Anne S. Strik

A Real-life Population Pharmacokinetic Study Reveals Factors Associated with Clearance and Immunogenicity of Infliximab in Inflammatory Bowel Disease.

Background: Several factors influencing the pharmacokinetics of infliximab (IFX) in inflammatory bowel disease (IBD) have been identified. We studied the impact of patient, disease, and treatment characteristics on clearance and immunogenicity of IFX in a real-world patient-with-IBD cohort. Methods: Serum concentrations of IFX and antibodies to IFX (ATIs) were measured in patients with IBD at a single center using an enzyme-linked immunosorbent assay and radioimmunoassay. Patient, disease, and treatment characteristics were retrospectively collected along with laboratory values. Pharmacokinetics and ATI titer were analyzed simultaneously by nonlinear mixed-effects modeling. Results: Nine hundred ninety-seven IFX concentrations and 756 ATI measurements from 332 patients with IBD (253 Crohns disease and 79 ulcerative colitis) were included. Mean (SD) IFX dose was 5.47 ± 1.33 mg/kg. ATIs were detected in 75/332 (23%) patients; insufficient exposure below an IFX trough level of 3 &mgr;g/mL was the most predictive factor of developing ATI and resulted in a 4-fold increased risk of ATI development. ATI titer was a better predictor of IFX clearance than ATI as a dichotomous parameter. ATI titers >30 AU/mL were consistently associated with undetectable IFX concentrations. IFX clearance was affected by body weight (40–149 kg) ranging from 0.27 to 0.53 L/d, serum albumin (2–5.4 g/dL) from 0.93 to 0.24 L/d, and titers of ATIs (0–53,000 AU/mL) from 0.36 L/d to 15.93 L/d (P < 0.001). Previously biologic-treated patients exhibited a higher clearance of IFX. Conclusions: IFX exposure below 3 &mgr;g/mL increases risk of ATIs. Identification of influential pharmacokinetics and ATI factors improves prediction of IFX levels, potentially allowing individualized dosing and cost reduction.

Suppression of anti‐drug antibodies to infliximab or adalimumab with the addition of an immunomodulator in patients with inflammatory bowel disease

Loss of response to anti‐tumour necrosis factor (TNF) therapy in patients with inflammatory bowel disease (IBD) is often caused by anti‐drug antibody formation with neutralisation of drug effect. Addition of an immunomodulator has been suggested to reduce immunogenicity, leading to regained response.

Serum concentrations after switching from originator infliximab to the biosimilar CT-P13 in patients with quiescent inflammatory bowel disease (SECURE): an open-label, multicentre, phase 4 non-inferiority trial

BACKGROUND Biological treatment of chronic inflammatory diseases has improved patient outcomes but increased health-care costs. Switching patients from originator infliximab to a biosimilar can reduce costs, but prospective data about pharmacokinetics and potential immunogenicity are scarce. We aimed to show that infliximab serum concentrations with biosimilar CT-P13 are non-inferior to those with originator infliximab after switching from originator infliximab in patients with inflammatory bowel disease. METHODS SECURE was a prospective, open-label, interventional, non-inferiority, multicentre, phase 4 trial at 13 academic and non-academic sites in Belgium and the Netherlands. Eligible participants were aged 18 years or older, had ulcerative colitis or Crohns disease, were in clinical remission, and were on continuous treatment with originator infliximab for more than 30 weeks. Patients were switched from originator infliximab to CT-P13 at a dose and infusion duration identical to those of originator infliximab (ie, ∼5 mg/kg every 7-9 weeks). Patients were followed up for 16 weeks after switching, with serum concentrations of infliximab measured at baseline (before the first dose of CT-P13), 8 weeks, and 16 weeks. The primary endpoint was serum concentrations of infliximab 16 weeks after switching, assessed separately in patients with ulcerative colitis and those with Crohns disease in the per-protocol population, which included all patients with available serum concentrations and without major protocol violations. A non-inferiority margin of 15% was set (the null hypothesis was that the geometric mean of the ratio of serum infliximab concentrations at 16 weeks to those at baseline was 85% or less). Safety analyses were done in the safety population, which included participants who received at least one dose of CT-P13 and attended at least one safety assessment after that dose. This trial is registered at www.ClinicalTrialsRegister.eu, number 2014-004904-31, and is completed. FINDINGS Between June 5, 2015, and April 6, 2016, 120 consecutive patients with inflammatory bowel disease were recruited: 59 with ulcerative colitis and 61 with Crohns disease. 46 patients with ulcerative colitis and 42 patients with Crohns disease comprised the per-protocol population. The geometric mean ratio of serum infliximab concentrations at week 16 (CT-P13) compared with those at baseline (originator) was 110·1% (90% CI 96·0-126·3) in patients with ulcerative colitis and 107·6% (97·4-118·8) in those with Crohns disease. In both cases, the lower bound of the 90% CI was higher than the prespecified non-inferiority margin of 85%. Six serious adverse events were reported in six patients. Only one of these adverse events, a perianal abscess, was judged to be related to study treatment. INTERPRETATION Switching to CT-P13 is safe and well tolerated in patients with inflammatory bowel disease in remission. Future trials should assess switching to CT-P13 in patients with active disease. FUNDING Mundipharma.

Pneumomediastinum and soft tissue emphysema in pediatric hanging

Postmortem computed tomography (CT) is increasingly being used as a tool in forensic pathology. The exact value of postmortem imaging in detecting specific conditions has not yet been established, but in specific cases, it can be used as a diagnostic tool demonstrating findings that remain undetected during autopsy, as in this case. Pneumomediastinum and soft tissue emphysema were detected with postmortem CT in a 3‐year‐old girl after hanging. It was not found during autopsy. This radiological finding matches 3 adult cases previously described. It is assumed that in this case, the first reported in a child, hanging was the most likely cause as well. In the adult cases, it was interpreted as a vital sign; the person must have been alive to create a pressure gradient causing rupture of the alveoli. This case demonstrates one of the added values of postmortem imaging, the possibility of demonstrating findings that remain undetected during autopsy.

Individualized Dosing of Therapeutic Monoclonal Antibodies—a Changing Treatment Paradigm?

The introduction of monoclonal antibodies (mAbs) to the treatment of inflammatory bowel disease (IBD) was an important medical milestone. MAbs have been demonstrated as safe and efficacious treatments of IBD. However, a large percentage of patients either fail to respond initially or lose response to therapy after a period of treatment. Although there are factors associated with poor treatment outcomes in IBD, one cause for treatment failure may be low mAb exposure. Consequently, gastroenterologists have begun using therapeutic drug monitoring (TDM) to guide dose adjustment. However, while beneficial, TDM does not provide sufficient information to effectively adjust doses. The pharmacokinetics (PK) and pharmacodynamics (PD) of mAbs are complex, with numerous factors impacting on mAb PK and PD. The concept of dashboard-guided dosing based on Bayesian PK models allows physicians to combine TDM with factors influencing mAb PK to individualize therapy more effectively. One issue with TDM has been the slow turnaround of assay results, either necessitating an additional clinic visit for a sample or reacting to TDM results at a subsequent, rather than the current, dose. New point-of-care (POC) assays for mAbs are being developed that would potentially allow physicians to determine drug concentration quickly. However, work remains to understand how to determine what target exposure is needed for an individual patient, and whether the combination of POC assays and dashboards presents a safe approach with substantial outcome benefit over the current standard of care.