Cancer Chemotherapy and Pharmacology

, Volume 69, Issue 2, pp 555–562 | Cite as

The effect of food on the bioavailability of panobinostat, an orally active pan-histone deacetylase inhibitor, in patients with advanced cancer

  • Geoffrey I. Shapiro
  • Richard Frank
  • Uday B. Dandamudi
  • Thomas Hengelage
  • Lily Zhao
  • Lucien Gazi
  • Maria Grazia Porro
  • Margaret M. Woo
  • Lionel D. Lewis
Clinical Trial Report



Panobinostat is a novel oral pan-deacetylase inhibitor with promising anti-cancer activity. The study aimed to determine the influence of food on the oral bioavailability of panobinostat.


This multicenter study consisted of a randomized, three-way crossover, food-effect study period (cycle 1) followed by single-agent panobinostat continual treatment phase in patients with advanced cancer. Patients received panobinostat 20 mg twice weekly, and panobinostat pharmacokinetics was investigated on days 1, 8, and 15 with a randomly assigned sequence of three prandial states (fasting, high-fat, and normal breakfast).


Thirty-six patients were assessed for the food effect on pharmacokinetics and safety in cycle 1, after which 29 patients continued treatment, receiving single-agent panobinostat. Safety and antitumor activity were assessed during the extension period. Panobinostat systemic exposure was marginally reduced (14–16%) following food [geometric mean ratio (GMR) of the AUC0−∞/high-fat breakfast/fasting, 0.84 (90% confidence interval {CI}, 0.74–0.96); normal breakfast/fasting, 0.86 (90% CI, 0.75–1.00)], and interpatient variability (coefficient of variation, 59%) remained essentially unchanged with or without food. Panobinostat C max was reduced by 44% (high-fat) and 36% (normal) with median T max prolonged by 1–1.5 h following food. Panobinostat was well tolerated, with thrombocytopenia, fatigue, nausea, and vomiting as common adverse events, and demonstrated antitumor activity with one patient with a partial response and six patients with stable disease as best response.


Food produced minor changes in oral panobinostat exposure; thus, panobinostat can be given without regard to food intake in future clinical studies.


Panobinostat Pharmacokinetics Histone deacetylase inhibitor Food 



We are grateful to the participating patients and their families. William Fazzone, PhD and Peter Simon, PhD provided medical editorial assistance for this manuscript. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals. We thank Wenkui Li, PhD, Jennifer Gallagher, and the study teams at our respective institutions for contributions to the conduct and analysis of the trial.


