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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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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.

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Abbreviations

AUC:

Area under the plasma concentration–time curve

CLss/F :

Apparent oral steady state clearance

C max :

Maximum plasma concentration

CV%:

Coefficient of Variation%

CYP:

Cytochrome P450 enzyme

DDI:

Drug–drug interaction

ECOG:

Eastern Cooperative Oncology Group

FGF:

Fibroblast growth factor

FGFR:

Fibroblast growth factor receptor

GIST:

Gastro-intestinal stromal tumor

MTD:

Maximum tolerated dose

PDGF:

Platelet-derived growth factor

PDGFR:

Platelet-derived growth factor receptor

PK:

Pharmacokinetics

PAS:

Pharmacokinetic analyses set

TDM:

Therapeutic drug monitoring

TK:

Tyrosine kinase

T max :

Time to reach maximum plasma concentration

T 1/2 :

Terminal half-life

VEGF:

Vascular endothelial growth factor

VEGFR:

Vascular endothelial growth factor receptor

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Acknowledgements

We thank all of the patients and their families for their participation.

Author information

Authors and Affiliations

  1. Division of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands

    Vincent A. de Weger & Jan H. M. Schellens

  2. Albert Einstein Cancer Center, Montefiore Medical Center, 111 E 210th Street, Bronx, NY, 10567, USA

    Sanjay Goel

  3. Department of Internal Medicine, Kantonsspital Graubünden, Loestrasse 170, 7000, Chur, Switzerland

    Roger von Moos

  4. Department of Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584CG, Utrecht, The Netherlands

    Jan H. M. Schellens

  5. Division of Oncology, University Hospital of Genève, Rue Gabrielle-Perret-Gentil 4, 1205, Geneva, Switzerland

    Nicholas Mach

  6. Novartis Pharmaceuticals Corporation, 1 Health Plaza, East Hanover, NJ, 07936, USA

    Eugene Tan, Suraj Anand & Jeffrey W. Scott

  7. Department of Oncology, Rigshospitalet, Blegsdamsvej 9, 2100, Copenhagen, Denmark

    Ulrik Lassen

Authors
  1. Vincent A. de Weger
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  8. Jeffrey W. Scott
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Corresponding author

Correspondence to Jan H. M. Schellens.

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Ethical standards

The study was performed in compliance with the Declaration of Helsinki and its amendments. All patients provided informed consent prior to participation. The study was registered in clinicaltrials.gov (identifier: NCT01700270).

Funding

This study (NCT01700270) was funded by Novartis Pharmaceuticals.

Conflict of interest

Jeffrey Scott, Arnand Suraj and Eugene Tan are employees of Novartis Pharmaceuticals. The other authors declare that they have no competing interests.

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de Weger, V.A., Goel, S., von Moos, R. et al. 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 Chemother Pharmacol 81, 73–80 (2018). https://doi.org/10.1007/s00280-017-3469-4

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  • DOI: https://doi.org/10.1007/s00280-017-3469-4

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