Molecular Medicine

, Volume 17, Issue 5–6, pp 353–362 | Cite as

Pharmacokinetics, Safety and Inducible Cytokine Responses during a Phase 1 Trial of the Oral Histone Deacetylase Inhibitor ITF2357 (Givinostat)

  • Antonio Furlan
  • Valmen Monzani
  • Leonid L Reznikov
  • Flavio Leoni
  • Gianluca Fossati
  • Daniela Modena
  • Paolo Mascagni
  • Charles A Dinarello
Research Article


ITF2357 (givinostat) is a histone deacetylase inhibitor with antiinflammatory properties at low nanomolar concentrations. We report here a phase I safety and pharmacokinetics trial in healthy males administered 50, 100, 200, 400 or 600 mg orally. After 50mg, mean maximal plasma concentrations reached 104 nmol/L 2 h after dosing, with a half-life of 6.9 h. After 100 mg, maximal concentration reached 199 nmol/L at 2.1 h with a half-life of 6.0 h. Repeat doses for 7 consecutive days of 50, 100 or 200 mg resulted in nearly the same kinetics. There were no serious adverse effects (AEs) and no organ toxicities. However, there was a dose-dependent but transient fall in platelets. After 7 daily doses of 50 or 100 mg, the mean decrease in platelets of 17 and 25% was not statistically significant and returned to baseline within 14 d. Blood removed from the subjects after oral dosing was cultured ex vivo with endotoxin, and the release of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-1Ra, interferon (IFN)-γ and IL-10 was determined. Maximal reduction in IL-1β, TNFα, IL-6 and IFNγ was observed 4 h after dosing but returned to baseline at 12 h. There was no significant reduction in IL-1Ra or IL-10. With daily dosing, the fall in cytokine production in blood cultures observed on day 7 was nearly the same as that of the first day. We conclude that dosing of 50 or 100 mg ITF2357 is safe in healthy humans and transiently but repeatedly reduces the production of proinflammatory cytokines without affecting production of antiinflammatory cytokines.



This study was supported by Italfarmaco, S.p.A., and by National Institutes of Health Grant AI-15614 (to CA Dinarello).


