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Clin Chim Acta. 2017 Sep;472:26-29. doi: 10.1016/j.cca.2017.07.012. Epub 2017 Jul 12.

Trough dabrafenib plasma concentrations can predict occurrence of adverse events requiring dose reduction in metastatic melanoma.

Author information

1
Département de Pharmacologie, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France; Univ. Bordeaux INSERM, Bordeaux Population Health Research Center, team PHARMACOEPIDEMIOLOGY, UMR 1219, F-33000 Bordeaux, France. Electronic address: marine.rousset@u-bordeaux.fr.
2
Département de Dermatologie, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
3
Département de Pharmacologie, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France; Univ. Bordeaux INSERM, Bordeaux Population Health Research Center, team PHARMACOEPIDEMIOLOGY, UMR 1219, F-33000 Bordeaux, France.
4
Département de Dermatologie, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France; EA2406 Histology and Molecular Pathology of Tumors, University of Bordeaux, F-33000, France.
5
Département de Pharmacologie, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France; Univ. Bordeaux INSERM, Bordeaux Population Health Research Center, team Cancer-environnement-EPICENE, UMR 1219, F-33000 Bordeaux, France.
6
Département de Pharmacologie, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
7
Département de Pharmacologie, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France; Univ. Bordeaux INSERM, Bordeaux Population Health Research Center, team PHARMACOEPIDEMIOLOGY, UMR 1219, F-33000 Bordeaux, France. Electronic address: mathieu.molimard@u-bordeaux.fr.

Abstract

INTRODUCTION:

Dabrafenib and trametinib bitherapy provides significant benefits in BRAFV600mut metastatic melanoma patients; however, adverse events (AE) occur, leading to dose reduction in 33% of patients. We aimed to investigate a relation between plasma dabrafenib and trametinib concentrations and occurrence of AE.

METHODS:

Plasma samples from metastatic BRAFV600mut melanoma patients treated with dabrafenib±trametinib were prospectively collected at trough concentration before any dose reduction. Dabrafenib and trametinib were measured by UPLC-MS/MS. Plasma threshold of concentration associated with dose reduction for AE was studied by ROC-curve analysis.

RESULTS:

Twenty-seven patients (13M/14F) were included. Dabrafenib trough plasma concentrations displayed high interindividual variability, ranging from 15.4 to 279.6ng/ml, mean±SD 58.7±61.1ng/ml. Trough trametinib plasma concentrations ranged from 4.1 to 23.8ng/ml, mean±SD 11.9±4.1ng/ml. Mean trough dabrafenib plasma concentration was higher in patients with AE requiring dose reduction (30%) than in other patients: 118.6ng/ml and 33.5ng/ml respectively (P<0.0001). Adverse events leading to dabrafenib dose reduction were all grade≥2. No differences in mean trametinib trough plasma concentrations were observed in patients requiring or not dose reduction. A dabrafenib trough plasma threshold of 48ng/ml can predict the occurrence of adverse events requiring dose reduction.

KEYWORDS:

Adverse events; Dabrafenib; Pharmaco-epidemiology; Safety; Therapeutic drug monitoring; Trametinib; Trough plasma concentration

PMID:
28709799
DOI:
10.1016/j.cca.2017.07.012
[Indexed for MEDLINE]

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