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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

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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. 2018 ; Vol. 81, No. 1. pp. 73-80.

Bibtex

@article{59f3e431afeb426a926a65cc7cb181b3,
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 (C max) 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 C max were 8290 ng/mL h (60{\%}) and 259 ng/mL (45{\%}), respectively. The estimated geometric mean ratios for dovitinib AUC0-72h and C max (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 C max 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 = "Journal Article",
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",
year = "2018",
doi = "10.1007/s00280-017-3469-4",
language = "English",
volume = "81",
pages = "73--80",
journal = "Cancer Chemotherapy and Pharmacology",
issn = "0344-5704",
publisher = "Springer",
number = "1",

}

RIS

TY - JOUR

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 - 2018

Y1 - 2018

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 (C max) 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 C max were 8290 ng/mL h (60%) and 259 ng/mL (45%), respectively. The estimated geometric mean ratios for dovitinib AUC0-72h and C max (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 C max 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 (C max) 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 C max were 8290 ng/mL h (60%) and 259 ng/mL (45%), respectively. The estimated geometric mean ratios for dovitinib AUC0-72h and C max (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 C max 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 - Journal Article

U2 - 10.1007/s00280-017-3469-4

DO - 10.1007/s00280-017-3469-4

M3 - Journal article

VL - 81

SP - 73

EP - 80

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

SN - 0344-5704

IS - 1

ER -

ID: 52045343