David Ternant

Withdrawal of immunosuppression in Crohn's disease treated with scheduled infliximab maintenance: a Randomized trial

BACKGROUND & AIMS The benefit to risk ratio of concomitant immunosuppressives with scheduled infliximab (IFX) maintenance therapy for Crohns disease is an issue of debate. We aimed to study the influence of immunosuppressives discontinuation in patients in remission with combination therapy in an open-label, randomized, controlled trial. METHODS Patients with controlled disease > or = 6 months after the start of IFX (5 mg/kg intravenously) combined with immunosuppressives were randomized to continue (Con) or to interrupt (Dis) immunosuppressives, while all patients received scheduled IFX maintenance therapy for 104 weeks. Primary end point was the proportion of patients who required a decrease in IFX dosing interval or stopped IFX therapy. Secondary end points included IFX trough levels, safety, and mucosal healing. RESULTS A similar proportion (24/40, 60% Con) and (22/40, 55% Dis) of patients needed a change in IFX dosing interval or stopped IFX therapy (11/40 Con, 9/40 Dis). C-reactive protein (CRP) was higher and IFX trough levels were lower in the Dis group (Dis: CRP, 2.8 mg/L; interquartile range [IQR], 1.0-8.0; Con: CRP, 1.6 mg/L; IQR, 1.0-5.6, P < .005; trough IFX: Dis: 1.65 microg/mL; IQR, 0.54-3.68; Con: 2.87 microg/mL; IQR, 1.35-4.72, P < .0001). Low IFX trough levels correlated with increased CRP and clinical score. Mucosal ulcers were absent at week 104 in 64% (Con) and 61% (Dis) of evaluated patients with ongoing response to IFX. CONCLUSIONS Continuation of immunosuppressives beyond 6 months offers no clear benefit over scheduled IFX monotherapy but is associated with higher median IFX trough and decreased CRP levels. The impact of these observations on long-term outcomes needs to be explored further.

Bevacizumab in Patients With Hereditary Hemorrhagic Telangiectasia and Severe Hepatic Vascular Malformations and High Cardiac Output

CONTEXT The only treatment available to restore normal cardiac output in patients with hereditary hemorrhagic telangiectasia (HHT) and cardiac failure is liver transplant. Anti-vascular endothelial growth factor treatments such as bevacizumab may be an effective treatment. OBJECTIVES To test the efficacy of bevacizumab in reducing high cardiac output in severe hepatic forms of HHT and to assess improvement in epistaxis duration and quality of life. DESIGN, SETTING, AND PATIENTS Single-center, phase 2 trial with national recruitment from the French HHT Network. Patients were 18 to 70 years old and had confirmed HHT, severe liver involvement, and a high cardiac index related to HHT. INTERVENTION Bevacizumab, 5 mg per kg, every 14 days for a total of 6 injections. The total duration of the treatment was 2.5 months; patients were followed up for 6 months after the beginning of the treatment. MAIN OUTCOME MEASURE Decrease in cardiac output at 3 months after the first injection, evaluated by echocardiography. RESULTS A total of 25 patients were included between March 2009 and November 2010. Of the 24 patients who had echocardiograms available for reread, there was a response in 20 of 24 patients with normalization of cardiac index (complete response [CR]) in 3 of 24, partial response (PR) in 17 of 24, and no response in 4 cases. Median cardiac index at beginning of the treatment was 5.05 L/min/m(2) (range, 4.1-6.2) and significantly decreased at 3 months after the beginning of the treatment with a median cardiac index of 4.2 L/min/m(2) (range, 2.9-5.2; P < .001). Median cardiac index at 6 months was significantly lower than before treatment (4.1 L/min/m(2); range, 3.0-5.1). Among 23 patients with available data at 6 months, we observed CR in 5 cases, PR in 15 cases, and no response in 3 cases. Mean duration of epistaxis, which was 221 minutes per month (range, 0-947) at inclusion, had significantly decreased at 3 months (134 minutes; range, 0-656) and 6 months (43 minutes; range, 0-310) (P = .008). Quality of life had significantly improved. The most severe adverse events were 2 cases of grade 3 systemic hypertension, which were successfully treated. CONCLUSION In this preliminary study of patients with HHT associated with severe hepatic vascular malformations and high cardiac output, administration of bevacizumab was associated with a decrease in cardiac output and reduced duration and number of episodes of epistaxis. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00843440.

