AJMC PredictrPK IFX Infliximab Precision Guided Dosing Test User Guide

PredictrPK IFX Infliximab Precision Guided Dosing Test

Real-World Impact of Infliximab

Precision-Guided Dosing on
Management of Patients With IBD

HIGHLIGHTS

• PredictrPK IFX: A Precision-Guided Dosing Test That Represents a Novel Approach to Dose Optimization
• PredictrPK IFX Impact on Health Care Provider Decision-Making
• Benefits and Usefulness of PredictrPK IFX

Supplement to The American Journal of Managed Care®
© 2023 Clinical Care Targeted Communications Group, LLC

Real-World Impact of Infliximab Precision-Guided Dosing

on Management of Patients With IBD

This study and supplement were funded by Prometheus Laboratories Inc.

The contents of this supplement may include information regarding the use of products that may be inconsistent with or outside the approved labeling for these products in the United States. Physicians should note that the use of these products
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OCTOBER 2023 www.ajmc.com

Real-World Impact of Infliximab

Precision-Guided Dosing
on Management of Patients With IBD

OVERVIEW
This supplement to
The American Journal of
Managed Care® describes
the results of the EMPOWER
(Effect on Decision-Making
of Precision Optimization in
Real-World Evidence Research)
study, which demonstrate the
real-world clinical utility of
PredictrPK IFX, a precisionguided
dosing assay, to prompt
early treatment decisions to
optimize IFX therapy with
greater value than standard
therapeutic drug monitoring.

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FACULTY

Bincy P. Abraham, MD, MS
Professor of Clinical Medicine
Department of Medicine
Houston Methodist Academic Institute
Houston, TX

Patricia Aragon Han, MD, MAS
Clinical Research Scientist
Prometheus Laboratories Inc
San Diego, CA

Robert Battat, MD, CM
Assistant Professor of Medicine (position during
program)
Division of Gastroenterology and Hepatology
NewYork-Presbyterian Hospital/Weill Cornell
Medical College
New York, NY
Director (current position)
Center for Clinical Excellence and Translational
Research in Inflammatory Bowel Diseases
Centre hospitalier de l’Université de Montréal
Montreal, Quebec
Canada

Thierry Dervieux, PharmD, PhD
Chief Scientific Officer
Prometheus Laboratories Inc
San Diego, CA

Andrew Shim, PharmD, JD
Vice President of Medical Affairs
Prometheus Laboratories, Inc
San Diego, CA

David A. Ziring, MD
Associate Director
Division of Pediatric Gastroenterology
Cedars-Sinai Medical Center
Los Angeles, CA

FACULTY DISCLOSURES

These faculty have disclosed the following relevant commercial financial relationships or affiliations
in the past 12 months.

Bincy P. Abraham, MD, MS
OTHER
EMPOWER Program

Patricia Aragon Han, MD, MAS
EMPLOYMENT
Prometheus Laboratories Inc

Robert Battat, MD, CM
CONSULTANCIES OR PAID ADVISORY BOARDS
AbbVie; Bristol Myers Squibb; Eli Lilly; Janssen;
Pfizer; Prometheus Laboratories Inc; Takeda
Pharmaceutical Company
OTHER
EMPOWER Program

Thierry Dervieux, PharmD, PhD
EMPLOYMENT
Prometheus Laboratories Inc

Andrew Shim, PharmD, JD
EMPLOYMENT
Prometheus Laboratories Inc
STOCK OWNERSHIP
Prometheus Laboratories Inc

David A. Ziring, MD
LECTURE FEES
Prometheus Laboratories Inc
OTHER
EMPOWER Program
INSTITUTIONAL CONFLICTS OF INTEREST
Cedars-Sinai Medical Center

Signed disclosures are on file at the office of The American Journal of Managed Care®,
Cranbury, New Jersey.

