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Amiot A.,Henri Mondor Hospital | Amiot A.,University Paris Est Creteil | Amiot A.,Laboratoire dInvestigation Clinique EA | Hulin A.,University Paris Est Creteil | And 19 more authors.
Clinics and Research in Hepatology and Gastroenterology | Year: 2016

Background: There is no evidence that therapeutic drug monitoring is helpful in patients with inflammatory bowel disease patients in clinical remission with infliximab therapy. Methods: Eighty consecutive inflammatory bowel disease patients in clinical remission on infliximab maintenance therapy were included and followed-up for at least one year. Infliximab trough level and antibody to infliximab concentration were measured prior to enrollment. At the time of enrollment, physicians in charge were free to alleviate infliximab therapy. Discrepancies between blind and therapeutic drug monitoring-based adjustments were assessed at the end of the follow-up period. Relapse-free survival was analyzed using univariate and multivariate analyses. Results: The mean infliximab trough level was 3.1 μg/mL. Antibody to infliximab was found in 15 (19%) patients. At the end of the follow-up period, 18 (22.5%) patients experienced a relapse. The 3, 6, 9 and 12-month relapse-free rates were 98%, 87%, 86% and 80%, respectively. In our multivariate analysis, relapse-free survival was negatively associated with discrepancies between therapeutic drug monitoring-based and blind adjustments of infliximab therapy, absence of concomitant immunomodulator, the absence of mucosal healing, prior use of infliximab, infliximab therapy duration > 2 years and C-reactive protein levels > 5 mg/L at the time of enrollment. Conclusion: In patients with inflammatory bowel disease in clinical remission on infliximab therapy, de-escalation of infliximab therapy should be considered based on therapeutic drug monitoring rather than according to symptoms and CRP. © 2015 Elsevier Masson SAS.

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.

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.

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.

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