Laboratory of Pharmacology Toxicology

Joué-lés-Tours, France

Laboratory of Pharmacology Toxicology

Joué-lés-Tours, France
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Lereclus E.,CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory | Tout M.,CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory | Girault A.,CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory | Baroukh N.,CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory | And 9 more authors.
BMC Cancer | Year: 2017

Background: Colorectal cancer is a major public health issue worldwide. Interleukin-17 (IL-17) and Th17 (T-helper cell type 17)-related molecules are involved in tumor development and in resistance to bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody used in association with chemotherapy in metastatic colorectal cancer. Some studies have previously shown that IL-17A and IL-17F polymorphisms, respectively rs2275913 and rs763780, are associated with gastric or colorectal cancer risk. Here we aimed at studying the influence of IL-17A-related individual factors on overall survival and progression-free survival in patients with metastatic colorectal cancer treated with a bevacizumab-based chemotherapy. Methods: Pre-treatment serum biomarkers were retrospectively evaluated in 122 metastatic colorectal cancer patients treated by bevacizumab in combination with chemotherapy at 2-weeks intervals in a prospective cohort study (NCT00489697). The polymorphisms of IL-17A and IL-17F were analyzed by polymerase chain reaction - restriction fragment length polymorphism. Serum concentrations of Th17-related cytokines were measured by MultiPlex. The impact of individual parameters on overall survival and progression-free survival was assessed using multivariate Cox models. Results: High baseline IL-17A serum concentrations were significantly associated with shorter progression-free survival [p = 0.043]. Other baseline serum Th17-related cytokines and polymorphisms of IL-17 were not associated with overall survival or progression-free survival. Conclusions: In this ancillary study, baseline serum IL-17A concentration is the only Th17/IL-17 related factor that was significantly associated with the response of patients with metastatic colorectal cancer to bevacizumab. But this main significant result is highly dependent on one case which, if left out, weakens the data. Other clinical studies are required to confirm this association. Trial registration:NCT00489697. June 20, 2007. © 2017 The Author(s).

Tout M.,University of Tours | Tout M.,CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory | Casasnovas O.,French Institute of Health and Medical Research | Meignan M.,Henri Mondor University Hospital | And 14 more authors.
Blood | Year: 2017

High variability in patient outcome after rituximab-based treatment is partly explained by rituximab concentrations, and pharmacokinetic (PK) variability could be influenced by tumor burden. We aimed at quantifying the influence of baseline total metabolic tumor volume (TMTV0) on rituximab PK and of TMTV0 and rituximab exposure on outcome in patients with diffuse large B-cell lymphoma (DLBCL). TMTV0 was measured by 18F-fluorodeoxyglucosepositron emission tomography-computed tomography in 108 previously untreated DLBCL patients who received four 375mg/m2 rituximab infusions every 2 weeks in combinationwith chemotherapy in 2 prospective trials. A 2-compartment populationmodel allowed describing rituximab PK and calculating rituximab exposure (area under the concentration-time curve; AUC). The association of TMTV0 and AUC with metabolic response after 4 cycles, as well as progression-free survival (PFS) and overall survival (OS), was assessed using logistic regression and Coxmodels, respectively. Cutoff values for patient outcomewere determined using receiver operating characteristic curve analysis. Exposure to rituximab decreased as TMTV0 increased (R2 5 0.41, P > .0001). A high AUC in cycle 1 (≥9400 mg × h per liter) was associated withbetter response (oddsratio, 5.56;P5.0006) and longerPFS(hazard ratio [HR], 0.38;P5.011) andOS(HR, 0.17;P5.001). A nomogram for rituximab dose needed to obtain optimal AUC according to TMTV0 was constructed, and the 375 mg/m2 classical dose would be suitable for patients with TMTV0 <281 cm3. In summary, rituximab exposure is influenced by TMTV0 and correlates with response and outcome of DLBCL patients. Dose individualization according to TMTV0 should be evaluated in prospective studies. These studies were registered at as #NCT00498043 and #NCT00841945. © 2017 by The American Society of Hematology.

Guilleminault L.,University of Tours | Guilleminault L.,Center dEtude des Pathologies Respiratoires | Azzopardi N.,CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory | Arnoult C.,CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory | And 21 more authors.
Journal of Controlled Release | Year: 2014

