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Association between clinically relevant toxicities of pazopanib and sunitinib and the use of weak CYP3A4 and P-gp inhibitors

  • Camille Azam
  • Pauline Claraz
  • Christine Chevreau
  • Camille Vinson
  • Ewa Cottura
  • Loïc Mourey
  • Damien Pouessel
  • Selena Guibaud
  • Olivia Pollet
  • Magali Le Goff
  • Catherine Bardies
  • Véronique Pelagatti
  • Jean Marie Canonge
  • Florent PuissetEmail author
Pharmacoepidemiology and Prescription

Abstract

Purpose

Sunitinib and pazopanib, two tyrosine kinase inhibitors (TKI), may be targets of potential pharmacokinetic drug-drug interactions (P-PK-DDIs). While strong cytochrome P4503A (CYP3A4) inhibitors or inducers should cause a clinically relevant modification in plasma TKI concentrations, the effect of weak inhibitors is unknown. The objective of this study was to evaluate the association between weak P-PK-DDI and clinically relevant toxicity in real life.

Patients and methods

This was a single-center retrospective study including patients treated with sunitinib or pazopanib for any malignancies, for whom a PK-DDI analysis was performed before starting TKI. The primary endpoint was the correlation between P-PK-DDIs and a dose decrease after 1 month of treatment. The secondary endpoint was the correlation between PK-DDIs and drug withdrawal due to toxicity.

Results

Seventy-six patients were assessed. A P-PK-DDI with weak CYP3A4 or P-gp inhibition was found in 14 patients. In patients with P-PK-DDI or without, the dose was reduced during the first month in 57.1% and 17.7% (p = 0.003) and the drug withdrawn in 42.8% and 11.3% (p = 0.011), respectively. In multivariate analysis, a significant correlation was found between P-PK-DDI (CYP3A4 and P-gp inhibitors) and dose reduction, and between drug withdrawal and PK-DDI (CYP3A4 inhibitors).

Conclusion

P-PK-DDI was correlated with dose reduction and drug withdrawal due to toxicity. The causality of this relationship warrants to be assessed; therefore, therapeutic drug monitoring is necessary in patients treated with TKI.

Keywords

Pazopanib Sunitinib Drug-drug interaction CYP3A4 P-gp 

Notes

Compliance with ethical standards

The study was performed in compliance with ethical standards.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval for retrospective study

As a retrospective study, no informed consent was required but patients were informed that their data could be used for clinical evaluation. None refused.

Supplementary material

228_2020_2828_MOESM1_ESM.docx (36 kb)
ESM 1 (DOCX 36 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2020

Authors and Affiliations

  • Camille Azam
    • 1
  • Pauline Claraz
    • 1
  • Christine Chevreau
    • 2
  • Camille Vinson
    • 1
  • Ewa Cottura
    • 2
  • Loïc Mourey
    • 2
  • Damien Pouessel
    • 2
  • Selena Guibaud
    • 2
  • Olivia Pollet
    • 2
  • Magali Le Goff
    • 2
  • Catherine Bardies
    • 2
  • Véronique Pelagatti
    • 1
  • Jean Marie Canonge
    • 3
  • Florent Puisset
    • 1
    • 4
    Email author
  1. 1.Pharmacy department IUCT (Institut Universitaire du Cancer) OncopoleInstitut Claudius RegaudToulouse CEDEX 9France
  2. 2.Oncology department IUCT (Institut Universitaire du Cancer) OncopoleInstitut Claudius RegaudToulouse CEDEX 9France
  3. 3.Pharmacy department IUCT (Institut Universitaire du Cancer) OncopoleCentre Hospitalier UniversitaireToulouse CEDEX 9France
  4. 4.Centre de Recherches en Cancérologie de Toulouse (CRCT), Team 14, INSERM UMR1037Université de ToulouseToulouse CEDEX 1France

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