Plasma vemurafenib exposure and pre-treatment hepatocyte growth factor level are two factors contributing to the early peripheral lymphocytes depletion in BRAF-mutated melanoma patients

Alicja Puszkiel; Mélanie White-Koning; Nicolas Dupin; Nora Kramkimel; Audrey Thomas-Schoemann; Gaëlle Noé; Nicolas Chapuis; Michel Vidal; François Goldwasser; Etienne Chatelut; Benoit Blanchet

doi:10.1016/j.phrs.2016.06.032

Plasma vemurafenib exposure and pre-treatment hepatocyte growth factor level are two factors contributing to the early peripheral lymphocytes depletion in BRAF-mutated melanoma patients

Pharmacol Res. 2016 Nov;113(Pt A):709-718. doi: 10.1016/j.phrs.2016.06.032. Epub 2016 Jul 1.

Authors

Affiliations

¹ Assistance Publique Hôpitaux de Paris, Unité Fonctionnelle de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, 27 rue du Faubourg Saint Jacques, 75014 Paris, France.
² Centre de Recherche en Cancérologie de Toulouse (CRCT), INSERM, Université de Toulouse, 1 avenue Irène Juliot-Curie, 31059 Toulouse, France.
³ Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Département de Dermatologie, 27 rue du Faubourg Saint Jacques, 75014 Paris, France; Institut Cochin, Inserm U1016, Université Paris Descartes, Sorbonne Paris Cité, 22 Rue Mechain, 75014 Paris, France.
⁴ Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Département de Dermatologie, 27 rue du Faubourg Saint Jacques, 75014 Paris, France.
⁵ Assistance Publique Hôpitaux de Paris, Unité Fonctionnelle de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, 27 rue du Faubourg Saint Jacques, 75014 Paris, France; UMR8638 CNRS, Faculté de Pharmacie, Université Paris Descartes, PRES Sorbonne Paris Cité, 4 avenue de l'Observatoire, 75006 Paris, France.
⁶ Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Laboratoire d'Hématologie biologique, 27 rue du Faubourg Saint Jacques, 75014 Paris, France.
⁷ Institut Cochin, Inserm U1016, Université Paris Descartes, Sorbonne Paris Cité, 22 Rue Mechain, 75014 Paris, France; Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Service de Cancérologie médicale, 123 Boulevard Port Royal, 75014 Paris, France.
⁸ Centre de Recherche en Cancérologie de Toulouse (CRCT), INSERM, Université de Toulouse, 1 avenue Irène Juliot-Curie, 31059 Toulouse, France; Institut Claudius Regaud, IUCT - Oncopole, 2 avenue Hubert Curien, 31037 Toulouse, France.
⁹ Assistance Publique Hôpitaux de Paris, Unité Fonctionnelle de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, 27 rue du Faubourg Saint Jacques, 75014 Paris, France. Electronic address: benoit.blanchet@aphp.fr.

PMID: 27378568
DOI: 10.1016/j.phrs.2016.06.032

Abstract

The therapeutic response to vemurafenib, a BRAF serine-threonine kinase inhibitor, exhibits large variations between patients. Evaluation of factors predicting the clinical efficacy of vemurafenib may help to identify patients at high risk of non-response in the early phase of treatment. The aim of this study was to analyze the pharmacokinetics of vemurafenib by a population approach and to evaluate the relationship between plasma drug exposure and pre-treatment plasma hepatocyte growth factor (HGF) levels with clinical effects (progression-free survival (PFS), peripheral lymphocytes depletion) in patients with metastatic BRAF^V600 mutated melanoma treated with single agent vemurafenib. Concentration-time data (n=332) obtained in 44 patients were analyzed using the NONMEM program. Pre-treatment plasma levels of HGF (n=36) were assayed by ELISA method. A Cox model was used to identify prognostic factors associated with progression-free survival (PFS), and a linear regression to identify factors contributing to the depletion of peripheral lymphocytes at day 15. Steady-state pharmacokinetics of vemurafenib was described by a one compartment model with first order absorption and first order elimination. None of the tested covariates explained the inter-patient variability in CL/F. A significant decrease in total lymphocytes count was observed within the first 15days (median ratio Day15/Day0=0.66, p<0.0001). Patients with Day15/Day0 ratio below 0.66 had longer PFS (14 vs 4 months, HR=0.41, CI95%=[0.15-0.77], p=0.0095). In the multivariate Cox model analysis, ECOG PS was the only parameter independently associated with PFS (grade 1 vs 0, HR=3.26, CI95%=[1.29-8.22], p=0.01 and grade ≥2 vs 0, HR=4.77, CI95%=[1.52-14.95], p=0.007). Plasma vemurafenib exposure (p=0.046) and pre-treatment HGF levels (p=0.003) were independently associated with the total lymphocyte ratio Day15/Day0. These findings show that plasma vemurafenib exposure and pre-treatment HGF levels are two factors contributing to the early peripheral lymphocytes depletion which itself is associated with PFS.

Keywords: Hepatocyte growth factor; Melanoma; PK/PD; Population pharmacokinetics; Total lymphocytes count; Vemurafenib.

Publication types

Multicenter Study

MeSH terms

Aged
Antineoplastic Agents / blood
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / therapeutic use
Disease-Free Survival
Female
Hepatocyte Growth Factor / blood*
Humans
Indoles / blood*
Indoles / pharmacokinetics
Indoles / therapeutic use*
Lymphocytes / drug effects
Lymphocytes / metabolism
Lymphocytes / pathology*
Male
Melanoma / blood*
Melanoma / drug therapy*
Melanoma / genetics
Middle Aged
Mutation / genetics
Prospective Studies
Protein Kinase Inhibitors / blood
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / therapeutic use
Proto-Oncogene Proteins B-raf / genetics*
Sulfonamides / blood*
Sulfonamides / pharmacokinetics
Sulfonamides / therapeutic use*
Vemurafenib

Substances

Antineoplastic Agents
Indoles
Protein Kinase Inhibitors
Sulfonamides
Vemurafenib
Hepatocyte Growth Factor
BRAF protein, human
Proto-Oncogene Proteins B-raf