Real-World Impact of Infliximab

Precision-Guided Dosing
on Management of Patients With IBD

Bincy P. Abraham, MD, MS; David A. Ziring, MD; Thierry Dervieux, PharmD, PhD;
Patricia Aragon Han, MD, MAS; Andrew Shim, PharmD, JD; and Robert Battat, MD, CM

Introduction and Objectives

Inflammatory bowel diseases (IBD), including Crohn disease (CD)
and ulcerative colitis (UC), are chronic debilitating lifelong conditions
involving inflammation/injury to the gut mucosa, dysbiosis,
and potentially lethal complications resulting from progressive
bowel damage.1,2 Effective, optimal, and personalized therapy for
IBD can maximize the likelihood of healing and relieve symptoms.
The rising prevalence, particularly in young adults (peak incidence
between 15-30 years)3 and older adults (> 60 years),4 places a substantial
burden on patients and health care systems due to substantial
IBD-related total cost of care.
Anti-TNFα therapies have revolutionized IBD care, are considered
when other conventional therapies have failed, and are often used
as first-line treatment in moderate to severe IBD. However, 40% of
patients may experience primary nonresponse to anti-TNFα therapies
such as infliximab (IFX).5 Among patients who do respond, almost
40% experience secondary loss of response within 1 year5 and up
to 55% receive treatment intensification upon loss of response.6
Moreover, in recent studies, 80% of patients had at least 1 end
point indicative of suboptimal therapy (defined as having at least
1 of the following treatment changes or events: dose escalation,
switch or discontinuation except for corticosteroid initiation,
augmentation, inadequate loading, prolonged corticosteroid use,
disease-related surgery, or disease-related hospitalization), indicating
substantial shortcomings in treatments, even among patients
not classified with loss of response.6
The health care cost of IBD is substantial, highlighting the importance
of optimizing the use of biologics and biosimilars. Results
of a Truven MarketScan Database analysis of 415,405 patients with
IBD (2007-2015) reported that the average patient who was taking
biologics accounted for $36,051 and $41,109 per member per year
(PMPY) in 2015 for adults and pediatric patients, respectively.7 The
US Centers for Disease Control and Prevention (CDC) estimates
that adults with IBD in 2015 and 2016 had higher health service use
compared with adults who did not have IBD.8 The results of another
study evaluating data from 2007 to 2016 from commercial and
Medicare Advantage patients reported 3-fold greater direct health

ABSTRACT

OBJECTIVES: Evaluate the clinical utility of a precision-guided dosing
test for infliximab (IFX) and its impact on treatment decision-making for
inflammatory bowel disease (IBD).
STUDY DESIGN: Prospective, multisite, clinical experience program.
METHODS: Health care providers were given access to PredictrPK
IFX, a precision-guided dosing test, for their patients with IBD on
maintenance IFX therapy. Blood samples were drawn 20 to 56 days post
infusion. A Bayesian data assimilation tool used clinical and serologic
data to generate individual pharmacokinetic profiles and forecast trough
IFX. Results were reported to providers to aid in-therapy management
decisions and the decision-making process was assessed through
questionnaires. Relationships between forecasted IFX concentration,
disease activity, and therapy management decisions were analyzed by
logistic regression.
RESULTS: PredictrPK IFX was used for 275 patients with IBD by 37
providers. In 58% of cases, providers modified treatment plans based
on the results, including dose modifications (41%; of these, one-third
decreased dose) and discontinuation (8%) of IFX. Of the 42% where
treatment was not modified, 99.1% had IFX levels of 5 μg/mL or greater.
Patients with IFX concentrations less than 5 μg/mL were 3 and 7.3
times more likely to have active disease or discontinue IFX, respectively.
There was unanimous agreement among providers who completed
a postprogram survey that PredictrPK IFX was beneficial in guiding
treatment decisions and added more value to their practice than routine
therapeutic drug monitoring.
CONCLUSIONS: PredictrPK IFX enables earlier and more precise dose
optimization of IFX in patients with IBD, exerting a substantial impact on
treatment decisions that may result in improved health outcomes and
overall cost savings.

Am J Manag Care. 2023;29:S227-S235
For author information and disclosures, see end of text.

THE AMERICAN JOURNAL OF MANAGED CARE® Supplement VOL. 29, NO. 12 S227

TAKEAWAY POINTS

• Precision-guided dosing of anti-tumor necrosis factor
  alpha (anti-TNFα) therapy has been associated with
  improved health outcomes in patients with IBD.

