With the introduction of monoclonal antibodies against tumor necrosis factor (TNF)-alpha, the concept of Therapeutic Drug Monitoring (TDM) has received increased attention. Anti-TNF-alpha monoclonal antibodies are a widely accepted therapy for inflammatory bowel disease (IBD); however, according to researchers, immunogenicity is a major disadvantage to using these biologic agents. The antidrug antibodies produced by the immune system as a result of using biologic agents often leads to lower drug concentrations and suboptimal response or loss of response in patients with IBD. Reactive and/or proactive TDM may be useful at informing clinicians about how biologic agents may be affecting patients with IBD so they can modify treatment as needed. In a review published in Clinical Gastroenterology and Hepatology, researchers discussed current techniques for measuring drug concentrations and antidrug antibodies for monoclonal antibodies, reviewed evidence for reactive vs proactive TDM, and recommended how TDM should be performed.

Current Techniques for Measuring Drug Concentrations

TDM of biological agents typically involves checking trough concentrations, requiring sample collection just before the next administration of the drug. However, there is limited evidence supporting the role of TDM based on intermediate and peak concentrations. In addition to focusing on appropriate timing, researchers said clinicians are required to focus on proper sample collection, preparation, storage, and shipment.

Many researchers currently use assays for the quantification of biological drugs and antibodies in the serum of patients — the most commonly used format being the solid-phase enzyme-linked immunosorbent assay (ELISA) on behalf of its automatization and ease of use.

ELISA requires 2 binding sites for the capture and detection of antidrug antibodies. If serum samples show that antidrug antibodies are already bound to the drug, the bivalency is compromised, and the antidrug antibodies cannot be quantified. Researchers recently developed a new ELISA that uses an antihuman λ-chain antibody for detection, which does not require antidrug antibodies to have a free binding site. Some laboratory quantification services use the radio-immunoassay and the homogenous mobility shift assay in addition to ELISAs.

Reactive TDM: Concept and Benefits

Reactive TDM is typically performed when patients stop responding to or become intolerant to anti-TNF monoclonal antibodies. Researchers indicated that clinicians who know the trough concentration of the drug and whether antidrug antibodies are present may be able to make more informed decisions surrounding whether doses should be changed, or whether patients should be switched to different agents.

The concept of reactive testing has been supported by studies showing associations among serum drug concentrations and clinical response, remission, and endoscopic healing. All these studies involved the use of anti-TNF-alpha agents. Investigators of more recent studies have shown that higher serum drug concentrations are associated with better therapeutic outcomes surrounding maintenance and in cases where inflammatory burden and drug clearance are high following induction therapy.

Instead of switching patients to another biological on behalf of loss of response — which puts the patient at risk for allergic reactions or high costs — researchers said clinicians should adopt a TDM-based strategy, which offers a higher number of advantages. A TDM-strategy may eliminate the need for more drugs for patients who do not need intensification and does not put patients who have developed high titer antibodies at risk for infusion reactions. Reactive TDM may also help distinguish between immunogenic, pharmacokinetic, and pharmacodynamic loss of response.

Proactive TDM and Dose Optimization: Concept and Benefits

According to researchers, the utility of proactive TDM and dose optimization in IBD in an everyday clinical setting remains debatable despite the increasing evidence surrounding the benefits of proactive TDM of anti-TNF-alpha agents over empiric dosing optimization and/or reactive TDM. Researchers of the latest studies revealed that the benefits of proactive TDM over reactive TDM had primary end points including clinical outcomes, pediatric Crohn disease activity index and/or partial Mayo Score whether or not combined with biochemical remission, corticosteroid-free remission, endoscopic improvement, and/or absence of need for bowel resection.

Researchers evaluating proactive TDM in IBD showed that, compared with conventional non-TDM-based management, proactive TDM with infliximab was independently associated with fewer IBD-related surgeries, higher rates of mucosal healing, and a significant decrease in unfavorable outcomes including IBD-related hospitalization and treatment failure.

The Future of TDM

According to the study’s researchers, the future of TDM should involve point of care (POC) testing and model-informed precision dosing (MIPD).  

POC Testing

Traditional assays require sample transport to a clinical laboratory and sample preparation, however, POC tests can be performed on-site by clinical staff without laboratory training and ideally without the need for sample preparation. This has resulted in decreasing the turnaround time by 15-20 minutes. Researchers said that POC assays may improve TDM by allowing for drug dosage optimization based on real-time pharmacokinetics information as opposed to outdated information from previous weeks or months. However, despite the quick turnaround time of POC tests, which may improve patient care and cost-effectiveness, a lack of evidence still surrounds feasibility and overall effectiveness of these tests.

At present, the use of POC tests in TDM of biologicals remains limited, with hurdles related to cost, quality control, external quality assurance procedures, and ease of access to the laboratory information system.

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MIPD

According to investigators, MIPD may be an effective strategy for overcoming hurdles related to fixed- and weight-based dosing of biologicals following standard induction and maintenance treatment regimens, which have been found to deprive many patients of their optimal dose. Therapeutic monoclonal antibodies offer greatly unpredictable pharmacokinetics variability, which may make it difficult for clinicians to quickly and precisely hit the exposure target.

Researchers said that a population pharmacokinetics model is the basis of MIPD and can be updated to a posterior model of an individual patient by taking into consideration the covariates and characteristics that explain variability in pharmacokinetics parameters, or by considering the measurements of previous drug concentrations in the patient. Individual pharmacokinetic parameters may be used to estimate and predict the next dosage a patient may need to achieve a predefined exposure target.

In recent years, researchers have developed several new MIPD software tools. These tools have not yet been implemented in daily clinical IBD practice given the lack of evidence surrounding their cost-effectiveness. Study researchers indicated that, if the pharmaceutical industry works with academic and regulatory agencies to recognize the benefits of MIPD of biologic therapies, the implementation of this practice may help prevent further undertreatment of IBD in everyday clinical settings.

Conclusion

Guidelines and common practice support the role of reactive-based dose optimization at the time of loss of response in patients with IBD being treated with biologics, according to researchers. However, reactive TDM may not be as advantageous as proactive TDM. Combining POC testing with proactive TDM may help maximize the effectiveness of biologics and improve outcomes in IBD.

Reference

Vermeire S, Dreesen E, Papamichael K, Dubinsky MC. How, when, and for whom should we perform therapeutic drug monitoring? [published online October 4, 2019]. Clin Gastroenterol Hepatol. doi: 10.1016/j.cgh.2019.09.041