Pharmacokinetic and cytokine profiles of melanoma patients with dabrafenib and trametinib-induced pyrexia

Cancer Chemother Pharmacol. 2019 Apr;83(4):693-704. doi: 10.1007/s00280-019-03780-y. Epub 2019 Jan 19.


Purpose: The combination of a BRAF inhibitor dabrafenib and a MEK inhibitor trametinib (CombiDT) has improved outcomes compared with chemotherapy or BRAF inhibitor monotherapy in advanced BRAF V600E/K melanoma. However, CombiDT causes a high incidence of pyrexia and treatment interruptions. Pharmacokinetic analysis may provide an explanation for the pyrexia.

Methods: 34 patients with Stage 3 BRAF V600 melanoma were treated with CombiDT on a clinical trial between August 2014 and June 2017. Plasma concentrations of drugs and metabolites were determined using validated LC-MS assays, in addition to analysis of a panel of cytokines.

Results: Pyrexia was experienced by 71% of the patients, with an additional 17% requiring dose interruption related to a pyrexia-like prodrome. Dabrafenib concentrations ranged from 4.0 to 4628 ng/ml and trametinib from 1.0 to 45 ng/ml in 34 patients. N-desmethyl-dabrafenib was the most prevalent metabolite, followed by carboxy- and hydroxy-dabrafenib. No definitive association between pyrexia and AUC or Cmin of the drugs, or metabolites could be observed. The level of IL-1B at the early during treatment (EDT) (as a % of pre-treatment) was higher in the pyrexia group (median 109% (range 32-681%) than in the no-incidence group [56% (26-79%)] (p = 0.029). Similarly, the level of IL-6 at EDT was higher in the pyrexia group [181% (34-3156%) vs 73% (57-101%)] (p = 0.028).

Conclusions: No apparent associations between pyrexia and exposure to the drugs or metabolites could be observed. Greater elevations in IL-1B and IL-6 were observed in patients with pyrexia during the first week of treatment compared to those without pyrexia.

Trial registration: NCT01972347.

Keywords: BRAF V600 melanoma; Cytokines; Dabrafenib; Pharmacokinetics; Pyrexia; Trametinib.

Publication types

  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics
  • Chromatography, Liquid
  • Cytokines / blood*
  • Drug Combinations
  • Female
  • Fever / chemically induced*
  • Humans
  • Imidazoles / administration & dosage
  • Interleukin-1beta / blood
  • Interleukin-6 / blood
  • Male
  • Mass Spectrometry
  • Melanoma / drug therapy*
  • Melanoma / genetics
  • Middle Aged
  • Neoplasm Staging
  • Oximes / administration & dosage
  • Proto-Oncogene Proteins B-raf / genetics
  • Pyridones / administration & dosage
  • Pyrimidinones / administration & dosage
  • Young Adult


  • Cytokines
  • Drug Combinations
  • Imidazoles
  • Interleukin-1beta
  • Interleukin-6
  • Oximes
  • Pyridones
  • Pyrimidinones
  • trametinib
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • dabrafenib

Associated data