A drug–drug interaction study to assess the effect of the CYP1A2 inhibitor fluvoxamine on the pharmacokinetics of dovitinib (TKI258) in patients with advanced solid tumors

Vincent A. de Weger, Sanjay Goel, Roger von Moos, Jan H.M. Schellens, Nicholas Mach, Eugene Tan, Suraj Anand, Jeffrey W. Scott, Ulrik Lassen

Research output: Contribution to journalArticle

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Abstract

Purpose: Dovitinib is an orally available multi tyrosine kinase inhibitor which inhibits VEGFR 1–3, FGFR 1–3, and PDGFR. This study was performed to investigate the potential drug–drug interaction of dovitinib with the CYP1A2 inhibitor fluvoxamine in patients with advanced solid tumors. Methods: Non-smoking patients of ≥ 18 years with advanced solid tumors, excluding breast cancer, were included. Patients were treated with a dose of 300 mg in 5 days on/2 days off schedule. Steady-state pharmacokinetic assessments of dovitinib were performed with or without fluvoxamine. Results: Forty-five patients were enrolled; 24 were evaluable for drug–drug interaction assessment. Median age was 60 years (range 30–85). At steady state the geometric mean for dovitinib (coefficient of variation%) of the area under the plasma concentration–time curve (AUC0–72h) and maximum concentration (Cmax) were 2880 ng/mL h (47%) and 144 ng/mL (41%), respectively. Following administration of dovitinib in combination with fluvoxamine the geometric mean of dovitinib AUC0–72h and Cmax were 8290 ng/mL h (60%) and 259 ng/mL (45%), respectively. The estimated geometric mean ratios for dovitinib AUC0–72h and Cmax (dovitinib + fluvoxamine vs. dovitinib alone) were 2.88 [90% confidence interval (CI) 2.58, 3.20] and 1.80 (90% CI 1.66, 1.95). This effect is considered a moderate drug–drug interaction. Conclusions: Fluvoxamine co-administration resulted in a 80% increase in Cmax and a 188% increase in AUC0–72h of dovitinib. Given the increase in exposure to dovitinib observed, patients are at risk of dovitinib related toxicity. Dovitinib should, therefore, not be co-administered with moderate and strong CYP1A2 inhibitors, without dose reduction.

Original languageEnglish (US)
Pages (from-to)1-8
Number of pages8
JournalCancer Chemotherapy and Pharmacology
DOIs
StateAccepted/In press - Nov 3 2017

Fingerprint

Fluvoxamine
Pharmacokinetics
Tumors
Neoplasms
Cytochrome P-450 CYP1A2 Inhibitors
4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one
Confidence Intervals
Protein-Tyrosine Kinases
Toxicity

Keywords

  • Dovitinib
  • Drug–drug interaction
  • Fluvoxamine CYP1A2
  • TKI258

ASJC Scopus subject areas

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

Cite this

A drug–drug interaction study to assess the effect of the CYP1A2 inhibitor fluvoxamine on the pharmacokinetics of dovitinib (TKI258) in patients with advanced solid tumors. / de Weger, Vincent A.; Goel, Sanjay; von Moos, Roger; Schellens, Jan H.M.; Mach, Nicholas; Tan, Eugene; Anand, Suraj; Scott, Jeffrey W.; Lassen, Ulrik.

In: Cancer Chemotherapy and Pharmacology, 03.11.2017, p. 1-8.

Research output: Contribution to journalArticle

de Weger, Vincent A. ; Goel, Sanjay ; von Moos, Roger ; Schellens, Jan H.M. ; Mach, Nicholas ; Tan, Eugene ; Anand, Suraj ; Scott, Jeffrey W. ; Lassen, Ulrik. / A drug–drug interaction study to assess the effect of the CYP1A2 inhibitor fluvoxamine on the pharmacokinetics of dovitinib (TKI258) in patients with advanced solid tumors. In: Cancer Chemotherapy and Pharmacology. 2017 ; pp. 1-8.
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title = "A drug–drug interaction study to assess the effect of the CYP1A2 inhibitor fluvoxamine on the pharmacokinetics of dovitinib (TKI258) in patients with advanced solid tumors",
abstract = "Purpose: Dovitinib is an orally available multi tyrosine kinase inhibitor which inhibits VEGFR 1–3, FGFR 1–3, and PDGFR. This study was performed to investigate the potential drug–drug interaction of dovitinib with the CYP1A2 inhibitor fluvoxamine in patients with advanced solid tumors. Methods: Non-smoking patients of ≥ 18 years with advanced solid tumors, excluding breast cancer, were included. Patients were treated with a dose of 300 mg in 5 days on/2 days off schedule. Steady-state pharmacokinetic assessments of dovitinib were performed with or without fluvoxamine. Results: Forty-five patients were enrolled; 24 were evaluable for drug–drug interaction assessment. Median age was 60 years (range 30–85). At steady state the geometric mean for dovitinib (coefficient of variation{\%}) of the area under the plasma concentration–time curve (AUC0–72h) and maximum concentration (Cmax) were 2880 ng/mL h (47{\%}) and 144 ng/mL (41{\%}), respectively. Following administration of dovitinib in combination with fluvoxamine the geometric mean of dovitinib AUC0–72h and Cmax were 8290 ng/mL h (60{\%}) and 259 ng/mL (45{\%}), respectively. The estimated geometric mean ratios for dovitinib AUC0–72h and Cmax (dovitinib + fluvoxamine vs. dovitinib alone) were 2.88 [90{\%} confidence interval (CI) 2.58, 3.20] and 1.80 (90{\%} CI 1.66, 1.95). This effect is considered a moderate drug–drug interaction. Conclusions: Fluvoxamine co-administration resulted in a 80{\%} increase in Cmax and a 188{\%} increase in AUC0–72h of dovitinib. Given the increase in exposure to dovitinib observed, patients are at risk of dovitinib related toxicity. Dovitinib should, therefore, not be co-administered with moderate and strong CYP1A2 inhibitors, without dose reduction.",
keywords = "Dovitinib, Drug–drug interaction, Fluvoxamine CYP1A2, TKI258",
author = "{de Weger}, {Vincent A.} and Sanjay Goel and {von Moos}, Roger and Schellens, {Jan H.M.} and Nicholas Mach and Eugene Tan and Suraj Anand and Scott, {Jeffrey W.} and Ulrik Lassen",
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T1 - A drug–drug interaction study to assess the effect of the CYP1A2 inhibitor fluvoxamine on the pharmacokinetics of dovitinib (TKI258) in patients with advanced solid tumors

