Precision IFX: Using a Dashboard to Individualize Infliximab Dosage
Condition: Inflammatory Bowel Disease
MeSH terms: Intestinal Diseases; Inflammatory Bowel Diseases
Study type: Interventional

Summary: 
      The introduction of infliximab (IFX) and other monoclonal antibodies (MAbs) targeting tumor
      necrosis factor (TNF) was a major advancement in the management of inflammatory bowel disease
      (IBD). These biologics were able to improve the health outcomes of many IBD patients for whom
      other treatments were neither satisfactory nor sufficient. Despite clear advantages and
      increased use of these treatments, physicians still see a loss of response in up to 50% of
      their IBD patients within one year of initiating these therapies. Most of these phenomena are
      attributed to low drug concentrations in the presence or absence of anti-drug antibodies
      (ADA).

      The fundamental issue is that approved/on-label dosing of these drug therapies does not take
      into account the various factors that impact the way an individual's body responds and
      processes these therapies. Dashboard software systems can quickly integrate patient data and
      serve as a revolutionary decision-support tool for physicians. The Precision IFX dashboard
      prototype was specifically developed to facilitate dosing of therapeutic monoclonal
      antibodies by integrating patient's clinical characteristics and drug concentrations into
      pharmacokinetic (PK) algorithms. Using clinical observations and patient laboratories, the
      system provides multiple dosing regimens that could allow the patient to attain and sustain a
      therapeutic drug trough level.

      Using the Precision IFX dashboard to analyze and forecast optimal dosing regimens with
      prospectively collected individual patient data, the clinician will select an appropriate
      dose to actively maintain therapeutic drug trough levels throughout the infliximab
      maintenance period. This study aims to examine the outcomes of one year of maintenance
      infusions in IBD patients dosed using the Precision IFX dashboard prototype and compare the
      results with historical controls.
    

Detailed description: 
      Therapeutic monoclonal antibodies (MAbs) targeting the tumor necrosis alpha pathway
      (anti-TNFα, anti-TNF) in the treatment of immune diseases such as rheumatoid arthritis,
      psoriasis, and inflammatory bowel diseases (IBD) have improved short and long term clinical
      outcomes. Crohn's Disease (CD) and ulcerative colitis (UC), two main subtypes of IBD, are
      chronic diseases resulting from immune dysregulation in genetically susceptible individuals.
      CD and UC are conventionally treated using anti-inflammatory agents including aminosalicylate
      based therapies (mesalamines), corticosteroids, and antimetabolites such as purine analogs
      (azathioprine and 6-mercaptopurine) and methotrexate. A high percentage of patients fail to
      respond or are intolerant to these therapies and require treatment with anti-TNF. However,
      despite their therapeutic efficacy, approximately 20% of patients show no or limited response
      during induction therapy (primary non-responders) and in up to 50% of responders, treatment
      becomes ineffective during maintenance therapy despite initial response (secondary
      non-responders). Recent publications have underscored substantial variability in patient
      exposure and response when anti-TNF therapies are administered at the labeled induction and
      maintenance dose, supporting the need to individualize dosing to account for variability and
      ensure safe and sustainable efficacy. Suboptimal exposure can be attributed to under-dosing,
      rapid drug clearance and/or the development of anti-drug antibodies (ADA) and can result in
      primary or secondary loss of response (LOR). Identifying an individual's effective dose and
      adjusting the doses of anti-TNF over the course of treatment to maintain effective
      concentrations is not intuitive.

      Software-guided dosing has been shown to effectively control doses for individual patients
      and to increase efficiency in clinics. Individualized adaptive dosing using PK models has
      been undertaken but was a labor-intensive process prior to using dashboard systems. Several
      dashboard systems already exist to improve dosing in pediatric patients. Clinical use of such
      systems is still limited, in part because of a lack of familiarity with dashboards,
      ineffective communication to practicing clinical staff on the use and benefits of such
      systems to facilitate decision making, and the resources required to use modeling to fully
      individualize treatment. However in the case of pediatric patients, particularly for those
      patients dosed based on body size (e.g. mg/kg or mg/m2), the drug exposure in pediatrics is
      often substantially lower than adult patients making these dosing metrics particularly
      difficult for patients with low body weight or pediatrics, as has been shown for infliximab.
      This suggests that pediatric patients would potentially garner the greatest benefit from
      individualized dosing.

