For patients living with inflammatory bowel disease (IBD), Infliximab (IFX), a monoclonal antibody, has emerged as an efficient treatment for disease activity reduction and IBD patient life quality improvement. However, while IFX is an effective treatment for some patients, a proportion of patients lose response to biologics within the first year of treatment, partly due to the formation of anti-drug antibodies (ADA). In other patients, the exposure to IFX is too low to be effective. This is due to the fact that dosing of MAbs does not consider the variation in patient clearance.
A recently published study exploring the use and impact of Baysient’s dashboard, iDose, on IFX durability and immunogenicity in a real-world IBD setting found that patients who were not compliant with the iDose recommendations had a substantially higher probability of treatment failure and developing ADA. These results were consistent with an earlier randomized controlled study of adult IBD patients in maintenance therapy with IFX using iDose versus standard of care. iDose has demonstrated impressive results in multiple clinical trials to date.
Understanding Why Patients Lose Response
IFX is approved for both Crohn’s disease (CD) and ulcerative colitis (UC) at 5 mg/kg given as an intravenous induction regimen at 0, 2, and 6 weeks, followed by a maintenance regimen of 5 mg/kg every 8 weeks. According to the study, secondary loss of response is often attributed to low trough levels, frequently in the presence of ADA. Multiple studies have demonstrated relationships between trough levels, ADA and efficacy. To maintain a durable response to IFX, it is crucial for clinicians to prevent low trough levels and subsequent ADA.
Clinicians have found that therapeutic drug monitoring (TDM) in IBD practice is predominantly reactive and often done too late to help the patient. However, proactive TDM can facilitate early dose optimization, preventing loss of response, ultimately improving patient outcomes, including fewer surgeries and hospitalizations.
Dashboard to Improve IFX Dosing
The need for personalized medicine continues to increase as we learn more about the complexity of immune-based conditions like IBD. Tools are needed to help identify those individuals who do need early optimization to minimize immunogenicity and increase IFX durability.
iDose is a prospectively validated system that is able to integrate individual clinical and PK data to generate dosing recommendations to achieve a physician specified target trough level using adaptive Bayesian forecasting. In this study, clinicians investigated iDose, which demonstrated that clinical intuition alone was not as accurate at predicting the need for dose escalation.
iDose uses Bayesian models, routine lab results and demographic information to allow physicians to individualize dosing to a specific target trough level. Bayesian forecasting works by utilizing actual patient data and then processes that patient-specific information via a pharmacokinetic/pharmacodynamic (PK) model.
Once all the patient specific data is processed into the system, the model estimates the patient’s ability to absorb, process and clear IFX from their system. This dashboard allows clinicians to interpret time-varying patient factors, and therefore, optimize dosing to maintain the selected target trough level concentrations.
iDose Shown to Improve Infliximab Durability and Reduce Immunogenicity
Within this study, both pediatric and adult IBD patients were enrolled in a prospective intervention trial. Weight, albumin, C-reactive protein, IFX dose, IFX trough level and ADA presence were all used to inform subsequent INF dosing. The forecasts driven by Bayesian models using iDose were generated to maintain trough levels for the third and fourth infusions of 17 μg/mL and 10 μg/mL.
The clinicians found that, “of the 180 per-protocol population, accelerated dosing (AD) was forecast for 41% (INF3) and 69% (INF4) of patients with median intervals of 17 (INF3) and 39 (INF4) days. Baseline age >18 years, albumin >3.5 g/L, and 10-mg/kg dose were independently associated with lower rates of AD by INF4. Nonadherence with the INF4 forecast (n = 39) was an independent predictor of antidrug antibody (P < .0001) and IFX discontinuation (P = .0006). A total of 119 of 123 patients on IFX at week 52 were in steroid-free remission.”
As the largest proactive IFX dose optimization research study, clinicians were able to demonstrate that the standard 8-week interval dosing between end of induction and first maintenance is too long for many patients. Clinicians found that precision dosing, using iDose, can minimize ADA development and maintain effective troughs without needing to introduce steroids or other immunomodulators, which will improve safety and compliance of patients taking anti-TNF therapy.
Dubinsky MC, Mendiolaza ML, Phan BL, Moran HR, Tse SS, Mould DR. Dashboard-Driven Accelerated Infliximab Induction Dosing Increases Infliximab Durability and Reduces Immunogenicity. Inflamm Bowel Dis. 2022 Jan 3:izab285. doi: 10.1093/ibd/izab285. Epub ahead of print. PMID: 34978325.