• The EMPOWER (Effect on Decision-Making of Precision
  Optimization in Real-World Evidence Research)
  study demonstrates the real-world clinical utility of
  PredictrPK IFX, a precision-guided dosing assay, to
  prompt early treatment decisions to optimize IFX
  therapy with greater value than standard therapeutic
  drug monitoring.

• Using PredictrPK IFX in the management of IBD may
  lead to a net decrease in health care expenditures
  by more rapidly optimizing IFX dosing, reducing
  unnecessary IFX use, avoiding disease-related adverse
  outcomes and treatment delays, and enhancing
  the durability of response to IFX compared with
  empiric dosing.

care costs among patients with IBD compared with those who did
not have IBD ($22,987 vs $6956); key drivers of cost included drug
costs; emergency department use; and other services associated
with relapsing disease, anemia, or mental health comorbidity.9
Among patients with CD who were treated with biologics between
January 2004 and March 2019, 79.4% had 1 or more suboptimal
treatment indicators (eg, nonadherence, dose escalation, chronic
corticosteroid use, augmentation, ≥ 1 CD surgery, ≥ 2 CD emergency
department visits, ≥ 1 CD inpatient stay, switch, cycling, restart,
inadequate induction) with mean PMPY costs ranging from $46,100
(no indicator) to $68,572 (≥ 4 indicators).10
A useful approach to biologic optimization in IBD is therapeutic
drug monitoring (TDM), which involves assessing serum levels of
drug and anti-drug antibodies to guide dosing decisions and to
improve the probability of sustained remission. Compared with
empiric changes in dosing that have been shown to lack correlation
with disease activity,11 TDM is considered to be both the standard
of care and more advantageous.12
Multiple publications describe the value of TDM in mitigating
loss of response12-15 and guidelines recommend using TDM in
patients with primary nonresponse or secondary loss of response
to determine when optimization of current therapies or change to
alternate therapies may be needed. Additionally, guidelines affirm
the medical value of TDM and benefits associated with improved
clinical, mucosal, and endoscopic remission.13,16-18 However, TDM
is limited in that clinical decision-making is inherently reactive
to measured drug and anti-drug antibody levels. In a patient with
active disease, the need to wait for several weeks to measure a

trough concentration for TDM often limits the use of this strategy.
In contrast, proactive TDM involves measuring drug levels in
asymptomatic patients without objective evidence of active disease
(ie, endoscopic, biochemical, and preemptively targeting specific
clinically defined thresholds). It is associated with higher treatment
persistence and lower health care resource utilization compared
with reactive or empiric monitoring.19
Precision-guided dosing enables estimations of trough serum IFX
concentrations without the need to wait for trough concentrations for
testing. Thus, it permits expedited and informed clinical decisionmaking
by clinicians. The clinical utility of precision-guided dosing
was recently demonstrated in the PRECISION trial (NCT02624037),
the results of which showed that 69% of patients with IBD treated
with IFX were predicted to benefit from dose optimization during
the induction phase of therapy and at week 52, 68% of the intentto-
treat group was still on IFX therapy.20 This increased to 81%
when data for patients who were lost to follow-up were removed.
In addition, 97% of patients who were still on IFX at week 52 were
in steroid-free clinical remission.21 For those patients who did not
adhere to dose optimization as suggested by the precision-guided
dosing tool, IFX durability was significantly reduced.20
PredictrPK IFX (Prometheus Laboratories Inc) is a clinically
validated, precision-guided dosing tool that incorporates Bayesian
population pharmacokinetic models and patient-specific clinical
and serological inputs, including TDM. It enables providers to more
rapidly and precisely optimize dosing to achieve target drug levels
for individual patients by producing individualized predictive
estimates of serum IFX concentration at the next trough, as well
as alternative IFX doses and intervals.21 To demonstrate the realworld
clinical utility of PredictrPK IFX and its impact on treatment
for patients with IBD, a prospective, multisite, clinical experience
program (CEP) was conducted among US health care providers (HCPs).

