimus a notarnment ete etudie en asso(cid:173)
`ciation avec la ciclosporine (Neoral®). Cette
`etude comportait 3 bras : le premier avec une
`dose de 0, 75 mg x 2/j d'everolimus, le second
`avec une dose de 1,5 mg x 2/j d'everolimus,
`le troisieme avec une dose de 2g/j d~ myco(cid:173)
`phenolate mofetil, tous les patients recevant
`en outre de la ciclosporine (Neoral®) a des
`doses beaucoup plus raisonnables que dans
`les essais avec le sirolimus [2] et des corti(cid:173)
`coides. L'everolimus s'est montre aussi effi(cid:173)
`cace que le mycophenolate mofetil vis-a-vis
`du rejet aigu et de la perte de greffon, mais au
`prix d'anomalies lipidiques un peu plus mar(cid:173)
`quees et surtout d'une augmentation de la
`creatininemie a un an. L'everolimus peut done
`etre considere comme une alternative valable
`au sirolimus.
`Une autre etude [3] s'est attachee a defi(cid:173)
`nir la zone therapeutique de l'everolimus a
`
`partir du dosage des concentrations plas(cid:173)
`matiques residuelles, chez des patients trai(cid:173)
`tes recevant 3 posologies differentes du
`produit pris de far;on fixe et reguliere. Les
`doses efficaces et non toxiques d'everoli(cid:173)
`mus ont ainsi ete determinees, apres un
`traitement de 6 mois, en fonction des taux
`residuels et de leurs correlations avec l'ef(cid:173)
`ficacite immunosuppressive et les effets
`·secondaires. On sait ainsi qu'il faut un taux
`circulant d'au minimum 3 ng/ ml d'everoli(cid:173)
`mus pour eviter le rejet et qu'un taux supe(cid:173)
`rieur a 15 ng/ ml augmente !'incidence des
`thrombopenies.
`
`___ i._
`
`FTY720
`11 s'agit d'un nouvel agent immunosuppres(cid:173)
`seur n'appartenant a aucune famille connue
`et possedant un mode d'action totalement
`different des immunosuppresseurs jusqu'a
`mainteriant disponibles. Le FTY 720 dimi(cid:173)
`nue de fa~on reversible le nombre de lym(cid:173)
`phocytes peripheriques. II ne joue absolu(cid:173)
`ment pas, sur l'apoptose mais augmente, a
`la surface des lymphocytes, I 'expression
`d'un recepteur des chemokines (CCR5) qui
`permet la « capture » des lymphocytes dans
`les ganglions et les organes lymphoides
`secondaires, modifiant le « homing » des
`lymphocytes et les rendant done indispo(cid:173)
`nibles pour declencher le rejet.
`La pharmacocinetique du FTY 720 a ete
`testee chez 16 patients insuffisants hepa(cid:173)
`tiques et un meme nombre de volontaires
`
`MAIN POINTS
`
`Inhibitors of mammalian target of rapamycin (mTOR)
`
`• Sirolimus: The leading member of the mTOR inhipitor family, sirolimus
`or rapamycin, has dose-dependent side effects that can generally be well
`controlled. Sirolimus can be combined with tacrolimus at therapeutic
`doses ; likewise for the sirolimus-cyclosporine combination at moderate
`dosage. Effective plasma concentrations of sirolimus vary from 5 to
`20 ng/ml depending on the combination of immunosuppressant agents
`used. Sirolimus has been shown to inhibit metastatic diffusion of renal ade(cid:173)
`nocarcinoma in the mouse. Its complex side effects on angiogenesis, fibro(cid:173)
`sis processes and chronic rejection are still being investigated.
`
`a Everolimus: Everolimus, or RAD, has a very short half-life, but induces
`fewer hematologic effects. The therapeutic dose must reach at least
`
`3 ng/ml to prevent·rejection. Doses above 15 ng/ml increase the risk
`of thrombocytopenia.
`
`• FTY 720: A new immunosuppressant agent, FrY 720, does not belong
`to any known family. It has a totally different mechanism of action
`compared with currently available immunosuppressants. FTY 720 increases
`the expression of chemokin receptors on the surface of T cells making
`them unavailable for the rejection reaction. FTY 720 has a very long half-life
`(108 hours). Due to its particular liver metabolism, there is a very low risk
`of drug interactions.
`
`Presse Med 2001 © 2001, Masson, Paris
`
`D. Morel
`
`I
`I'
`L
`
`

`

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`
`D. Morel
`
`sains [4]. Le FTY 720 administre par voie
`orate a une.tres bonne absorption digestive
`avec un pie de concentration tres etale dans
`le temps (de l'ordre de 40 heures). Sa
`demi-vie est tres longue, de J1ordre de 108
`heures, et son metabolisme hepatique uti(cid:173)
`lise une sous-classe de cytochrome P 450
`tres peu employee par Jes medicaments
`connus, ce qui lui confere un tres faible
`risque d 1interactions medicamenteuses.
`L'elimination des metabolites, biologique(cid:173)
`ment inactifs, se fait principalement par
`
`voie urinaire. Cette molecule s 1utilise en
`dose unique avec la ciclosporine A. 0
`
`Texte redige par Marie Solignac d'apres Jes
`informations recueillies aupres de D. Morel,
`Hopital Pellegrin, Bordeaux.
`
`[References 1
`
`1. Kahan 8D, Katz SM, Knight RJ. Outcome of 300 renal
`transplant recipients treated de novo with a sirolimus~
`
`cydosporine regimen at a single center. AJT 200 l
`1 (supp 1) :abstract 145.
`2. Vitko R, Margreiter R, Weimar Wet al. The Rad 201
`Study Group International. double-blind, parallel group
`study of the safety and efficacy of Certican TM(RAD)
`versus myocphenolate mof etil in combination with
`Neoral® and steroids. AJT 200 l 1 ( supp 1 ) :abstract 1337.
`3. Kovarik JM, Rordorf C, McMahon L, Berthier S, Boger R.
`Exposure-response relationship for everolimus in
`de novo renal transplantation : towards defning
`a therapeutic range. AJT 2001 1 (supp 1 ):abstract 1336.
`4. Barilla D, Choudhury S, Ledford P, Figueiredo J,
`Schmouder R Effect of impaired hepatic function
`on the systemic exposure of FTY 720. AJT 2001
`l(suppl):abstract 1342.
`
`-rl
`
`1 er septembre 2001 / 30 / n° 24 .,.. Cahier 2
`
`La Presse Medicale .... 3 7
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`

`

`Tome 30 / n° 24 - Cahier 2 / 1 er septembre 2001
`
`ISSN 0755-4982
`
`TRANSPLANT
`2001
`
`11-16 mai 2001
`Chicago, Illinois
`
`fD MASSON __ __.
`
`