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

Hannah Yejin Kim, Janna K. Duong, Maria Gonzalez, Georgina V. Long, Alexander M. Menzies, Helen Rizos, Su Yin Lim, Jenny Lee, Alan V. Boddy

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4 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)693-704
Number of pages12
JournalCancer Chemotherapy and Pharmacology
Volume83
Issue number4
DOIs
Publication statusPublished - 8 Apr 2019

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Keywords

  • BRAF V600 melanoma
  • Cytokines
  • Dabrafenib
  • Pharmacokinetics
  • Pyrexia
  • Trametinib

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