Methods
EMPOWER (Effect on Decision-Making of Precision Optimization
in Real-World Evidence Research) was a prospective, multisite,
survey-based study that enrolled academic and community HCPs
treating pediatric and adult patients with IBD (Figure 1).

Clinical Experience Program
Prior to program initiation, HCPs were presented with PredictrPK
IFX validation data and test criteria. HCPs completed a prestudy
survey that explored practice details and how IFX TDM was currently
utilized in their practice. Subsequently, HCPs were provided access
to 10 PredictrPK IFX precision-guided dosing tests to utilize in the
clinical scenarios of their choosing during the maintenance phase
of IFX therapy. Tests could be used in different patients or for repeat
testing in the same patient. HCPs completed a posttest survey for
each patient after receiving PredictrPK IFX test results. The survey

captured patient phenotype, how and why the test was ordered,
how results were used, and whether the results were considered
beneficial for guiding patient care. HCPs also completed a postprogram
survey to share overall feedback about the usefulness of
PredictrPK IFX. National Institutes of Health criteria for exemption
from human subject regulations (category 4) were met because all
personal information was removed to protect privacy.22

PredictrPK IFX
PredictrPK IFX includes a determination of IFX serum levels (> 1.0
μg/mL), antibodies-to-IFX (ATI) (> 3.1 U/mL), and albumin (g/dL). All
assays were performed in a CLIA-certified laboratory (Prometheus
Laboratories Inc, San Diego, CA). Assay results, patient dosing
provided by the HCP, and patient weight were included in a validated
Bayesian data assimilation tool that produces pharmacokinetic
profiles.21 PredictrPK results included forecasted IFX trough levels
based on the actual dosing, as well as patient-specific alternative
dosing regimens.

PredictrPK IFX tests were used on patients for whom the physician
would have otherwise ordered TDM and utilized the following
EMPOWER inclusion criteria: a) confirmed diagnosis of IBD;
b) received IFX treatment with or without concomitant immunotherapy;
and c) received IFX treatment for at least 14 continuous
weeks (maintenance phase). Blood samples for PredictrPK IFX could
be collected any time from 20 days postinfusion until immediately
prior to the subsequent infusion.

Data Analyses
Relationships between patient characteristics and therapy discontinuation
were assessed by univariate and bivariate analyses (Table 1).
Simple logistic regression was used to quantify the risk associated
with estimated drug concentration, clearance, disease activity, and
therapy discontinuation. Results were reported as odds ratios and
confidence intervals.

Results
Characteristics of Clinical Practice
A total of 37 HCPs specializing in IBD from academic and community
settings in 19 states and Puerto Rico participated in EMPOWER.
HCPs were highly experienced in treating patients with IBD using
biologics, with 62% of HCPs in practice for 10 years or more, 36 of
37 treating at least 10 patients with IBD per month, and 59% treating
50 or more patients per month. Biologics were used in 21% to 40%
of patients by 73% of HCP practices (see eAppendix Table 1 for
complete presurvey results. eAppendices available at AJMC.com).
HCPs most frequently ordered PredictrPK IFX to optimize IFX therapy
in the absence of symptoms (61%; proactive TDM); the test was also
ordered to assess the need for change in a symptomatic patient
(47%; reactive TDM), soon after initiating IFX therapy (7%; early
proactive), after an infusion reaction (4%), or after another type
of adverse event (4%). HCPs were allowed to provide more than
1 explanation for ordering the test. Thus, the sum of responses is
greater than 100% (Figure 2).

Characteristics of Patient Cohort
The median age of patients (N = 275) was 32 years; 45% of patients
were female; 64% had CD, 34% had UC, and 1.5% had an indeterminate
colitis (Table 1). At study entry, 32% of the patients were
classified as being in remission, 38% as having mild-to-moderate
disease, and 29% as having moderate to severe disease by physician
global assessment (PGA); 52% had been on IFX therapy for at least
24 months, and 30% of patients had exposure to prior biologics.

