Pharmacokinetic and cytokine profiles of melanoma patients with dabrafenib and trametinib-induced pyrexia
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.
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.
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).
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.
KeywordsDabrafenib Trametinib BRAF V600 melanoma Pharmacokinetics Pyrexia Cytokines
This work was funded by the University of Sydney, and is a sub-analysis of the trial (NCT01972347) funded by Novartis. We also acknowledge Melanoma Institute Australia for their provision of the patient samples.
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Conflict of interest
A.M. Menzies is a consultant/advisor for Bristol-Myers Squibb, MSD, Novartis, Pierre-Fabre, and Roche. G.V. Long is a consultant/advisor for Amgen, Array, Bristol-Myers Squibb, Merck, Novartis, Pierre-Fabre, and Roche. All other authors have declared no conflicts of interest.
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