      Until recently, effective use of drug concentrations and biomarkers has been limited by the
      lack of decision support tools allowing physicians to integrate patient data and generate
      treatment recommendations. Implementation of adaptive Bayesian dosing in the clinic has not
      yet gained wide acceptance, and requires careful evaluation and testing. However Bayesian
      forecasting has been shown to substantially increase the number of patients whose trough
      phenytoin levels were within the target range and improve clinical outcomes in pediatric
      oncology patients. Van Lent-Evers at all found that the use of Bayesian adaptive dosing of
      aminoglycosides offered resulted in higher antibiotic efficacy, shorter hospitalization, and
      reduced incidence of nephrotoxicity. The authors also found lower treatment costs in patients
      who were dosed using Bayesian approaches. There have been a number of dashboard systems
      developed recently for improving treatment in pediatric oncology and infectious disease
      although these have not yet gained widespread clinical use.

      From a clinician's perspective, it would be highly advantageous to be able to optimize the
      exposure of MAbs in patients receiving these therapies for disease control. The advent of
      commercially available drug and ADA concentration assays has indeed improved understanding of
      why patients are not responding or are losing response while in maintenance. With
      conventional weight based (on label) dosing, the investigators make the assumption that all
      patients clear anti-TNF therapies at the same rate and do not take into account
      inter-individual variability. A model that selects the correct induction dose based on
      clinical variables that alter clearance and allows clinicians to dose adjust in maintenance
      as the disease activity, weight, and drug concentrations fluctuate over the course of disease
      would not only be helpful but also economical. Consistent with the potential advantage of
      dashboards, a recent evaluation found individualized infliximab dosing reduced treatment
      costs compared to conventional dosing.

      Presently for infliximab, patients are escalated from 5 mg/kg to 10 mg/kg and without
      necessarily considering that a patient may benefit from just increasing to 6 mg/kg to
      maintain therapeutic concentrations based on the dashboard predictions. Moreover it could be
      that a frequency change in dosing (e.g., from every 8 weeks to every 4 or 6 weeks) should be
      considered rather than dose escalation which carries significantly more cost than more
      frequent infusions. Rather than waiting for a patient to declare themselves a failure of the
      indicated dosing, predictive models can ensure the investigators are dosing correctly up
      front and being proactive and flexible with dosing regimens.

      The ultimate goal of precision medicine is to utilize new information to optimize therapy for
      individual patients so that patients are treated with the right dose of the right drug at the
      right time. This approach is intended maximize benefit and minimize risk. Research has
      provided a wealth of new information, but health care providers are not always equipped to
      collect and manage this information in the patient care setting. Thus, dashboard systems may
      provide an important decision-support tool to facilitate the use of this new information into
      patient care.

      The shift from conventional empirical dose adjustments to dashboard facilitated dosing will
      require access to the models developed during drug development or during post-marketing
      evaluations. However, prior to routine implementation in clinical use, dashboard systems will
      need to be designed to merge seamlessly with current clinical practice and the use of these
      systems will need to be verified by prospective clinical trials showing the benefit of this
      approach, and education about these systems will have to be made available to practicing
      physicians.

      Preliminary data of a retroactive study completed using an IFX dashboard prototype showed a
      there was 0.70 concordance of actual trough values with forecasted trough values when using
      clinical profiles with laboratory observations from the first maintenance infusion. The
      dashboard retroactively evaluated dosing regimens for the patients and recommended every 7-8
      week dosing in 56% of patients who received every 7-8 week. The dashboard system recommended
      a dose decrease for 52% of subjects and dose increased for 38% of patients. Additionally,
      71.4% of subjects who developed antibodies were recommended dose changes and/or dosing
      frequency changes.

      The dashboard system will actively monitor and dose to target a maintenance drug trough level
      after the standard induction period is complete. By proactively monitoring and dosing
      patients, this study hopes to reduce the frequency of subjects losing response due to
      anti-drug antibody development and to increase the frequency of subjects attaining and
      sustaining therapeutic drug. Overall, the Precision IFX dashboard will serve as a decision
      support tool for the clinician. The clinician will ultimately determine the appropriate
      dosing regimen to use for the patient. The dosing regimen will be within standard-of-care
      guidelines and within guideline and limits usually practiced in clinic and authorized by
      insurances.
    

Intervention name(s): Individualized Dosage Precision IFX Dashboard
Intervention type(s): Other
Intervention description(s): Pharmacokinetic Dashboard Recommended Dosage and Dosing Frequency of Infliximab
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Inflammatory Bowel Disease, Ulcerative Colitis; Crohn's Disease; Pharmacokinetics, Individualized Dosage, Dashboard System; Remicade, Infliximab