PredictrPK IFX Impact on Health Care Provider
Decision-Making
Of the 275 patients in the study, HCPs decreased the IFX dose or
increased the dosing interval in 36 (13%) patients who had elevated
measured (28 μg/mL) and forecasted (30 μg/mL) trough IFX concentrations.
HCPs increased the dose or shortened the interval in 75 (28%)

FIGURE 1. EMPOWER Program Outline

TABLE 1. Patient Characteristics and PredictrPK IFX Assay Data

ATI, antibodies to infliximab; IFX, infliximab; IQR, interquartile range.
aFactors associated with discontinuation of IFX therapy; comparisons by Kruskal-Wallis rank sum test, Pearson chi-squared test, or Fisher exact test, as appropriate.
bVariables significantly associated (P < .001) with IFX therapy discontinuation on bivariate analysis.

FIGURE 2. Reasons for Ordering PredictrPK IFX Testa

IFX, infliximab.
aShown are the percentages of health care provider responses to each category. Health care providers were allowed to provide more than 1 explanation for ordering the
test. Thus, the sum of responses is greater than 100%.

REAL-WORLD IMPACT OF INFLIXIMAB PRECISION-GUIDED DOSING

patients who had lower measured (8 μg/mL) and forecasted (6 μg/mL)
trough IFX concentrations (Table 1 and Figure 3). No patients who
had their IFX dose decreased had detectable antibodies to infliximab
(ATI) and only 1 of 141 patients (0.7%) who had no change to their
IFX dose had detectable ATI. Of those patients who had their IFX
dose increased, 15% had detectable ATI prior to dose escalation. In
patients who were switched to a different primary therapy, 57% had
detectable ATI prior to the switch. In patients with dose de-escalation
or unchanged dosing, 58% and 37% were in remission, respectively.
A forecasted IFX trough of less than 5 μg/mL was associated with
7.3 times the odds of IFX discontinuation and 3.0 times the odds of
active disease compared with a forecasted IFX concentration of more
than 5 μg/mL on logistic regression (Table 2). Similarly, a clearance
rate of more than 0.294 L/day was associated with 4.1 times the
odds of IFX discontinuation and 3.2 times the odds of active disease
compared with a clearance rate of less than 0.294 L/day. As shown
in Table 1 and Figure 3, other clinicopharmacologic features associated
with the decision to stop IFX (8%) were albumin and ATI levels.
After receiving the results of PredictrPK IFX, HCPs modified their
treatment plan in 58% of cases (Figure 4). Treatment modifications
can be further broken down by the type of change: 41% modified
biologic dosing (68% dose escalated and 32% dose de-escalated),
8% switched biologic or therapy, 6% adjusted immunosuppressant
therapy (add, remove, or change dose), 9% ordered colonoscopy or
other imaging, 7% added additional tests (ie, fecal calprotectin),
and 2% made other changes (ie, surgery). These numbers are not
additive, as HCPs may have made multiple modifications. Among
42% of cases with no treatment modification, 83.6% had IFX trough
concentrations of at least 10 μg/mL, 15.5% had IFX trough concentrations
of 5 to 10 μg/mL, and 0.9% had IFX trough concentrations
of less than 5 μg/mL.

Benefits and Usefulness of PredictrPK IFX
In the postprogram survey, 83.8% of HCPs responded. Among these
HCPs, 100% indicated PredictrPK IFX was deemed beneficial for
ongoing treatment decisions, 97% reported utility for determining
optimal dose/interval, and 77% reported utility for providing confidence
for maintaining current dose/interval (eAppendix Table 2).
When asked about the usefulness in specific situations, the strongest
levels of agreement were for consideration of dose increase in
primary nonresponse or secondary loss of response, followed by
consideration for dose decrease, patients on maintenance IFX, and
patients starting on a biologic (ie, postinduction, first maintenance
dose) (Figure 5). PredictrPK IFX was also helpful in providing justification
for adjustments with insurance providers (55%) or assisting
in discussions with patients regarding adverse events (32%). HCPs
unanimously agreed that PredictrPK IFX added more value to their
practice than standard TDM.
Almost all HCPs reported that ordering PredictrPK IFX was easy
(90%), results were received in reasonable time (97%) to support/
impact their clinical decision-making, and the test report was easy
to understand and informative (100%).
The survey responses in the postprogram survey were more
subjective, as the survey looked at overall experience with the test
across multiple samples and patients. However, the objective data
were captured following the individual postsample surveys.

