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

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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.

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Acknowledgements

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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Authors and Affiliations

  1. Faculty of Medicine and Health, School of Pharmacy, The University of Sydney, Sydney, NSW, Australia

    Hannah Yejin Kim, Janna K. Duong & Alan V. Boddy

  2. Melanoma Institute Australia, Wollstonecraft, NSW, Australia

    Maria Gonzalez, Georgina V. Long & Alexander M. Menzies

  3. Faculty of Medicine and Health, School of Medicine, The University of Sydney, Sydney, NSW, Australia

    Georgina V. Long & Alexander M. Menzies

  4. Royal North Shore Hospital, St Leonards, NSW, Australia

    Georgina V. Long & Alexander M. Menzies

  5. Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Macquarie Park, NSW, Australia

    Helen Rizos, Su Yin Lim & Jenny Lee

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  1. Hannah Yejin Kim
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Correspondence to Hannah Yejin Kim.

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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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Kim, H.Y., Duong, J.K., Gonzalez, M. et al. Pharmacokinetic and cytokine profiles of melanoma patients with dabrafenib and trametinib-induced pyrexia. Cancer Chemother Pharmacol 83, 693–704 (2019). https://doi.org/10.1007/s00280-019-03780-y

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  • DOI: https://doi.org/10.1007/s00280-019-03780-y

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