Pharmacokinetics of Biologics and the Role of Therapeutic Monitoring

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Key points

  • Therapeutic drug monitoring (TDM) is an evidence-based strategy for managing biologic therapies in inflammatory bowel disease (IBD) after the loss of clinical response.

  • Clinicians’ understanding of the pharmacokinetics of biologic therapy and the application of TDM is instrumental in the optimal management of moderate-to-severely active IBD.

  • The newest assays for monitoring anti-TNF therapy consistently demonstrate that serum drug and antidrug antibodies (ADA) levels correlate with endoscopic and

Pharmacokinetics

TNF-α is a proinflammatory cytokine that mediates gut recruitment of neutrophils, procoagulation, and fibrinolytic cascades, and promotes granuloma formation. Given the pivotal role of TNF-α in the pathogenesis of IBD, the available array of anti–TNF-α biologics continues to expand. Infliximab (IFX; Remicade; Janssen, Malvern, PA), the earliest and most well-studied TNF-α inhibitor, is an intravenously (IV) administered chimeric monoclonal antibody comprised of a human constant region IgG1κ

Natalizumab

Natalizumab (NAT), a forerunner of the emerging class of selective adhesion molecule inhibitors, is a recombinant monoclonal antibody (95% human and 5% murine) directed against the α4 subunit of the integrins α4β1 and α4β7 expressed on the surface of lymphocytes and monocytes. It is an IV biologic administered every 4 weeks (weeks 0, 4, 8 induction), and most patients have detectable serum NAT levels (mean, 0.99 μg/mL) at 4 weeks after their first infusion.3 Possibly because of higher levels of

TDM in clinical practice

The clinical efficacy of biologic therapies, whether anti–TNF-α or CAMi, depends on optimally titrating serum drug concentrations to effectively saturate proinflammatory targets. Dosing adjusted to maintain therapeutic drug levels over time promotes sustained clinical remission and may help to minimize the development of persistent antibodies. TDM respects that a given patient’s serum drug levels temporally evolve depending on disease activity, drug clearance, and immunotolerance to monoclonal

Future research

There is a clear role for TDM to guide treatment decisions in the setting of LOR, but the cost-effectiveness and clinical use of proactive TDM to dose-optimize clinically well patients in the maintenance phase of therapy are less well-studied. Emerging data in this population suggest that lower serum troughs may be associated with endoscopic disease activity despite normal biomarkers, and increase risk for ADA formation.39, 60 In the Trough Level Adapted Infliximab Treatment trial,74 263

Summary

Clinicians’ understanding of the pharmacokinetics of biologic therapy and the application of TDM is instrumental in the optimal management of moderate-to-severely active IBD. Significant interindividual variability exists with regards to disease activity, drug bioavailability and clearance, and immunotolerance. This variability manifests in the differential magnitude and duration of response to biologic therapies among patients. Within a given individual, the dose-response may evolve temporally

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