A clinical investigation of inhibitory effect of panobinostat on CYP2D6 substrate in patients with advanced cancer.

Abstract

PURPOSE:

Panobinostat is a potent oral pan-deacetylase inhibitor with promising clinical activity in hematologic malignancies. Panobinostat was shown to inhibit CYP2D6 activity in vitro; thus understanding the magnitude of the potential clinical inhibition of panobinostat on co-medications that are CYP2D6 substrates becomes important.

METHODS:

This study evaluated the effects of co-administration of panobinostat with a sensitive CYP2D6 substrate, dextromethorphan (DM), in patients with advanced cancer who have functional CYP2D6 genes. Patients received 60 mg DM alone on day 1, panobinostat at 20 mg alone on days 3 and 5, and both agents on day 8. Plasma concentrations of DM and its metabolite dextrorphan (DX) were determined by liquid chromatography-tandem mass spectrometry following serial blood collections on day 1 (DM alone) and day 8 (in combination with panobinostat).

RESULTS:

Panobinostat increased DM exposure by 64 % [geometric mean ratio (GMR), 1.64 (90 % confidence interval (CI), 1.17-2.31)] and DX exposure by 29 % (GMR, 1.29 [90 % CI, 1.10-1.51]). These results indicated that panobinostat weakly inhibited a sensitive CYP2D6 substrate in cancer patients by increasing DM exposure by less than twofold.

CONCLUSION:

Safety monitoring of sensitive CYP2D6 substrates with narrow therapeutic index is recommended when co-administering with panobinostat in future clinical practice.

• Authors: Ronald Feld, Margaret M Woo, Natasha Leighl, Frances A Shepherd, J Thaddeus Beck, Lihui Zhao, Lucien Gazi, Thomas Hengelage, Maria Grazia Porro, Asha Nayak
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 72 Issue 4 Pg. 747-55 (Oct 2013) ISSN: 1432-0843 [Electronic] Germany
• PMID: 24013574 (Publication Type: Controlled Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Cytochrome P-450 CYP2D6 Inhibitors
• Hydroxamic Acids
• Indoles
• Dextrorphan
• Dextromethorphan
• Panobinostat
• Cytochrome P-450 CYP2D6

Topics

• Aged
• Antineoplastic Agents (pharmacology)
• Chromatography, Liquid
• Cytochrome P-450 CYP2D6 (metabolism)
• Cytochrome P-450 CYP2D6 Inhibitors
• Dextromethorphan (pharmacokinetics)
• Dextrorphan (pharmacokinetics)
• Drug Interactions
• Female
• Humans
• Hydroxamic Acids (pharmacology)
• Indoles (pharmacology)
• Male
• Middle Aged
• Neoplasms (pathology)
• Panobinostat
• Tandem Mass Spectrometry