Precision IFX: Using a Dashboard to Individualize Infliximab Dosage
| Status: | Recruiting |
|---|---|
| Conditions: | Irritable Bowel Syndrome (IBS), Gastrointestinal |
| Therapuetic Areas: | Gastroenterology |
| Healthy: | No |
| Age Range: | 6 - 45 |
| Updated: | 12/26/2018 |
| Start Date: | January 2015 |
| End Date: | December 2024 |
| Contact: | Becky L Phan, BSc |
| Email: | becky.phan@mssm.edu |
| Phone: | 212-824-7785 |
Precision IFX: Using a Pharmacokinetic Dashboard to Optimize and Individualize Infliximab Dosage for Pediatric Inflammatory Bowel Disease Patients
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.
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.
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.
(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.
Inclusion Criteria:
- Patients with Inflammatory Bowel Disease
- Patients at least 6 years of age, upper limit of 45 years old
- Recently Indicated for (or already scheduled for) infliximab induction as per
standard-of-care by treating gastroenterologist
- Patient consent/assent and/or parent/guardian consent
Exclusion Criteria:
- Patients do not consent to participate in study
- Patients unable to comply with protocol
We found this trial at
1
site
New York, New York 10029
Principal Investigator: Marla C Dubinsky, MD
Phone: 212-842-7785
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