Discussion
EMPOWER included a geographically diverse group of gastroenterology
practitioners treating pediatric and adult patients in academic
and community settings. PredictrPK IFX was ordered to optimize IFX
therapy, both proactively (61%) and reactively to assess the need for
change in symptomatic patients (47%), suggesting that clinicians

FIGURE 3. Associations Between PredictrPK IFX Test Results (Measured and Forecasted Trough Values), Patient Disease Status, and
Changes to IFX Dosing Regimensa

ATI, antibodies to infliximab; IFX, infliximab.
aInfliximab concentrations are shown as median values with interquartile ranges. The percentage of patients with detectable antibodies to infliximab are indicated by
the superimposed orange bars.

TABLE 2. Relationships Between Physician Decision-Making
and PredictrPK IFX Test Results and Status of Patient Disease
Activity Calculated by Simple Logistic Regression

Association Odds ratio 95% CI P Value
Forecasted IFX concentration < 5 μg/mL
Active disease 3.0 1.4-7.3 < .01
Discontinue IFX therapy 7.3 3.1-18.3 < .01
Clearance rate > 0.294 L/day
Active disease 3.2 1.8-5.9 < .01
Discontinue IFX therapy 4.1 1.7-11.0 < .01

were comfortable in adopting a precision-guided dosing method
in a variety of clinical scenarios.
Overall, PredictrPK IFX showed clinical utility in health care
provider decision-making. In 58% of cases, test results were utilized
in the decision to modify treatment plans and to confirm existing
therapy plans where dosing was appropriately controlling IBD.
Our EMPOWER data demonstrate that the most common treatment
modification was a change in biologic dosing (41%) and that
within this group, 32% had dose de-escalation (Figure 4). This is
an important finding, showing that TDM may be a valuable tool
to avoid unnecessary biologic drug use when dose reduction is
warranted based on the combination of clinical symptoms and

FIGURE 4. Impact of PredictrPK IFX Test Results on Clinical Decision- Makinga

IFX, infliximab.
aHealth care providers may have made multiple modifications to the treatment plan of any given patient. Thus, the sum of responses is greater than 100%.

FIGURE 5. Usefulness of the PredictrPK IFX Testa

AE, adverse event; IFX, infliximab.
aShown are the percentages of health care providers (n = 31) responding “yes” for the usefulness of the test in the various circumstances listed.

REAL-WORLD IMPACT OF INFLIXIMAB PRECISION-GUIDED DOSING

results of individualized pharmacokinetic profiles from PredictrPK
IFX testing. Among patients with no treatment modification (42%),
83.6% had serum IFX of at least 10 μg/mL, which has been associated
with corticosteroid-free clinical remission in 97% of patients
still on IFX at week 52.20 In addition, 15.5% of patients with no
treatment modification had IFX trough concentratons between 5
and less than 10 μg/mL and only 0.9% had serum IFX of less than 5
μg/mL, concentrations that are associated with active disease and
result in the discontinuation of IFX.20
In the postprogram survey, HCPs unanimously agreed that
PredictrPK IFX was beneficial for ongoing treatment decisions.
They also had a high level of agreement that the test was beneficial
for optimizing IFX dosage/interval and providing confidence for
maintaining the current IFX dose and/or interval. Almost all HCPs
believed that it was easy to order PredictrPK IFX, understand the
test report, and receive it within a reasonable time. Importantly,
HCPs unanimously agreed that PredictrPK IFX precision-guided
dosing added more value to their practice than standard TDM. Given
the diverse group of clinical specialists, the findings suggest that
precision-guided dosing tools will likely be accepted and valued
by the broader gastroenterology community.
The adoption of TDM has been variable among different practices
due to knowledge gaps in clinicians’ understanding of optimal
target drug concentration and the need for ideal (trough) timing of
measurement.23,24 However, a recent expert consensus statement
on biologics in IBD recommended that TDM should be performed
for patients treated with anti-TNFα therapies at least once during
the maintenance phase and specifically when IFX dose reduction
is being considered for patients in remission.24 PredictrPK IFX
provides increased utility relative to TDM by forecasting trough
IFX in blood samples drawn at least 20 days post infusion and prior
to the next IFX infusion. This precision-guided approach provides
predictive data in a timely manner, which helps to avoid delays in
therapeutic decision-making. In addition, PredictrPK IFX simultaneously
generates a personalized profile unique to each patient,
affording clinicians an opportunity to make decisions about dose
or interval adjustments prior to the next infusion without having
to estimate future levels and outcomes.
Responses from the postprogram survey indicated that the
main benefit of PredictrPK IFX was in providing rationale and
guidance for dosing decisions. Patients who discontinued IFX
therapy had the lowest concentrations of measured and forecasted
serum IFX and were among the highest proportion of patients
with detectable levels of ATI (57%), whereas patients who either
maintained or decreased their IFX dosing had the highest concentrations
of serum IFX and were among the lowest proportion of
patients with detectable ATI (< 1%). Patients with IBD who were
in remission were also more likely to have higher levels of forecasted
IFX, exceeding 5 μg/mL. These associations strengthen

