Therapeutic Drug Monitoring

Supporting Clinical Data

Anser^® tests are proprietary therapeutic drug monitoring (TDM) tests that support biologic optimization and guide clinical decisions for patients treated with the following drugs or their respective biosimilars:

Infliximab (IFX) (Anser IFX cat. #3150)
Adalimumab (ADA) (Anser ADA cat. #3170)
Vedolizumab (VDZ) (Anser VDZ cat. #3180)
Ustekinumab (UST) (Anser UST cat. #3190)
Risankisumab (RZB) (Anser RZB cat. #3140)

Anser tests simultaneously quantify drug and anti-drug antibody (ADAb) levels in serum using drug-tolerant homogeneous mobility shift assay (HMSA) methods, which enables ADAb quantification without interference from detectable drug.^1,2 The IFX and ADA HMSA platforms have been validated against World Health Organization (WHO) IFX and ADA standards (WHO standards are not yet available for VDZ, UST or RZB).^3,4

Guidelines and Expert Statements on Therapeutic Drug Monitoring (TDM) of Biologics in Inflammatory Bowel Disease (IBD)

2017 American Gastroenterological Association (AGA) Guidelines⁵: The AGA recommends the use of TDM in IBD management to monitor and guide infliximab (IFX) and adalimumab (ADA) treatment changes to target IFX serum levels ≥5 µg/mL and ADA levels ≥7.5 µg/mL.

2021 IBD Expert Consensus Statement on Therapeutic Drug Monitoring⁶: An expert panel of US gastroenterologists with expertise in IBD recommend the following utilization of TDM to optimize biologic dosing for IBD:

Recommendations for patients treated with infliximab, adalimumab, vedolizumab or ustekinumab:

TDM is a valuable tool in severely active patients and those who have higher drug clearance.
TDM should be performed in confirmed primary nonresponse (PNR) and secondary loss of response (SLR) before switching therapy and following an IFX drug holiday, prior to the second dose.
If dosing adjustments are made following SLR, TDM should be used proactively to assess drug and antidrug antibody (ADAb) levels following the change.

Recommendations for patients treated specifically with infliximab or adalimumab:

Only the Prometheus Anser HMSA assay has sufficient data to define clinically relevant high titer IFX ADAbs (defined as ≥10 U/mL).
If high titers of ADAbs are observed with TDM, a switch in therapy may be necessary.
If low titer ADAbs (which can result in inadequate drug exposure and SLR) are observed with TDM, providers can attempt to overcome these ADAbs through dose and/or therapy adjustments.
Therapy failure following SLR should not be considered until drug levels of ≥10-15 µg/mL have been achieved.
TDM should be performed after induction and at least once during maintenance.
TDM, to optimize monotherapy, is preferred to unoptimized monotherapy and may be an alternative to combination therapy with an immunomodulator in select patients.
Recommend IFX levels: ≥20-25 µg/mL prior to week 2, ≥15-20 µg/mL prior to week 6, and ≥7-10 µg/mL for weeks 14+.
Recommended ADA levels: ≥8-12 µg/mL prior to week 4 and throughout maintenance.

2024 American Gastroenterological Association (AGA) Position Statement⁷: The AGA indicated that drug dose optimization requires drug level and antidrug antibody testing and these tests are essential for appropriate medication escalation and de-escalation and especially when patients show indications of loss of response.

2019 British Society of Gastroenterology (BSG) Guidelines⁸: The BSG recommends TDM to inform anti-TNF treatment options for patients experiencing PNR; to guide anti-TNF optimization for patients who respond to induction; for patients experiencing SLR to anti-TNF therapy; and proactively for patients in remission if considering de-escalation.

2017 Australian Consensus Statement on Therapeutic Drug Monitoring of Anti-TNF Therapy⁹: TDM is recommended to inform anti-TNF treatment options for patients experiencing PNR; to guide anti-TNF optimization for patients who respond to induction; for patients experiencing SLR to anti-TNF therapy; when contemplating a drug holiday; and proactively for patients in remission if results would change management (i.e., de-escalation, discontinuation, etc.).

