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

Abstract

Purpose

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.

Methods

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).

Results

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.

Conclusions

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

Keywords

Panobinostat Pharmacokinetics Histone deacetylase inhibitor Food 

Notes

Acknowledgments

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.

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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

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