the perspective that early dose optimization of IFX may reduce
the burden of illness.
Logistic regression coupled with machine learning may be
used to estimate the association of an independent variable (ie,
risk factor) with the probability or risk of a particular outcome
of interest (ie, disease).25 Logistic regression analysis showed
that patients who had estimated IFX concentrations of less than
5 μg/mL have 3 and 7 times the odds of active disease and discontinuation
therapy, respectively, when compared with IFX concentrations
of at least 5 μg/mL. PredictrPK IFX can facilitate timely, clinical
decision-making, providing dose optimization that is tailored to
the individual patient.
At present, studies examining the relationship between precisionguided
dosing and direct impact on health care costs have not yet
been initiated. However, cost impact may be cautiously extrapolated
based on anticipated impact to IBD-related outcomes when
biologics are optimized appropriately. Proactive dose optimization
with TDM in patients with IBD has been associated with improved
health outcomes (ie, lower rates of IBD-related hospitalization) when
compared with empiric dosing or reactive dose optimization.23,26,27
Specifically for IFX therapy, proactive TDM has been associated with
significantly higher primary response rates and significantly lower
rates of adverse clinical outcomes (severe flare, hospitalization, or
surgery) when compared with empiric treatment.28 In a study that
analyzed data collected from June 2016 to July 2017, TDM (reactive
and proactive) was deemed to identify unnecessary use of IFX in
31% of patients with IBD.29
Despite the benefits of proactive TDM, a survey of more than
400 US gastroenterologists indicated that the greatest barriers to
TDM were uncertainty about insurance coverage (78%) and high
out-of-pocket costs to patients (76%).30 Also, dose escalation
accounted for 12% of the reasons given for submitting an insurance
prior authorization (PA) request. The low approval rate of
67.6% suggests that PAs do not account for available evidence on
the importance of dose modifications to achieve therapeutic trough
targets of anti-TNFα therapies for more effective disease management.
31 It is notable that cost constraints and management thereof
constitute the greatest barriers, despite the potential opportunities
for overall IBD health care savings that can result from dose
optimization of these biologics.
In our study, 13% of tests resulted in dose tapering, which represents
a potential reduction in costs by avoiding unnecessary drug
utilization. Even IFX dose escalation (28%) represents an opportunity
to expediently identify patients at risk of losing response. It also
allows HCPs to adjust dosing to enable drug persistence and mitigate
adverse clinical outcomes, which is now more important with the
availability of biosimilars. In a prospective observational study of
CD patients, treatment failure was predicted by low concentrations
of anti-TNFα therapies and the development of immunogenicity.32The results of a systematic review and meta-analysis of serum IFX
levels and outcomes in IBD found that patients in clinical remission
had significantly higher mean trough IFX than patients who
were not in remission.33 This is consistent with our findings that
patients in remission had a higher likelihood of a forecasted IFX of
greater than 5 μg/mL and that higher clearance rates were associated
with active disease and patients who discontinued IFX therapy.
Limitations
PredictrPK IFX is intended to provide guidance to clinicians in
continuing or modifying their management strategy for any given
patient, but currently, guidelines do not address how such testing
should be best utilized. Since there is no standard of practice for use
