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Clinical Pharmacokinetics and Pharmacodynamics of Dabrafenib

  • Alicja Puszkiel
  • Gaëlle Noé
  • Audrey Bellesoeur
  • Nora Kramkimel
  • Marie-Noëlle Paludetto
  • Audrey Thomas-Schoemann
  • Michel Vidal
  • François Goldwasser
  • Etienne Chatelut
  • Benoit Blanchet
Review Article
  • 40 Downloads

Abstract

Dabrafenib is a potent and selective inhibitor of BRAF-mutant kinase that is approved, as monotherapy or in combination with trametinib (mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor), for unresectable or metastatic BRAF-mutated melanoma, advanced non-small cell lung cancer and anaplastic thyroid cancer harbouring the BRAFV600E mutation. The recommended dose of dabrafenib is 150 mg twice daily (bid) under fasted conditions. After single oral administration of the recommended dose, the absolute oral bioavailability (F) of dabrafenib is 95%. Dabrafenib shows a time-dependent increase in apparent clearance (CL/F) following multiple doses, which is likely due to induction of its own metabolism through cytochrome P450 (CYP) 3A4. Therefore, steady state is reached only after 14 days of daily dose administration. Moreover, the extent of this auto-induction process is dependent on the dose, which explains why dabrafenib systemic exposure at steady state increases less than dose proportionally over the dose range of 75–300 mg bid. The main elimination route of dabrafenib is the oxidative metabolism via CYP3A4/2C8 and biliary excretion. Among the three major metabolites identified, hydroxy-dabrafenib appears to contribute to the pharmacological activity. Age, sex and body weight did not have any clinically significant influence on plasma exposure to dabrafenib. No dose adjustment is needed for patients with mild renal or hepatic impairment, whereas the impacts of severe impairment on dabrafenib pharmacokinetics remain unknown. Considering that dabrafenib is a substrate of CYP3A4/2C8 and is a CYP3A4/2B6/2C inducer, drug–drug interactions are expected with dabrafenib. The relationship between clinical outcomes and plasma exposure to dabrafenib and hydroxy-dabrafenib should be investigated more deeply.

Notes

Compliance with Ethical Standards

Funding

No funding was received for preparation of this review.

Conflict of interest

Alicja Puszkiel, Gaëlle Noé, Audrey Bellesoeur, Nora Kramkimel, Marie-Noëlle Paludetto, Audrey Thomas-Schoemann, Michel Vidal, François Goldwasser, Etienne Chatelut and Benoit Blanchet declare that they have no conflicts of interest to disclose.

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Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Alicja Puszkiel
    • 1
  • Gaëlle Noé
    • 2
  • Audrey Bellesoeur
    • 3
    • 4
  • Nora Kramkimel
    • 5
  • Marie-Noëlle Paludetto
    • 1
    • 6
  • Audrey Thomas-Schoemann
    • 4
    • 7
  • Michel Vidal
    • 7
    • 8
  • François Goldwasser
    • 3
  • Etienne Chatelut
    • 1
    • 9
    • 10
  • Benoit Blanchet
    • 7
    • 8
    • 10
  1. 1.Cancer Research Center of Toulouse (CRCT), Inserm U1037Université Paul SabatierToulouseFrance
  2. 2.Department of Pharmacology and ToxicologyBicetre Hospital, AP-HPKremlin BicetreFrance
  3. 3.Department of Medical OncologyCERIA, CARPEM, Cochin University Hospital, APHPParisFrance
  4. 4.Multidisciplinary Risk Assessment and Drug Monitoring UnitCERIA, CARPEM, Cochin University Hospital, AP-HPParisFrance
  5. 5.Department of DermatologyCochin University Hospital, AP-HPParisFrance
  6. 6.Department of PharmacyInstitut Universitaire du Cancer de Toulouse - OncopoleToulouseFrance
  7. 7.UMR8638 CNRS, Faculty of PharmacyUniversity Paris Descartes, PRES Sorbonne Paris CitéParisFrance
  8. 8.Department of Pharmacokinetics and PharmacochemistryCERIA, CARPEM, Cochin University Hospital, AP-HPParisFrance
  9. 9.Institut Claudius RegaudInstitut Universitaire du Cancer de Toulouse - OncopoleToulouseFrance
  10. 10.Groupe de Pharmacologie Clinique Oncologique (GPCO)ParisFrance

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