RÉSUMÉ
PURPOSE: Dabrafenib plus trametinib combination has greatly improved survival in BRAFV600mut metastatic melanoma patients. However, data regarding the influence of pharmacokinetic markers in real-life patients are lacking. In this study, we aimed to explore dabrafenib and trametinib pharmacokinetic impact on progression-free survival (PFS), duration of response (DOR) or all grades treatment-related adverse events (ARAE) occurrence in routine care patients. METHODS: BRAFV600mut metastatic melanoma patients initiating standard doses of dabrafenib 150 mg BID plus trametinib 2 mg QD were included. Clinical data were collected via the French biobank MelBase, prospectively enrolling unresectable stage III or IV melanoma. Clinical response evaluation, ARAE reporting and dabrafenib and trametinib plasma quantification were performed. Association of individual Bayesian-estimated pharmacokinetic markers (AUC0-τ and Ctrough) and baseline clinical variables with DOR, PFS, clinical response, and ARAE was then assessed. RESULTS: Fifty patients (comprising 4 AJCC stage IIIc and 46 stage IV) were included. Median PFS reached 11.4 months, and overall response rate 70%. Fifty percent of patients experienced ARAE (G3 n = 10, G4 n = 0). In univariate analysis, median dabrafenib Ctrough within intermediate range was associated with a significantly higher PFS (HR [95% CI] = 0.41 [0.18; 0.91], p = 0.029) and DOR (HR [95% CI] = 0.39 [0.16; 0.94], p = 0.024), and association with DOR remained significant in multivariate analysis (HR [95% CI] = 0.34 [0.12; 0.95], p = 0.040). Trametinib pharmacokinetic markers were significantly higher in patients experiencing ARAE compared to patients without ARAE. CONCLUSION: In this study, exposure-efficacy and tolerance analysis highlighted the interest of therapeutic drug monitoring to optimize therapeutic management in BRAFV600mut metastatic melanoma patients based on trough concentrations of dabrafenib and trametinib.
Sujet(s)
Protocoles de polychimiothérapie antinéoplasique/administration et posologie , Mélanome/traitement médicamenteux , Protéines proto-oncogènes B-raf/génétique , Adulte , Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Protocoles de polychimiothérapie antinéoplasique/pharmacocinétique , Aire sous la courbe , Théorème de Bayes , Surveillance des médicaments/méthodes , Femelle , Humains , Imidazoles/administration et posologie , Mâle , Mélanome/génétique , Mélanome/anatomopathologie , Adulte d'âge moyen , Mutation , Stadification tumorale , Oximes/administration et posologie , Survie sans progression , Études prospectives , Pyridones/administration et posologie , Pyrimidinones/administration et posologie , Résultat thérapeutiqueRÉSUMÉ
A precise and accurate high-performance liquid chromatography (HPLC) quantification method of rifampicin in human plasma was developed and validated using ultraviolet detection after an automatized solid-phase extraction. The method was validated with respect to selectivity, extraction recovery, linearity, intra- and inter-day precision, accuracy, lower limit of quantification and stability. Chromatographic separation was performed on a Chromolith RP8 column using a mixture of 0.05 m acetate buffer pH 5.7-acetonitrile (35:65, v/v) as mobile phase. The compounds were detected at a wavelength of 335 nm with a lower limit of quantification of 0.05 mg/L in human plasma. Retention times for rifampicin and 6,7-dimethyl-2,3-di(2-pyridyl) quinoxaline used as internal standard were respectively 3.77 and 4.81 min. This robust and exact method was successfully applied in routine for therapeutic drug monitoring in patients treated with rifampicin.