  1. 1.
    Bolden JE, Peart MJ, Johnstone RW (2006) Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 5:769–784PubMedCrossRefGoogle Scholar
  2. 2.
    Atadja P (2009) Development of the pan-DAC inhibitor panobinostat (LBH589): successes and challenges. Cancer Lett 280:233–241PubMedCrossRefGoogle Scholar
  3. 3.
    Prince HM, Bishton MJ, Johnstone RW (2009) Panobinostat (LBH589): a potent pan-deacetylase inhibitor with promising activity against hematologic and solid tumors. Future Oncol 5:601–612PubMedCrossRefGoogle Scholar
  4. 4.
    Catley L, Weisberg E, Kiziltepe T, Tai YT, Hideshima T, Neri P, Tassone P, Atadja P, Chauhan D, Munshi NC, Anderson KC (2006) Aggresome induction by proteasome inhibitor bortezomib and alpha-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells. Blood 108:3441–3449PubMedCrossRefGoogle Scholar
  5. 5.
    Ocio EM, Vilanova D, Atadja P, Maiso P, Crusoe E, Fernandez-Lazaro D, Garayoa M, San-Segundo L, Hernandez-Iglesias T, de Alava E, Shao W, Yao YM, Pandiella A, San-Miguel JF (2010) In vitro and in vivo rationale for the triple combination of panobinostat (LBH589) and dexamethasone with either bortezomib or lenalidomide in multiple myeloma. Haematologica 95:794–803PubMedCrossRefGoogle Scholar
  6. 6.
    Maiso P, Colado E, Ocio EM, Garayoa M, Martin J, Atadja P, Pandiella A, San-Miguel JF (2009) The synergy of panobinostat plus doxorubicin in acute myeloid leukemia suggests a role for HDAC inhibitors in the control of DNA repair. Leukemia 23:2265–2274PubMedCrossRefGoogle Scholar
  7. 7.
    Lemoine M, Buglio D, Jona A, Derenzini E, Medeiros LJ, Berry DA, Younes A (2010) The pan-deacetylase inhibitor panobinostat downregulates HIF-1{alpha} and VEGF and, synergizes with everolimus in Hodgkin lymphoma cell lines [abstract]. Blood 116:2851CrossRefGoogle Scholar
  8. 8.
    Welsbie DS, Xu J, Chen Y, Borsu L, Scher HI, Rosen N, Sawyers CL (2009) Histone deacetylases are required for androgen receptor function in hormone-sensitive and castrate-resistant prostate cancer. Cancer Res 69:958–966PubMedCrossRefGoogle Scholar
  9. 9.
    Rao R, Nalluri S, Kolhe R, Yang Y, Fiskus W, Chen J, Ha K, Buckley KM, Balusu R, Coothankandaswamy V, Joshi A, Atadja P, Bhalla KN (2010) Treatment with panobinostat induces glucose-regulated protein 78 acetylation and endoplasmic reticulum stress in breast cancer cells. Mol Cancer Ther 9:942–952PubMedCrossRefGoogle Scholar
  10. 10.
    Prince HM, Bishton MJ, Harrison SJ (2009) Clinical studies of histone deacetylase inhibitors. Clin Cancer Res 15:3958–3969PubMedCrossRefGoogle Scholar
  11. 11.
    Mateos M, Spencer A, Taylor K, Lonial S, De La Rubia J, Facon T, Bengoudifa B, Hazell K, Bourquelot PM, San-Miguel JF (2010) Phase Ib study of oral panobinostat (LBH589) plus lenalidomide (LEN) plus dexamethasone (DEX) in patients (Pts) with relapsed (Rel) or Rel and refractory (Ref) multiple myeloma (MM) [abstract]. J Clin Oncol 28(15S):8030Google Scholar
  12. 12.
    San-Miguel JF, Richardson PGG, Sezer O, Guenther A, Siegel DSD, Blade J, LeBlanc R, Sutherland HJ, Mateos M, Gramatzki M, Hazell KM, Bengoudifa P, Bourquelot PM, Anderson KC (2010) A phase lb study of oral panobinostat and IV bortezomib in relapsed or relapsed and refractory multiple myeloma [abstract]. J Clin Oncol 28(15S):8001Google Scholar
  13. 13.
    Sureda A, Younes A, Ben-Yehuda D, Ong T, Kaufman JL, Le Corre CL, Gallagher J, Shen A, Engert A (2010) Final analysis: phase II study of oral panobinostat in relapsed/refractory Hodgkin lymphoma patients following autologous hematopoietic stem cell transplant [abstract]. Blood 116:419Google Scholar
  14. 14.
    San Miguel JF, Lonial S, Hungria V, Moreau P, Einsele H, Lee JH, Yoon S, Corradini P, Jedrzejczak WW, Tan DC, Yong K, Guenther A, Wroclawsk-Swacha MM, Weber HJ, Bourquelot PM, Richardson PGG (2011) PANORAMA1: a randomized, double-blind, placebo controlled phase III study of panobinostat in combination with bortezomib and dexamethasone in patients with relapsed multiple myeloma. J Clin Oncol 29(15S):TPS227Google Scholar
  15. 15.
    Prince HM, George D, Patnaik A, Mita M, Dugan M, Butterfoss D, Masson E, Culver KW, Burris HA III, Beck J (2007) Phase I study of oral LBH589, a novel deacetylase (DAC) inhibitor in advanced solid tumors and non-Hodgkin’s lymphoma [abstract]. J Clin Oncol 25(18S):3500Google Scholar
  16. 16.
    Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216PubMedCrossRefGoogle Scholar
  17. 17.
    Jones HM, Parrott N, Ohlenbusch G, Lave T (2006) Predicting pharmacokinetic food effects using biorelevant solubility media and physiologically based modelling. Clin Pharmacokinet 45:1213–1226PubMedCrossRefGoogle Scholar
  18. 18.
    Singh BN, Malhotra BK (2004) Effects of food on the clinical pharmacokinetics of anticancer agents: underlying mechanisms and implications for oral chemotherapy. Clin Pharmacokinet 43:1127–1156PubMedCrossRefGoogle Scholar
  19. 19.
    Woo MM, Culver K, Li W, Liu A, Scott J, Parker K, Jalaluddin M, Laird G, Cooper MR, Schran HF (2008) Panobinostat (LBH589) pharmacokinetics (PK): implication for clinical safety and efficacy [abstract]. Ann Oncol 19(suppl 8):viii161. Abstract 478PGoogle Scholar
  20. 20.
    Amidon GL, Lennernas H, Shah VP, Crison JR (1995) A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res 12:413–420PubMedCrossRefGoogle Scholar
  21. 21.
    Rubin EH, Agrawal NG, Friedman EJ, Scott P, Mazina KE, Sun L, Du L, Ricker JL, Frankel SR, Gottesdiener KM, Wagner JA, Iwamoto M (2006) A study to determine the effects of food and multiple dosing on the pharmacokinetics of vorinostat given orally to patients with advanced cancer. Clin Cancer Res 12:7039–7045PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Geoffrey I. Shapiro
    • 1
  • Richard Frank
    • 2
  • Uday B. Dandamudi
    • 3
  • Thomas Hengelage
    • 4
  • Lily Zhao
    • 5
  • Lucien Gazi
    • 4
  • Maria Grazia Porro
    • 4
  • Margaret M. Woo
    • 5
  • Lionel D. Lewis
    • 3
  1. 1.Early Drug Development Center, Department of Medical Oncology, Dana-Farber Cancer InstituteHarvard Medical SchoolBostonUSA
  2. 2.Whittingham Cancer Center at Norwalk HospitalNorwalkUSA
  3. 3.Section of Clinical Pharmacology, Department of MedicineDartmouth-Hitchcock Medical Center and Dartmouth Medical SchoolLebanonUSA
  4. 4.Novartis Pharma AGBaselSwitzerland
  5. 5.Novartis OncologyEast HanoverUSA

Personalised recommendations