Monoclonal antibodies (mAbs) are usually delivered systemically, but only a small proportion of the drug reaches the lung after intravenous injection. The inhalation route is an attractive alternative for the local delivery of mAbs to treat lung diseases, potentially improving tissue concentration and exposure to the drug while limiting passage into the bloodstream and adverse effects. Several studies have shown that the delivery of mAbs or mAb-derived biopharmaceuticals via the airways is feasible and efficient, but little is known about the fate of inhaled mAbs after the deposition of aerosolized particles in the respiratory system. We used cetuximab, an anti-EGFR antibody, as our study model and showed that, after its delivery via the airways, this mAb accumulated rapidly in normal and cancerous tissues in the lung, at concentrations twice those achieved after intravenous delivery, for early time points. The spatial distribution of cetuximab within the tumor was heterogeneous, as reported after i.v. injection. Pharmacokinetic (PK) analyses were carried out in both mice and macaques and showed aerosolized cetuximab bioavailability to be lower and elimination times shorter in macaques than in mice. Using transgenic mice, we showed that FcRn, a key receptor involved in mAb distribution and PK, was likely to make a greater contribution to cetuximab recycling than to the transcytosis of this mAb in the airways. Our results indicate that the inhalation route is potentially useful for the treatment of both acute and chronic lung diseases, to boost and ensure the sustained accumulation of mAbs within the lungs, while limiting their passage into the bloodstream. © 2014 Elsevier B.V. All rights reserved.

Termant D.,CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory | Termant D.,Laboratory of Pharmacology Toxicology | Berkane Z.,CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory | Berkane Z.,Laboratory of Pharmacology Toxicology | And 7 more authors.
Clinical Pharmacokinetics | Year: 2015

Background and Objectives: Infliximab is a monoclonal anti-tumor necrosis factor-α (anti-TNFα) antibody that profoundly modified the treatment of Crohn’s disease (CD). The polymorphism of Fc fragment of IgG, low affinity IIIa, receptor (CD16a) [FCGR3A] influences the biological response to infliximab in patients with CD. Our aim was to study its influence on infliximab pharmacokinetics and risk of relapse after infliximab discontinuation. Methods: In 111 CD patients in remission, infliximab was discontinued and its concentrations were measured for 30 months or until relapse. Infliximab pharmacokinetics were described using monocompartmental population modeling. Results: The elimination rate of infliximab increased with C-reactive protein (CRP) [p = 0.00018] and was 16 % higher in FCGR3A-158V/V patients than in F carriers (p = 0.0028). Risk of relapse was higher in patients with baseline CRP ≥5 mg/L than in those with a lower value (p = 0.0000029). In addition, there was a first-order interaction between CRP and the FCGR3A genotype; in patients with high CRP, risk of relapse was higher for V/V patients than for F carriers (hazard ratio 4.80 and 2.84 for V/V and F carriers, respectively; p = 0.013). Conclusion: Both increased inflammation and FCGR3A-158V/V genotype are associated with increased infliximab elimination and risk of relapse after infliximab discontinuation in patients with CD. © 2014, Springer International Publishing Switzerland.

Passot C.,CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory | Azzopardi N.,CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory | Renault S.,University of Tours | Baroukh N.,CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory | And 11 more authors.
mAbs | Year: 2013

The neonatal Fc receptor (FcRn) encoded by FCGRT is known to be involved in the pharmacokinetics (PK) of therapeutic monoclonal antibodies (mAbs). Variability in the expression of FCGRT gene and consequently in the FcRn protein level could explain differences in PK observed between patients treated with mAbs. We studied whether the previously described variable number tandem repeat (VNTR) or copy number variation (CNV) of FCGRT are associated with individual variations of PK parameters of cetuximab. VNTR and CNV were assessed on genomic DNA of 198 healthy individuals and of 94 patients treated with the therapeutic mAb. VNTR and CNV were analyzed by allele-specific PCR and duplex real-time PCR with Taqman® technology, respectively. The relationship between FCGRT polymorphisms (VNTR and CNV) and PK parameters of patients treated with cetuximab was studied. VNTR3 homozygote patients had a lower cetuximab distribution clearance than VNTR2/VNTR3 and VNTR3/VNTR4 patients (p = 0.021). We observed no affects of VNTR genotype on elimination clearance. One healthy person (0.5%) and 1 patient (1.1%) had 3 copies of FCGRT. The PK parameters of this patient did not differ from those of patients with 2 copies. The FCGRT promoter VNTR may influence mAbs' distribution in the body. CNV of FCGRT cannot be used as a relevant pharmacogenetic marker because of its low frequency. © 2013 Landes Bioscience.

Ternant D.,University of Tours | Ternant D.,French National Center for Scientific Research | Ternant D.,Laboratory of Pharmacology Toxicology | Cartron G.,Montpellier University | And 7 more authors.
British Journal of Clinical Pharmacology | Year: 2012