Infliximab Pharmacokinetics in Inflammatory Bowel Disease Patients

Infliximab, a chimeric monoclonal antibody, has profoundly modified the treatment of several inflammatory diseases, but no satisfactory description of its pharmacokinetics is available. The objective of this study is to describe the pharmacokinetics of infliximab and to explore the sources of its interindividual variability. Thirty-three chronic inflammatory bowel disease patients were studied. Infliximab serum concentrations, obtained during therapeutic drug monitoring, were analyzed using a population approach. Influence of sex, weight, age, concomitant immunosuppressive treatment, and development of antibodies toward infliximab (ATI) on pharmacokinetic parameters was investigated. A two-compartment model with first-order distribution and elimination constants allowed a satisfactory description of infliximab serum concentrations. Mean population distribution and elimination half-lives were 4.3 and 18.5 days, respectively. Weight and sex were found to significantly influence volume of distribution of the central compartment, which increased with weight and was higher in men. Clearance was 2.7 times higher, and elimination half-life was 34% lower in the presence of ATI. In two patients, an increase in infliximab dose or a decrease in dosing interval lead to a decrease in infliximab clearance toward its value in patients without ATI. Infliximab pharmacokinetics are similar to those of other monoclonal antibodies, notably with an elimination half-life of approximately 3 weeks. Both body weight and sex were found to influence infliximab pharmacokinetics, and its clearance increased thrice in the presence of ATI.

Antibodies toward infliximab are associated with low infliximab concentration at treatment initiation and poor infliximab maintenance in rheumatic diseases

IntroductionA proportion of patients receiving infliximab have antibodies toward infliximab (ATI), which are associated with increased risk of infusion reaction and reduced response to treatment. We studied the association of infliximab concentration at treatment initiation and development of ATI as well as the association of the presence of ATI and maintenance of infliximab.MethodsAll patients with rheumatoid arthritis (RA) or spondyloarthritis (SpA) receiving infliximab beginning in December 2005 were retrospectively followed until January 2009 or until infliximab discontinuation. Trough serum infliximab and ATI concentrations were measured at each visit. The patients were separated into two groups: ATIpos if ATI were detected at least once during the follow-up period and ATIneg otherwise. Repeated measures analysis of variance was used to study the association of infliximab concentration at treatment initiation and the development of ATI. Maintenance of infliximab in the two groups was studied by using Kaplan-Meier curves.ResultsWe included 108 patients: 17 with RA and 91 with SpA. ATI were detected in 21 patients (19%). The median time to ATI detection after initiation of infliximab was 3.7 months (1.7 to 26.0 months). For both RA and SpA patients, trough infliximab concentration during the initiation period was significantly lower for ATIpos than ATIneg patients. RA patients showed maintenance of infliximab at a median of 19.5 months (5.0 to 31.0 months) and 12.0 months (2.0 to 24.0 months) for ATIneg and ATIpos groups, respectively (P = 0.08). SpA patients showed infliximab maintenance at a median of 16.0 months (3.0 to 34.0 months) and 9.5 months (3.0 to 39.0 months) for ATIneg and ATIpos groups, respectively (P = 0.20). Among SpA patients, those who were being treated concomitantly with methotrexate had a lower risk of developing ATI than patients not taking methotrexate (0 of 14 patients (0%) vs. 25 of 77 patients (32%); P = 0.03).ConclusionsHigh concentrations of infliximab during treatment initiation reduce the development of ATI, and the absence of ATI may be associated with prolonged maintenance of infliximab. Thus, trough serum infliximab concentration should be monitored early in patients with rheumatic diseases.