of this predictive dosing test, the results may not broadly apply to all
HCPs. However, there were diverse participating sites ranging from
academic to community practices that treated adult and pediatric
patients, so the results were representative of real-world practice.
Also, all survey responses were self-reports with no confirmation
of changes to patient care by medical records and no follow-up to
determine actual real-world outcomes; however, the program intent
was to assess initial treatment decisions rather than a long-term
outcome assessment. Lastly, any cost savings are inferred since we
did not directly determine economic outcomes.
Conclusions
PredictrPK IFX is a precision-guided dosing test that represents a
novel approach to dose optimization by providing predictive pharmacokinetic
data to clinicians to generate a personalized profile
unique to each patient. Precision-guided dosing allows for earlier
optimization of IFX dosing in patients with IBD, is associated with
an increased likelihood of remission, reduces unnecessary drug
use, and is associated with reduced loss of treatment response.
Our data validate the consistent relationship of the PredictrPK
IFX test with disease activity and its clinical utility to HCPs in
managing patients with IBD who are being treated with IFX or
its biosimilars. n
Acknowledgments
EMPOWER IFX CEP was designed by the Chief Scientific Officer of Prometheus
Laboratories Inc, Thierry Dervieux, PharmD, PhD. We would like to thank
all the health care providers who participated in the program, and Judy
Gohndrone for providing exceptional support during the program. Assistance
with medical writing and data presentation was provided by Noel N. Kim,
PhD, under the direction of the authors.
Author Affiliations: Department of Medicine, Houston Methodist Academic
Institute (BPA), Houston, TX; Division of Pediatric Gastroenterology, Cedars-
Sinai Medical Center (DAZ), Los Angeles, CA; Prometheus Laboratories Inc
(PAH, AS), San Diego, CA; during program, Division of Gastroenterology and
Hepatology, NewYork-Presbyterian Hospital/Weill Cornell Medical College (RB),
New York, NY, and now with Center for Clinical Excellence and Translational
Research in Inflammatory Bowel Diseases, Centre hospitalier de l’Université
de Montréal (RB), Montreal, Quebec, Canada.
Source of Funding: This supplement was supported by Prometheus
Laboratories Inc.
Author Disclosures: Drs Abraham and Ziring report being a participant
physician/site and receiving fair market value compensation for being part
of the EMPOWER program. Dr Ziring also reports receiving compensation for
providing lectures for Prometheus Laboratories Inc and has disclosed that
Cedars-Sinai Medical Center has a royalty interest in Prometheus Laboratories
Inc. Drs Dervieux and Aragon are employed by Prometheus Laboratories Inc.
Dr Shim is employed by and owns stock in Prometheus Laboratories Inc.
Dr Battat has been a paid consultant or advisory board member for AbbVie;
Bristol Myers Squibb; Eli Lilly; Janssen; Pfizer; Prometheus Laboratories Inc;
and Takeda Pharmaceutical Company.
Authorship Information: Concept and design (TD); acquisition of data
(BPA, DAZ, TD, PAH, AS); analysis and interpretation of data (BPA, DAZ, TD, PAH,
AS); drafting of the manuscript (PAH, RB); critical revision of the manuscript
for important intellectual content (BPA, DAZ, TD, PAH, AS, RB); statistical
analysis (PAH); provision of study materials or patients (BPA, DAZ, TD, PAH,
AS, RB); administrative, technical, or logistic support (PAH); and supervision
(BPA, DAZ, TD, PAH, AS).
Address Correspondence to: Andrew Shim, PharmD, JD; Prometheus
Laboratories Inc, 9410 Carroll Park Dr, San Diego, CA 92121. Email: ashim@
prometheuslabs.com
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