Céline Desvignes

Pharmacokinetics of adalimumab in Crohn’s disease

Adalimumab, an anti-TNF-α monoclonal antibody, is approved for the treatment of rheumatoid arthritis (RA), ankylosing spondylitis, psoriatic arthritis, Crohn’s disease (CD), and ulcerative colitis. The pharmacokinetics (PK) of adalimumab in RA patients was investigated using compartmental modeling [1, 2], but its characteristics in CD patients has never been reported. Patients may develop antiadalimumab antibodies (AAA) which are responsible for a decrease in adalimumab serum concentration [3] and a loss of clinical response [4, 5, 3, 6, 7]. Antibodies towards another anti-TNF-α monoclonal antibody, infliximab, were shown to increase its clearance [8-11]. The quantitative influence of anti-adalimumab antibodies (AAA) on adalimumab clearance has not been reported yet. We report the first quantitative description of adalimumab pharmacokinetics in Crohn’s disease patients. This is a post hoc analysis of a prospective cohort of 65 patients, being part of a larger cohort, who participated in an observational study in the Inflammatory Bowel Disease unit of the University Hospital of Leuven and for whom at least four adalimumab concentrations were available. [3] Patients were treated subcutaneously either with 160/80 mg at weeks 0/2, or 80/40 mg as an induction phase. Following this phase, all patients were treated with 40-mg adalimumab every 2 weeks. Median follow-up was 20 months. Median [range] age and body weight were 37 years [17–61] and 68 kg [43– 109], and 49 (75 %) were women. For 30 out of 65 patients, dosing regimen was increased to 40 mg every week. A total of 341 adalimumab serum concentrations were available. Antiadalimumab antibodies were detected in nine patients. Adalimumab concentrations were measured using an ELISA technique derived from the one developed for infliximab, [12] and AAA were measured using a double-antigen ELISA based on their capture by adalimumab-coated plates. Adalimumab concentrations and AAA detection were performed in Tours University Hospital, France. Adalimumab pharmacokinetics was studied by a population approach using MONOLIX 4.3.2 (Lixoft, Saclay, France). A one-compartment model with first-order absorption and elimination rates was used. Apparent volume of distribution (V/F), clearance (CL/F), and first-order absorption rate constant (ka) were estimated. Interindividual and residual models were exponential and mixed additive-proportional, respectively. The presence of AAAwas tested as a covariate on V/F and CL/F. All parameters were estimated with satisfactory accuracy, and no obvious model misspecification was observed. Estimated typical parameters (relative standard error) were V/F = 13.5 L (10 %), CL/F = 0.42 L/day (9 %) and ka = 0.15 day . Interindividual standard deviations for V/F and CL/F (relative standard error) were Konstantinos Karmiris is the Principal investigator.

Efficacy of a rituximab regimen based on B cell depletion in thrombotic thrombocytopenic purpura with suboptimal response to standard treatment: Results of a phase II, multicenter noncomparative study.

The standard four‐rituximab infusions treatment in acquired thrombotic thrombocytopenic purpura (TTP) remains empirical. Peripheral B cell depletion is correlated with the decrease in serum concentrations of anti‐ADAMTS13 and associated with clinical response. To assess the efficacy of a rituximab regimen based on B cell depletion, 24 TTP patients were enrolled in this prospective multicentre single arm phase II study and then compared to patients from a previous study. Patients with a suboptimal response to a plasma exchange‐based regimen received two infusions of rituximab 375 mg m−2 within 4 days, and a third dose at day +15 of the first infusion if peripheral B cells were still detectable. Primary endpoint was the assessment of the time required to platelet count recovery from the first plasma exchange. Three patients died after the first rituximab administration. In the remaining patients, the B cell‐driven treatment hastened remission and ADAMTS13 activity recovery as a result of rapid anti‐ADAMTS13 depletion in a similar manner to the standard four‐rituximab infusions schedule. The 1‐year relapse‐free survival was also comparable between both groups. A rituximab regimen based on B cell depletion is feasible and provides comparable results than with the four‐rituximab infusions schedule. This regimen could represent a new standard in TTP. This trial was registered at www.clinicaltrials.gov (NCT00907751). Am. J. Hematol. 91:1246–1251, 2016.