Behavior and serotonergic disorders in rats exposed prenatally to valproate: A model for autism

In order to explore whether some aspects of the autistic phenotype could be related to impairment of the serotonergic system, we chose an animal model which mimics a potential cause of autism, i.e. rats exposed to valproate (VPA) on the 9th embryonic day (E9). Previous studies have suggested that VPA exposure in rats at E9 caused a dramatic shift in the distribution of serotonergic neurons on postnatal day 50 (PND50). Behavioral studies have also been performed but on rats that were exposed to VPA later (E12.5). Our aim was to test whether VPA exposure at E9 induces comparable behavioral impairments than at E12.5 and causes serotonergic impairments which could be related to behavioral modifications. The results showed significant behavioral impairments such as a lower tendency to initiate social interactions and hyperlocomotor activity in juvenile male rats. The serotonin levels of these animals at PND50 were decreased (-46%) in the hippocampus, a structure involved in social behavior. This study suggests that VPA could have a direct or indirect action on the serotonergic system as early as the progenitor cell stage. Early embryonic exposure to VPA in rats provides a good model for several specific aspects of autism and should help to continue to explore pathophysiological hypotheses.

An enzyme-linked immunosorbent assay for therapeutic drug monitoring of cetuximab.

An enzyme-linked immunosorbent assay (ELISA) measuring serum infliximab concentrations in treated patients was developed. Microtiter plates were sensitized with tumor necrosis factor α (TNF-α) and saturated with phosphate-buffered saline (PBS) containing 1% bovine serum albumin (BSA). Samples diluted 1:100 in PBS-1% BSA were added and bound infliximab was detected using peroxidase-conjugated goat anti-human immunoglobulin G specific for Fc fragment (HRP-anti hIgG). Reading was performed using an ELISA plate reader. The limit of detection, calculated by assaying 10 replicates of a drug-free serum sample or blank sample and defined as the lowest concentration distinguishable from zero at 2 standard deviations, was 0.014 μg/mL. Each quality control sample was tested on 7 occasions on 1 day and on 5 separate days. The intraday precision indices of the method were (percent coefficients of variation, CV%) 11.7%, 6.2%, and 6.9% for 0.04 μg/mL, 2 μg/mL, and 4.5 μg/mL, respectively. The corresponding bias measures (percent deviation) were −5.5%, −1.9%, and −7.9%, respectively. The between-days precision was 9.8%, 5.3%, and 5.3% for 0.04 μg/mL, 2 μg/mL, and 4.5 μg/mL, respectively. The corresponding bias were +0.3%, −0.3%, and −7.8%, respectively. Lower limit of quantitation and upper limit of quantitation were 0.04 μg/mL and 4.5 μg/mL, respectively. Trough serum concentrations of infliximab were measured in 6 adult patients with various diseases and in 5 pediatric patients with Crohns disease. For the latter group, samples drawn 1 hour after the end of the infusion and repeated measurements also were available. Data were described using a 1-compartment population pharmacokinetic model. Terminal elimination half-life was 10.9 days. This method is rapid, accurate, and reproducible, and may be useful in therapeutic drug monitoring of infliximab.

Pharmacokinetics and concentration–effect relationships of therapeutic monoclonal antibodies and fusion proteins

Although monoclonal antibodies (mAbs) constitute a major advance in therapeutics, their pharmacokinetic (PK) and pharmacodynamic (PD) properties are not fully understood. Saturable mechanisms are thought to occur in distribution and elimination of mAbs, which are protected from degradation by the Brambell’s receptor (FcRn). The binding of mAbs to their target antigen explains part of their nonlinear PK and PD properties. The interindividual variability in mAb PK can be explained by several factors, including immune response against the biodrug and differences in the number of antigenic sites. The concentration–effect relationships of mAbs are complex and dependent on their mechanism of action. Interindividual differences in mAb PD can be explained by factors such as genetics and clinical status. PK and concentration–effect studies are necessary to design optimal dosing regimens. Because of their above-mentioned characteristics, the interindividual variability in their dose–response relationships must be studied by PK–PD modelling.