  1. 1.
    Narlikar GJ, Fan HY, Kingston RE. (2002) Cooperation between complexes that regulate chromatin structure and transcription. Cell. 108:475–87.CrossRefGoogle Scholar
  2. 2.
    Johnstone RW. (2002) Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat. Rev. Drug. Discov. 1:287–99.CrossRefGoogle Scholar
  3. 3.
    Marks PA, Miller T, Richon VM. (2003) Histone deacetylases. Curr. Opin. Pharmacol. 3:344–51.CrossRefGoogle Scholar
  4. 4.
    Kelly WK, et al. (2005) Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J. Clin. Oncol. 23:3923–31.CrossRefGoogle Scholar
  5. 5.
    Kelly WK, et al. (2003) Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously. Clin. Cancer Res. 9:3578–88.PubMedGoogle Scholar
  6. 6.
    Butler LM, et al. (2002) The histone deacetylase inhibitor SAHA arrests cancer cell growth, up-regulates thioredoxin-binding protein-2, and down-regulates thioredoxin. Proc. Natl. Acad. Sci. U. S. A. 99:11700–5.CrossRefGoogle Scholar
  7. 7.
    Della Ragione F, et al. (2001) Genes modulated by histone acetylation as new effectors of butyrate activity. FEBS Lett. 499:199–204.CrossRefGoogle Scholar
  8. 8.
    Van Lint C, Emiliani S, Verdin E. (1996) The expression of a small fraction of cellular genes is changed in response to histone hyperacetylation. Gene Expr. 5:245–53.PubMedGoogle Scholar
  9. 9.
    Suzuki H, et al. (2002) A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nat. Genet. 31:141–9.CrossRefGoogle Scholar
  10. 10.
    Leoni F, et al. (2002) The antitumor histone deacetylase inhibitor suberoylanilide hydroxamic acid exhibits antiinflammatory properties via suppression of cytokines. Proc. Natl. Acad. Sci. U. S. A. 99:2995–3000.CrossRefGoogle Scholar
  11. 11.
    Skov S, et al. (2003) Histone deacetylase inhibitors: a new class of immunosuppressors targeting a novel signal pathway essential for CD154 expression. Blood. 101:1430–8.CrossRefGoogle Scholar
  12. 12.
    Mishra N, Reilly CM, Brown DR, Ruiz P, Gilkeson GS. (2003) Histone deacetylase inhibitors modulate renal disease in the MRL-lpr/lpr mouse. J. Clin. Invest. 111:539–52.CrossRefGoogle Scholar
  13. 13.
    Reddy P, et al. (2004) Histone deacetylase inhibitor suberoylanilide hydroxamic acid reduces acute graft-versus-host disease and preserves graft-versus-leukemia effect. Proc. Natl. Acad. Sci. U. S. A. 101:3921–6.CrossRefGoogle Scholar
  14. 14.
    Reilly CM, et al. (2004) Modulation of renal disease in MRL/lpr mice by suberoylanilide hydroxamic acid. J. Immunol. 173:4171–8.CrossRefGoogle Scholar
  15. 15.
    Leng C, et al. (2006) Reduction of graft-versus-host disease by histone deacetylase inhibitor suberonylanilide hydroxamic acid is associated with modulation of inflammatory cytokine milieu and involves inhibition of STAT1. Exp. Hematol. 34:776–87.CrossRefGoogle Scholar
  16. 16.
    Glauben R, et al. (2008) Histone deacetylases: novel targets for prevention of colitis-associated cancer in mice. Gut. 57:613–22.CrossRefGoogle Scholar
  17. 17.
    Glauben R, et al. (2006) Histone hyperacetylation is associated with amelioration of experimental colitis in mice. J. Immunol. 176:5015–22.CrossRefGoogle Scholar
  18. 18.
    Mishra N, Brown DR, Olorenshaw IM, Kammer GM. (2001) Trichostatin A reverses skewed expression of CD154, interleukin-10, and interferon-gamma gene and protein expression in lupus T cells. Proc. Natl. Acad. Sci. U. S. A. 98:2628–33.CrossRefGoogle Scholar
  19. 19.
    Leoni F, et al. (2005) The histone deacetylase inhibitor ITF2357 reduces production of pro-inflammatory cytokines in vitro and systemic inflammation in vivo. Mol. Med. 11:1–15.CrossRefGoogle Scholar
  20. 20.
    Vojinovic J, Damjanov N. (2011) HDAC inhibition in rheumatoid arthritis and juvenile idiopathic arthritis. Mol. Med. 17:397–403.CrossRefGoogle Scholar
  21. 21.
    Vojinovic J, et al. (2011) Safety and efficacy of an oral histone deacetylase inhibitor in systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 63:1452–8.CrossRefGoogle Scholar
  22. 22.
    Wakabayashi K, et al. (2005) Gene expression associated with the decrease in malignant phenotype of human liver cancer cells following stimulation with a histone deacetylase inhibitor. Int. J. Oncol. 26:233–9.PubMedGoogle Scholar
  23. 23.
    Marks PA, Richon VM, Rifkind RA. (2000) Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells. J. Natl. Cancer Inst. 92:1210–6.CrossRefGoogle Scholar
  24. 24.
    Chen L, Fischle W, Verdin E, Greene WC. (2001) Duration of nuclear NF-kappaB action regulated by reversible acetylation. Science. 293:1653–7.CrossRefGoogle Scholar
  25. 25.
    Pascual V, Allantaz F, Arce E, Punaro M, Banchereau J. (2005) Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade. J. Exp. Med. 201:1479–86.CrossRefGoogle Scholar
  26. 26.
    Hawkins PN, Lachmann HJ, Aganna E, McDermott MF. (2004) Spectrum of clinical features in Muckle-Wells syndrome and response to anakinra. Arthritis Rheum. 50:607–12.CrossRefGoogle Scholar
  27. 27.
    Agostini L, et al. (2004) NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity 20:319–25.CrossRefGoogle Scholar
  28. 28.
    Hoffman HM, et al. (2004) Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist. Lancet 364:1779–85.CrossRefGoogle Scholar
  29. 29.
    Lovell DJ, Bowyer SL, Solinger AM. (2005) Interleukin-1 blockade by anakinra improves clinical symptoms in patients with neonatal-onset multisystem inflammatory disease. Arthritis Rheum. 52:1283–6.CrossRefGoogle Scholar
  30. 30.
    Drenth JP, Goertz J, Daha MR, van der Meer JW. (1996) Immunoglobulin D enhances the release of tumor necrosis factor-alpha, and interleukin-1 beta as well as interleukin-1 receptor antagonist from human mononuclear cells. Immunology. 88:355–62.CrossRefGoogle Scholar
  31. 31.
    de Koning HD, et al. (2006) Beneficial response to anakinra and thalidomide in Schnitzler’s syndrome. Ann. Rheum. Dis. 65:542–4.CrossRefGoogle Scholar
  32. 32.
    Hoffman HM, Wright FA, Broide DH, Wanderer AA, Kolodner RD. (2000) Identification of a locus on chromosome 1q44 for familial cold urticaria. Am. J. Hum. Genet. 66:1693–98.CrossRefGoogle Scholar
  33. 33.
    Andrei C, et al. (2004) Phospholipases C and A2 control lysosome-mediated IL-1 beta secretion: implications for inflammatory processes. Proc. Natl. Acad. Sci. U. S. A. 101:9745–50.CrossRefGoogle Scholar
  34. 34.
    Solle M, et al. (2001) Altered cytokine production in mice lacking P2X(7) receptors. J. Biol. Chem. 276:125–32.CrossRefGoogle Scholar
  35. 35.
    Laliberte RE, Eggler J, Gabel CA. (1999) ATP treatment of human monocytes promotes cas-pase-1 maturation and externalization. J. Biol. Chem. 274:36944–51.CrossRefGoogle Scholar
  36. 36.
    Carta S, et al. (2006) Histone deacetylase inhibitors prevent exocytosis of interleukin-1beta-containing secretory lysosomes: role of microtubules. Blood. 108:1618–26.CrossRefGoogle Scholar
  37. 37.
    Dinarello CA. (2005) Differences between antitumor necrosis factor-alpha monoclonal antibodies and soluble TNF receptors in host defense impairment. J. Rheumatol. Suppl. 74:40–47.PubMedGoogle Scholar

Copyright information

© The Feinstein Institute for Medical Research 2011

Authors and Affiliations

  • Antonio Furlan
    • 1
    • 2
  • Valmen Monzani
    • 3
  • Leonid L Reznikov
    • 1
  • Flavio Leoni
    • 3
  • Gianluca Fossati
    • 3
  • Daniela Modena
    • 3
  • Paolo Mascagni
    • 3
  • Charles A Dinarello
    • 1
  1. 1.Department of MedicineUniversity of Colorado DenverAuroraUSA
  2. 2.Department of Clinical and Experimental Medicine, Rheumatology UnitUniversity of PadovaPadovaItaly
  3. 3.Italfarmaco, S.p.A.Cinisello BalsamoItaly

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