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

Research output: Contribution to journalArticleResearchpeer-review

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.
LanguageEnglish
Pages693-704
Number of pages12
JournalCancer Chemotherapy and Pharmacology
Volume83
Issue number4
DOIs
Publication statusPublished - 8 Apr 2019

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Pharmacokinetics
Metabolites
Melanoma
Fever
Cytokines
Interleukin-6
Pharmaceutical Preparations
Chemotherapy
Mitogen-Activated Protein Kinase Kinases
Assays
Association reactions
Plasmas
dabrafenib
trametinib
Therapeutics
Incidence
Area Under Curve
Clinical Trials
Drug Therapy

Keywords

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

Cite this

Kim, Hannah Yejin ; Duong, Janna K. ; Gonzalez, Maria ; Long, Georgina V. ; Menzies, Alexander M. ; Rizos, Helen ; Lim, Su Yin ; Lee, Jenny ; Boddy, Alan V. / Pharmacokinetic and cytokine profiles of melanoma patients with dabrafenib and trametinib-induced pyrexia. In: Cancer Chemotherapy and Pharmacology. 2019 ; Vol. 83, No. 4. pp. 693-704.
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title = "Pharmacokinetic and cytokine profiles of melanoma patients with dabrafenib and trametinib-induced pyrexia",
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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Pharmacokinetic and cytokine profiles of melanoma patients with dabrafenib and trametinib-induced pyrexia. / Kim, Hannah Yejin; Duong, Janna K.; Gonzalez, Maria; Long, Georgina V.; Menzies, Alexander M.; Rizos, Helen; Lim, Su Yin; Lee, Jenny; Boddy, Alan V.

In: Cancer Chemotherapy and Pharmacology, Vol. 83, No. 4, 08.04.2019, p. 693-704.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Pharmacokinetic and cytokine profiles of melanoma patients with dabrafenib and trametinib-induced pyrexia

AU - Kim,Hannah Yejin

AU - Duong,Janna K.

AU - Gonzalez,Maria

AU - Long,Georgina V.

AU - Menzies,Alexander M.

AU - Rizos,Helen

AU - Lim,Su Yin

AU - Lee,Jenny

AU - Boddy,Alan V.

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N2 - 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.

AB - 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.

KW - BRAF V600 melanoma

KW - Cytokines

KW - Dabrafenib

KW - Pharmacokinetics

KW - Pyrexia

KW - Trametinib

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