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

doi:10.1007/s00280-017-3469-4

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

Institut for Klinisk Medicin

1 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Cancer Chemotherapy and Pharmacology
Vol/bind	81
Udgave nummer	1
Sider (fra-til)	73-80
Antal sider	8
ISSN	0344-5704
DOI	https://doi.org/10.1007/s00280-017-3469-4
Status	Udgivet - 1 jan. 2018

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de Weger, V. A., Goel, S., von Moos, R., Schellens, J. H. M., Mach, N., Tan, E., Anand, S., Scott, J. W., & Lassen, U. (2018). 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. Cancer Chemotherapy and Pharmacology, 81(1), 73-80. https://doi.org/10.1007/s00280-017-3469-4

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 et al.
I: Cancer Chemotherapy and Pharmacology, Bind 81, Nr. 1, 01.01.2018, s. 73-80.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

de Weger, VA, Goel, S, von Moos, R, Schellens, JHM, Mach, N, Tan, E, Anand, S, Scott, JW & Lassen, U 2018, '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', Cancer Chemotherapy and Pharmacology, bind 81, nr. 1, s. 73-80. https://doi.org/10.1007/s00280-017-3469-4

@article{e8b051a0e2ad4c908b12b25ef3fe2303,

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 = "Adult, Aged, Aged, 80 and over, Antineoplastic Agents/administration & dosage, Area Under Curve, Benzimidazoles/administration & dosage, Cytochrome P-450 CYP1A2 Inhibitors/administration & dosage, Drug Administration Schedule, Drug Interactions, Female, Fluvoxamine/administration & dosage, Half-Life, Humans, Male, Maximum Tolerated Dose, Middle Aged, Neoplasms/drug therapy, Quinolones/administration & dosage",

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",

month = jan,

day = "1",

doi = "10.1007/s00280-017-3469-4",

language = "English",

volume = "81",

pages = "73--80",

journal = "Cancer Chemotherapy and Pharmacology",

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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 - 2018/1/1

Y1 - 2018/1/1

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.

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KW - Aged

KW - Aged, 80 and over

KW - Antineoplastic Agents/administration & dosage

KW - Area Under Curve

KW - Benzimidazoles/administration & dosage

KW - Cytochrome P-450 CYP1A2 Inhibitors/administration & dosage

KW - Drug Administration Schedule

KW - Drug Interactions

KW - Female

KW - Fluvoxamine/administration & dosage

KW - Half-Life

KW - Humans

KW - Male

KW - Maximum Tolerated Dose

KW - Middle Aged

KW - Neoplasms/drug therapy

KW - Quinolones/administration & dosage

U2 - 10.1007/s00280-017-3469-4

DO - 10.1007/s00280-017-3469-4

M3 - Journal article

C2 - 29101463

SN - 0344-5704

VL - 81

SP - 73

EP - 80

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

IS - 1

ER -

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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