Recent advances in clearance monitoring of monoclonal antibodies in patients with inflammatory bowel diseases

ABSTRACT

Introduction

Less than 50% of patients with inflammatory bowel diseases (IBD) receiving monoclonal antibody (mAb) therapy achieve endoscopic remission. Poor outcomes may indicate a need for dose optimization. During therapeutic drug monitoring (TDM), drug concentrations are measured, and when found too low, dosage regimen escalations are performed. To date, benefits of TDM of mAbs in patients with IBD are uncertain.

Areas covered

This review presents an overview of what clearance monitoring is, how it can be performed, and why and when it may be valuable in treating patients with IBD. Virtual patients were used for illustration. A literature search was performed to summarize current evidence for clearance monitoring in IBD and other disease settings.

Expert opinion

During clearance monitoring, mAb clearance is calculated and monitored over time. Higher mAb clearance in patients with IBD has been associated with higher target load (target-mediated drug disposition), protein-losing enteropathy (fecal drug loss), and immunogenicity. Although not prospectively confirmed, clearance monitoring might facilitate identification of (yet) asymptomatic disease flares or presence of (yet) undetectable anti-drug antibodies. Furthermore, clearance monitoring may be used to predict treatment outcomes. Whether dosage regimen adjustments can modify the clearance time course and the treatment outcome is to be determined.

KEYWORDS:

• Anti-tumor necrosis factor (TNF) therapy
• clearance
• Crohn’s disease
• inflammatory bowel disease (IBD)
• infliximab
• model-informed precision dosing
• monoclonal antibodies (mAbs)
• population pharmacokinetics (popPK)
• therapeutic drug monitoring (TDM)
• ulcerative colitis

Article highlights

• Monoclonal antibody (mAb) therapies play a prominent role in IBD management. Label-recommended dosing of mAb leads to highly variable exposure between patients, jeopardizing therapeutic outcomes in patients with low trough concentrations.

• The benefits of therapeutic drug monitoring (TDM) over label-recommended dosing of mAb are unclear. TDM provides insight into mAb exposure but not into its pharmacokinetics. Drug concentrations result from the interplay between dosage regimen (extrinsic factor) and pharmacokinetics (intrinsic factor), and the dosage regimen confounds the relative contribution of the pharmacokinetics.

• During clearance monitoring, Bayesian forecasting is used to calculate the mAb clearance by considering both the dosage regimen and the mAb concentrations. The mAb clearance can be monitored over the course of the treatment.

• The mAb clearance can serve as an indicator of disease activity (target-mediated drug disposition and fecal drug loss) and immunogenicity in patients with IBD. Therefore, clearance monitoring may allow for the early detection of (yet) asymptomatic disease flares and (yet) undetectable anti-drug antibodies. Furthermore, clearance monitoring may be used to predict treatment outcomes.

The Bayesian forecasting algorithm for calculating the mAb clearance is also used in model-informed precision dosing (MIPD). The difference between clearance monitoring and MIPD is that MIPD derives a dosage regimen recommendation from the clearance estimate, while clearance monitoring provides no clinical dosing support. Whether dosage regimen adjustments can modify the mAb clearance time course and treatment outcomes is yet to be determined.

Declaration of interest

I Spriet received unrestricted research grants from Pfizer and Merck; travel support from Pfizer, Merck and Gilead; and is supported by the Clinical Research Fund of the University Hospitals Leuven. M Ferrante received consultancy fees from Abbvie, Boehringer-Ingelheim, Celltrion, Janssen, Lilly, Medtronic, MSD, Pfizer, Sandoz, Takeda, and Thermo Fisher; and consultancy fees from Abbvie, Boehringer-Ingelheim, Celltrion, Janssen, Lilly, Medtronic, MSD, Pfizer, Sandoz, Takeda, and Thermo Fisher. E Dreesen received consultancy fees from argenx and Janssen (all fees paid to the University). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the Research Foundation – Flanders (FWO), Belgium, under a postdoctoral fellowship [E Dreesen; grant number: 12X9420N] and a PhD fellowship strategic basic research [Z Wang; grant number: 1SF2922N].