AIMS Rituximab has dramatically improved the survival of patients with non-Hodgkin's lymphoma (NHL). However, studies have suggested that the dose regimen currently used (i.e. 375mgm -2) could be optimized. The aims of this study were to quantify the benefits of the new dose regimen for rituximab in follicular NHL (FL) patients using a previously validated PK-PD model and to design clinical trials investigating optimization of rituximab dosage. METHODS A PK-PD model was used to predict progression-free survival (PFS) of FL patients treated by rituximab alone in asymptomatic FL, and those treated by rituximab combined with chemotherapy (R-CHOP) in relapsed/resistant FL. This model accounts for the influence of a polymorphism in FCGR3A, the gene encoding the FcγRIIIa receptor, on clinical efficacy. Several induction and maintenance dose regimens using rituximab alone or in combination with conventional chemotherapy (CHOP) were tested. The benefits of rituximab dose adjustment for F carriers were investigated. The numbers of subjects required for the design of two-armed clinical trials were calculated using model-predicted PFS at a power of 80%. RESULTS The model predicted a potential benefit of 1500mgm -2 maintenance doses of rituximab for both rituximab monotherapy and R-CHOP. The model shows that the PFS of FCGR3A-F carriers remains lower than that of homozygous FCGR3A-VV patients, even with markedly increased rituximab doses. CONCLUSION Our results suggest a benefit of increasing doses of rituximab in FL, both during induction and maintenance. These results need to be confirmed in controlled clinical trials. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

Ternant D.,University of Tours | Ternant D.,French National Center for Scientific Research | Ternant D.,Laboratory of Pharmacology Toxicology | Mulleman D.,University of Tours | And 14 more authors.
British Journal of Clinical Pharmacology | Year: 2012

AIMS: Infliximab, an anti-tumour necrosis factorα monoclonal antibody, has profoundly modified the treatment of several inflammatory diseases. The objective was to assess the influence of methotrexate on the variability of infliximab pharmacokinetics and concentration-effect relationship in axial ankylosing spondylitis (AAS) patients. METHODS: Twenty-six patients with AAS were included in a prospective study. They were treated by infliximab 5mgkg -1 infusions at weeks 0, 2, 6, 12 and 18. Infliximab concentrations were measured before, and 2 and 4h after each infusion, and at each intermediate visit (weeks 1, 3, 4, 5, 8, 10 and 14). Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was measured at each visit. Infliximab pharmacokinetics was described using a two-compartment model with first-order distribution and elimination constants. A population approach was used. Infliximab pharmacodynamics was described using the area under the BASDAI curve. RESULTS: A total of 507 blood samples and 329 BASDAI measurements were collected. The following pharmacokinetic parameters were obtained (interindividual coefficient of variation): volumes of distribution for the central compartment = 2.4l (9.6%) and peripheral compartment = 1.8l (26%), systemic clearance = 0.23l day -1 (22%) and intercompartment clearance = 2.3l day -1. Methotrexate influenced neither pharmacokinetic nor BASDAI variability. CONCLUSIONS: Using the present dosage, the clinical efficacy of infliximab is only weakly influenced by its serum concentrations. The results do not support the combination of methotrexate with infliximab in ankylosing spondylitis. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

Zehnacker L.,University of Nice Sophia Antipolis | Abe E.,Laboratory of Pharmacology Toxicology | Mathez D.,Immunology and Virology Unit | Alvarez J.-C.,Laboratory of Pharmacology Toxicology | And 2 more authors.
AIDS Research and Treatment | Year: 2014

Study of plasma and intracellular concentrations of atazanavir, lopinavir, nevirapine, and efavirenz was conducted on 48 patients under short cycles of antiretroviral therapy. Intracellular concentrations (IC) were still measurable for all drugs after 85 h or 110 h drug intake despite the absence of drug in plasma for atazanavir and lopinavir. A linear relationship between plasma and intracellular efavirenz was observed. Further studies to fully understand the impact of IC in the intermittent antiviral treatment are required. © 2014 Laura Zehnacker et al.

Grassin Delyle S.,Laboratory of Pharmacology Toxicology | Grassin Delyle S.,CNRS Laboratory for Molecular and Pharmacological Mechanisms of Bronchial Obstruction | Abe E.,Laboratory of Pharmacology Toxicology | Batisse A.,Laboratory of Pharmacology Toxicology | And 4 more authors.
Clinica Chimica Acta | Year: 2010

Background: Tranexamic acid is a synthetic lysine analog used for management of bleeding disorders. The objective of this study was first to develop a method for measurement of tranexamic acid in human serum using liquid chromatography coupled to ion-trap mass spectrometry (LC-MS/MS), and then to validate it throughout a wide range of concentrations allowing quantification in patients receiving tranexamic acid infusion during surgery. Methods: Serum samples (100 μL) were subjected to protein precipitation with perchloric acid, and after pH adjustment, tranexamic acid and internal standard were separated on a C18 column and isocratically eluted using a mobile phase constituted of formate buffer/acetonitrile (95:5, v/v). Tranexamic acid was ionized by electrospray in positive mode. Parent [M + H]+ ions were m/z 158.0 for tranexamic acid and m/z 144.0 for IS. The most intense product ion of tranexamic acid (m/z 122.7) and IS (m/z 126.0) were used for quantification. Results: The assay was accurate and precise over the range of 1.0 (lower limit of quantification) to 200.0 μg/mL (upper limit of quantification), and has been successfully applied to study the clinical pharmacokinetics in two volunteers undergoing cardiac surgery. Conclusion: A reliable method for quantification of tranexamic acid for analysis in clinical studies was obtained. © 2010 Elsevier B.V. All rights reserved.

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