Tumor burden influences exposure and response to rituximab: pharmacokinetic-pharmacodynamic modeling using a syngeneic bioluminescent murine model expressing human CD20

Clinical studies have shown a large interindividual variability in rituximab exposure and its significant influence on clinical response in patients receiving similar doses of antibody. The aim of this study was to evaluate the influence of tumor burden on dose-concentration-response relationships of rituximab. Murine lymphoma cells (EL4, 8 x 10(3)), transduced with human CD20 cDNA and transfected with luciferase plasmid (EL4-huCD20-Luc), were intravenously injected into C57BL/6J mice. Tumor burden detection, dissemination, and progression were evaluated quantitatively by in vivo bioluminescence imaging. Different doses of rituximab (6, 12, 20, or 40 mg/kg) were infused 13 days after lymphoma cell inoculation, and rituximab serum concentrations were measured by enzyme-linked immunosorbent assay. Without rituximab, all mice developed disseminated lymphoma and died within 30 days, whereas a significant dose-response relationship was observed in mice receiving rituximab. The 20-mg/kg dose was adequate to study interindividual variability in response because 23% of mice were cured, 59% had partial response, and 18% had disease progression. Rituximab concentrations were inversely correlated with tumor burden; mice with low tumor burden had high rituximab concentrations. Furthermore, rituximab exposure influenced response and survival. Finally, using a pharmacokinetic-pharmacodynamic model, we demonstrated that tumor burden significantly influenced rituximab efficacy.

Cetuximab Pharmacokinetics Influences Progression-Free Survival of Metastatic Colorectal Cancer Patients

Purpose: An ancillary phase II study was conducted to study interindividual variability in cetuximab pharmacokinetics and its influence on progression-free survival (PFS) in metastatic colorectal cancer patients cotreated with irinotecan and 5-fluorouracil. Experimental Design: Ninety-six patients received cetuximab as an infusion loading dose of 400 mg/m2 followed by weekly infusions of 250 mg/m2. Doses of irinotecan and 5-fluorouracil were adjusted individually. Cetuximab concentrations were measured by ELISA. Compartmental pharmacokinetic parameters were estimated by a population approach, and PFS was analyzed using a Cox model. Results: Cetuximab pharmacokinetics was best described using a two-compartment model with both first-order and saturable (zero-order) elimination. Estimated pharmacokinetic parameters (% standard error) were as follows: central volume of distribution V1 = 2.96 L (4%), peripheral volume of distribution V2 = 4.65 L (6%), elimination clearance CL = 0.497 L/d (4%), distribution clearance Q = 0.836 L/d (8%), and zero-order elimination rate k0 = 8.71 mg/d (10%). Body surface area influenced V1, V2, and k0. Pretreatment serum albumin influenced CL. Risk of disease progression decreased with cetuximab global clearance (cumulative dose/cumulative area under the concentration versus time curve; P = 0.00016). Median PFS of patients with a cetuximab residual concentration on day 14 below median value was 3.3 months as compared with 7.8 months for the other patients (P = 0.004). Conclusions: Cetuximab pharmacokinetics in colorectal cancer patients can be described using a model combining linear and nonlinear elimination rates. PFS is influenced by global clearance of cetuximab, a parameter that can be estimated using cetuximab residual concentration on day 14. Clin Cancer Res; 17(19); 6329–37. ©2011 AACR.

Trough infliximab concentrations predict efficacy and sustained control of disease activity in rheumatoid arthritis.

Infliximab is a chimeric monoclonal antibody that binds to human tumor necrosis factor alpha and is approved for refractory rheumatoid arthritis. We studied the association between infliximab concentration and long-term control of disease activity in patients with rheumatoid arthritis treated on a routine basis both in cross-sectional analysis and over the long term. Trough serum infliximab concentrations were measured in patients with rheumatoid arthritis receiving infliximab infusions during the period August to October 2006. Disease activity was assessed by the Disease Activity Score for 28 Joints (DAS28) and usual biologic markers. During a 42-week follow-up period, patients were classified into two groups: those continuing with the same or lower doses of infliximab (Group A = treatment success) and those who switched to another biopharmaceutical or required an increase in infliximab dose (Group B = treatment failure). Treatment maintenance for Group A was analyzed by categories of infliximab concentration at baseline and compared by the log rank test. In 28 patients, C-reactive protein and infliximab concentrations were inversely related. Infliximab concentration in patients with low disease activity (DAS28 3.2 or less) was higher than in those with persistent active disease (DAS28 greater than 3.2); median values were 3.26 and 0.16 mg/L, respectively (P < 0.01). Analysis after 42 weeks showed that patients in Group A had higher infliximab concentrations at baseline than those with treatment failure (P < 0.01). In rheumatoid arthritis, infliximab concentration is predictive of sustained efficacy with the same infliximab regimen and should be considered on a routine basis.