Additional Published Data

Infliximab (IFX) and adalimumab (ADA):
In the first year of therapy, up to 40% of anti-TNF treated IBD patients will experience PNR and 50% of responders will experience SLR due to subtherapeutic drug exposure.^10,11 A real-world TDM analysis of three national payors, covering 57 million member lives (IBD n ≈741,000), found that 26% of IFX- and 38% of ADA-treated patients, were at medium or high risk of loss of response due to suboptimal dosing.¹²

Multiple studies conclude that higher overall anti-TNF levels as well as proactive TDM (biologic optimization to therapeutic targets in the absence of symptoms) and reactive TDM (biologic optimization to therapeutic targets following SLR) are less costly, prevent disease flares and ADAb development, and associate with better clinical outcomes (i.e., reduced risk of IBD-related complications, surgeries, hospitalization, treatment failure and serious infusion reactions) as compared to empiric dosing based on symptoms alone.^13-21 A randomized, parallel group, open-label trial of IFX-treated patients with immune-mediated inflammatory diseases, including IBD, found sustained disease control was achieved in 74% (167/228) of patients in the proactive TDM group as compared to only 56% (127/230) in the dosing group receiving standard IFX dosing of 5 mg/kg every 8 weeks.²²

Vedolizumab (VDZ):
Retrospective analysis of 89 VDZ-treated IBD patients with data on clinical scoring, endoscopic outcomes, laboratory markers of IBD, and TDM results found that higher VDZ levels (≥20 µg/mL), achieved after dose optimization following TDM, associated with higher albumin, lower erythrocyte sedimentation rate (ESR), and mild disease or endoscopic remission (p=0.02).²³ A separate analysis of 72 VDZ-treated IBD patients found that those whose drug levels were optimized using proactive TDM had significantly higher drug persistence compared to those who had only reactive TDM (p<.001), with proactive TDM being the only factor associated with improved drug persistence.²⁴

Ustekinumab (UST):
Multiple studies have found a positive association between TDM-guided UST dose optimization and improved treatment outcomes. Overall, patients achieving clinical remission, endoscopic healing and normalization of inflammatory markers had significantly higher UST levels compared to those who did not.^25-30

A retrospective analysis of 125 UST-treated IBD patients found that TDM-guided dose optimization increased clinical remission rates from 21.7% to 73.9%.²⁶ In 62 UST-treated Crohn’s disease patients who were either refractory or intolerant to a previous anti-TNF biologic, a UST cutoff of 4.5 µg/mL associated with endoscopic response and reduction of inflammatory biomarkers.²⁷ A separate TDM analysis of 177 UST-treated IBD patients determined a UST cut-off of 5.8 μg/mL predicted endoscopic remission in Crohn’s disease (sensitivity: 80%; specificity: 81%) while a UST cut-off of 4.7 μg/mL was predictive of clinical remission in ulcerative colitis²⁸ and a multicenter retrospective study of 71 UST-treated IBD patients found that UST levels of 5.5 µg/mL associated with endoscopic healing and normalized C-reactive protein (CRP).²⁹ In 33 UST-treated Crohn’s disease patients with matching magnetic resonance enterography (MRE) scoring [Simplified Magnetic Resonance Index of Activity (sMARIA)], fecal calprotectin (FC) levels and UST concentrations, trough UST concentrations ≥6.1 µg/mL associated with FC <50 µg/g (sensitivity: 93%; specificity: 58%) and trough UST concentrations ≥8.4 µg/mL associated with radiologic remission (sMARIA <2 points) (sensitivity: 75%; specificity: 68%).³⁰

Risankizumab (RZB)
Serum concentrations of risankizumab may vary among equally dosed patients which can ultimately affect patient outcomes. Therefore, the quantitative measurement of risankizumab and antibody-to-risankizumab levels in serum provides valuable information to healthcare providers to better assess a patient’s risk or reason for losing response to risankizumab and can guide an appropriate course of action.

In adult Crohn’s disease (CD) patients, an exposure-response relationship was observed for risankizumab with significantly higher mean serum risankizumab concentrations in cases of clinical and biochemical remission than in the absence of remission (p=0.001).³¹

Antibody-to-risankizumab development can associate with lower risankizumab concentrations, reduced clinical response, hypersensitivity and infusion site reactions.³²

References