Development and validation of an enzyme-linked immunosorbent assay to measure adalimumab concentration

BACKGROUND Adalimumab is a therapeutic antibody used for treating inflammatory diseases. To understand interindividual PK variability, there is a need to develop and validate an assay to measure serum adalimumab concentrations. METHODS An ELISA was developed on microtiter plates coated with TNF-α. Seven nonzero adalimumab standards ranging from 0.05 to 50 mg/l and three quality controls (0.2, 2.5 and 7 mg/l) were tested for their intra and interday precision on six occasions. RESULTS The LOD, LLOQ and ULOQ of the assay were 0.022, 0.073 and 9 mg/l, respectively. CONCLUSION This method is accurate, reproducible and may be useful for PK studies and for therapeutic drug monitoring of adalimumab.

Crucial Role for Immune Complexes but Not FcRn in Immunization against Anti–TNF-α Antibodies after a Single Injection in Mice

The immunogenicity of infliximab and adalimumab is a major concern because patients may develop Abs also called antidrug Abs (ADA), directed against these anti–TNF-α Abs after just a few weeks of treatment. These ADAs can lead to a decrease in biologic concentration, which is associated with lower treatment efficacy. Our aim was to study the involvement of immune complexes and neonatal Fc receptor (FcRn) in the emergence of ADAs in the case of anti–TNF-α Abs. Wild type and FcRn knockout mice were injected once with either infliximab or adalimumab, alone or preincubated with TNF-α. Adalimumab cross-reacts with murine TNF-α whereas infliximab is species specific. When injected alone, only adalimumab elicited a humoral response. By preforming immune complexes with TNF-α, an anti-infliximab response was elicited. Surprisingly, both wild type and FcRn knockout mice were able to mount an immune response against anti–TNF-α Abs, suggesting that immune complexes are a major determinant of this immunization.

Development and validation of an enzyme-linked immunosorbent assay to measure free eculizumab concentration in serum

AIM Eculizumab is a monoclonal antibody toward C5 fraction of the complement system. It is approved to treat paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. To perform pharmacokinetic studies and therapeutic drug monitoring, a validated assay is required. MATERIALS & METHODS An indirect ELISA with recombinant human C5 sensitized microtiter plates were developed. RESULTS The assay allows the measurement of free eculizumab concentration in human serum. The LOD, LLOQ and ULOQ were 0.091, 0.25 and 82.35 mg/l, respectively. The assay meets EMA and US FDA guidelines criteria for the validation of a ligand-binding assay. CONCLUSION This method is validated and can be used in PK and PK-PD studies as well as to perform therapeutic drug monitoring of free eculizumab.

Model-Based Therapeutic Drug Monitoring of Infliximab Using a Single Serum Trough Concentration

Background and ObjectivesThe pharmacokinetics of infliximab are highly variable and influence clinical response in chronic inflammatory diseases. The goal of this study was to build a Bayesian model allowing predictions of upcoming infliximab concentrations and dosing regimen adjustment, using only one concentration measurement and information regarding the last infliximab infusion.MethodsThis retrospective study was based on data from 218 patients treated with infliximab in Tours University Hospital who were randomly assigned to learning (two-thirds) or validation (one-third) data subsets. One-compartment pharmacokinetic and time since last dose (TLD) models were built and compared using learning and validation subsets. From these models, Bayesian pharmacokinetic and TLD models using one concentration measurement (1C-PK and 1C-TLD) were designed. The predictive performances of the 1C-TLD model were tested on two external validation cohorts.ResultsPharmacokinetic and TLD models described the data satisfactorily and provided accurate parameter estimations. Comparable predictions of infliximab concentrations were obtained from pharmacokinetic versus TLD models, as well as from Bayesian 1C-PK versus 1C-TLD models. The 1C-TLD model showed satisfactory prediction of future infliximab concentrations and provided satisfactory predictions of infliximab steady-state concentration for up to three upcoming visits after a blood sample.ConclusionsAccurate individual concentration predictions can be obtained using a single infliximab concentration measurement and information regarding only the last infusion. The 1C-TLD model may help to optimize the dosing regimen of infliximab in routine therapeutic drug monitoring.