AU - de Weger, Vincent A.

AU - Goel, Sanjay

AU - von Moos, Roger

AU - Schellens, Jan H.M.

AU - Mach, Nicholas

AU - Tan, Eugene

AU - Anand, Suraj

AU - Scott, Jeffrey W.

AU - Lassen, Ulrik

PY - 2017/11/3

Y1 - 2017/11/3

N2 - Purpose: Dovitinib is an orally available multi tyrosine kinase inhibitor which inhibits VEGFR 1–3, FGFR 1–3, and PDGFR. This study was performed to investigate the potential drug–drug interaction of dovitinib with the CYP1A2 inhibitor fluvoxamine in patients with advanced solid tumors. Methods: Non-smoking patients of ≥ 18 years with advanced solid tumors, excluding breast cancer, were included. Patients were treated with a dose of 300 mg in 5 days on/2 days off schedule. Steady-state pharmacokinetic assessments of dovitinib were performed with or without fluvoxamine. Results: Forty-five patients were enrolled; 24 were evaluable for drug–drug interaction assessment. Median age was 60 years (range 30–85). At steady state the geometric mean for dovitinib (coefficient of variation%) of the area under the plasma concentration–time curve (AUC0–72h) and maximum concentration (Cmax) were 2880 ng/mL h (47%) and 144 ng/mL (41%), respectively. Following administration of dovitinib in combination with fluvoxamine the geometric mean of dovitinib AUC0–72h and Cmax were 8290 ng/mL h (60%) and 259 ng/mL (45%), respectively. The estimated geometric mean ratios for dovitinib AUC0–72h and Cmax (dovitinib + fluvoxamine vs. dovitinib alone) were 2.88 [90% confidence interval (CI) 2.58, 3.20] and 1.80 (90% CI 1.66, 1.95). This effect is considered a moderate drug–drug interaction. Conclusions: Fluvoxamine co-administration resulted in a 80% increase in Cmax and a 188% increase in AUC0–72h of dovitinib. Given the increase in exposure to dovitinib observed, patients are at risk of dovitinib related toxicity. Dovitinib should, therefore, not be co-administered with moderate and strong CYP1A2 inhibitors, without dose reduction.

AB - Purpose: Dovitinib is an orally available multi tyrosine kinase inhibitor which inhibits VEGFR 1–3, FGFR 1–3, and PDGFR. This study was performed to investigate the potential drug–drug interaction of dovitinib with the CYP1A2 inhibitor fluvoxamine in patients with advanced solid tumors. Methods: Non-smoking patients of ≥ 18 years with advanced solid tumors, excluding breast cancer, were included. Patients were treated with a dose of 300 mg in 5 days on/2 days off schedule. Steady-state pharmacokinetic assessments of dovitinib were performed with or without fluvoxamine. Results: Forty-five patients were enrolled; 24 were evaluable for drug–drug interaction assessment. Median age was 60 years (range 30–85). At steady state the geometric mean for dovitinib (coefficient of variation%) of the area under the plasma concentration–time curve (AUC0–72h) and maximum concentration (Cmax) were 2880 ng/mL h (47%) and 144 ng/mL (41%), respectively. Following administration of dovitinib in combination with fluvoxamine the geometric mean of dovitinib AUC0–72h and Cmax were 8290 ng/mL h (60%) and 259 ng/mL (45%), respectively. The estimated geometric mean ratios for dovitinib AUC0–72h and Cmax (dovitinib + fluvoxamine vs. dovitinib alone) were 2.88 [90% confidence interval (CI) 2.58, 3.20] and 1.80 (90% CI 1.66, 1.95). This effect is considered a moderate drug–drug interaction. Conclusions: Fluvoxamine co-administration resulted in a 80% increase in Cmax and a 188% increase in AUC0–72h of dovitinib. Given the increase in exposure to dovitinib observed, patients are at risk of dovitinib related toxicity. Dovitinib should, therefore, not be co-administered with moderate and strong CYP1A2 inhibitors, without dose reduction.

KW - Dovitinib

KW - Drug–drug interaction

KW - Fluvoxamine CYP1A2

KW - TKI258

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