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

Ronald Feld, Margaret M. Woo, Natasha Leighl, Frances A. Shepherd, J. Thaddeus Beck, Lihui Zhao, Lucien Gazi, Thomas Hengelage, Maria Grazia Porro, Asha Nayak

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)747-755
Number of pages9
JournalCancer Chemotherapy and Pharmacology
Volume72
Issue number4
DOIs
StatePublished - Oct 1 2013

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Cytochrome P-450 CYP2D6
Dextromethorphan
Substrates
Neoplasms
Dextrorphan
Confidence Intervals
panobinostat
Liquid chromatography
Hematologic Neoplasms
Metabolites
Tandem Mass Spectrometry
Liquid Chromatography
Mass spectrometry
Blood
Genes
Plasmas
Safety
Monitoring

Keywords

  • CYP2D6
  • Dextromethorphan
  • Panobinostat
  • Pharmacokinetics

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

A clinical investigation of inhibitory effect of panobinostat on CYP2D6 substrate in patients with advanced cancer. / Feld, Ronald; Woo, Margaret M.; Leighl, Natasha; Shepherd, Frances A.; Beck, J. Thaddeus; Zhao, Lihui; Gazi, Lucien; Hengelage, Thomas; Porro, Maria Grazia; Nayak, Asha.

In: Cancer Chemotherapy and Pharmacology, Vol. 72, No. 4, 01.10.2013, p. 747-755.

Research output: Contribution to journalArticle

Feld, R, Woo, MM, Leighl, N, Shepherd, FA, Beck, JT, Zhao, L, Gazi, L, Hengelage, T, Porro, MG & Nayak, A 2013, 'A clinical investigation of inhibitory effect of panobinostat on CYP2D6 substrate in patients with advanced cancer', Cancer Chemotherapy and Pharmacology, vol. 72, no. 4, pp. 747-755. https://doi.org/10.1007/s00280-013-2237-3
Feld, Ronald ; Woo, Margaret M. ; Leighl, Natasha ; Shepherd, Frances A. ; Beck, J. Thaddeus ; Zhao, Lihui ; Gazi, Lucien ; Hengelage, Thomas ; Porro, Maria Grazia ; Nayak, Asha. / A clinical investigation of inhibitory effect of panobinostat on CYP2D6 substrate in patients with advanced cancer. In: Cancer Chemotherapy and Pharmacology. 2013 ; Vol. 72, No. 4. pp. 747-755.
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AU - Feld, Ronald

AU - Woo, Margaret M.

AU - Leighl, Natasha

AU - Shepherd, Frances A.

AU - Beck, J. Thaddeus

AU - Zhao, Lihui

AU - Gazi, Lucien

AU - Hengelage, Thomas

AU - Porro, Maria Grazia

AU - Nayak, Asha

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N2 - 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.

AB - 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.

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