Brain Penetration of the Oral Immunomodulatory Drug FTY720 and Its Phosphorylation in the Central Nervous System during Experimental Autoimmune Encephalomyelitis: Consequences for Mode of Action in Multiple Sclerosis

  1. Carolyn A. Foster,
  2. Laurence M. Howard,
  3. Alain Schweitzer,
  4. Elke Persohn,
  5. Peter C. Hiestand,
  6. Balázs Balatoni1,
  7. Roland Reuschel,
  8. Christian Beerli,
  9. Manuela Schwartz2 and
  10. Andreas Billich
  1. Novartis Institutes for BioMedical Research, Vienna, Austria (C.A.F., L.M.H., B.B., R.R., M.S., A.B.); Novartis Institutes for BioMedical Research, Basel, Switzerland (P.C.H., C.B.); Novartis Pharma AG, Basel, Switzerland (A.S.); and Novartis Pharma AG, Muttenz, Switzerland (E.P.)
  1. Address correspondence to:
    Dr. Andreas Billich, Novartis Institutes for BioMedical Research, Brunner Strasse 59, A-1235 Vienna, Austria. E-mail: andreas.billich{at}novartis.com

Abstract

FTY720 [2-amino-2-[2-(4-octylphenyl) ethyl]propane-1,3-diol hydrochloride] is an oral sphingosine-1-phosphate receptor modulator under development for the treatment of multiple sclerosis (MS). The drug is phosphorylated in vivo by sphingosine kinase 2 to its bioactive form, FTY720-P. Although treatment with FTY720 is accompanied by a reduction of the peripheral lymphocyte count, its efficacy in MS and experimental autoimmune encephalomyelitis (EAE) may be due to additional, direct effects in the central nervous system (CNS). We now show that FTY720 localizes to the CNS white matter, preferentially along myelin sheaths. Brain trough levels of FTY720 and FTY720-P in rat EAE are of the same magnitude and dose dependently increase; they are in the range of 40 to 540 ng/g in the brain tissue at efficacious doses and exceed blood concentrations severalfold. In a rat model of chronic EAE, prolonged treatment with 0.03 mg/kg was efficacious, but limiting the dosing period failed to prevent EAE despite a significant decrease in blood lymphocytes. FTY720 effectiveness is likely due to a culmination of mechanisms involving reduction of autoreactive T cells, neuroprotective influence of FTY720-P in the CNS, and inhibition of inflammatory mediators in the brain.

Footnotes

  • This work was supported by Novartis Pharma AG.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.107.127183.

  • ABBREVIATIONS: FTY720, fingolimod, 2-amino-2-[2-(4-octylphenyl) ethyl]propane-1,3-diol hydrochloride; MS, multiple sclerosis; EAE, experimental autoimmune encephalomyelitis; SPHK, sphingosine kinase; CNS, central nervous system; DA, Dark Agouti; CFA, complete Freund's adjuvant; CsA, cyclosporine A; QWBA, quantitative whole-body autoradiography; CSF, cerebrospinal fluid; ANOVA, analysis of variance; AUC, area under the curve; FTY720-P, 2-amino-2-[2-(4-octylphenyl) ethyl) propane-1,3-diol-1-(dihydrogen phosphate); FK506, tacrolimus.

  • ↵1 Current affiliation: Novartis Hungary Healthcare, Budapest, Hungary.

  • ↵2 Current affiliation: Evangelisches Krankenhaus, Vienna, Austria.

    • Received June 24, 2007.
    • Accepted August 3, 2007.
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  1. Published online before print August 6, 2007, doi: 10.1124/jpet.107.127183 JPET November 2007 vol. 323 no. 2 469-475
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