Monitoring Drug Levels Improves Infliximab Efficacy

A strategy of proactive therapeutic drug monitoring (TDM) among patients with immune-mediated inflammatory diseases being treated with infliximab (Remicade) was associated with improved sustained disease control during maintenance therapy, Norwegian researchers found.

Among 458 patients undergoing infliximab treatment, sustained disease control over 52 weeks without worsening was observed in 73.6% of patients randomized to TDM compared with 55.9% of those receiving standard therapy, according to Silje Watterdal Syversen, MD, PhD, of Diakonhjemmet Hospital in Oslo, and colleagues.

The estimated adjusted difference between the two groups was a significant 17.6% (95% CI 9-26.2, P<0.001), the researchers reported in JAMA.

While tumor necrosis factor (TNF) inhibitors have dramatically improved the well being of patients with immune-mediated inflammatory diseases, some 30-50% of patients lose their response to these agents within the first few years of treatment. This has been explained by the loss of therapeutic drug levels and the appearance of neutralizing antidrug antibodies, particularly with infliximab.

Proactive TDM has been proposed as a strategy to increase the long-term efficacy of TNF inhibitors through routinely scheduled measurements of drug concentrations and detection of antidrug antibodies.

Two Norwegian trials addressed the question of whether TDM could improve the efficacy of infliximab. NOR-DRUM A considered TDM versus standard therapy for achieving remission during the induction phase of treatment, finding no greater benefit in the TDM group: The rates of remission during induction in that trial were 50.5% and 53.0% in the TDM and standard therapy groups, respectively.

The current NOR-DRUM B compared TDM versus standard therapy for disease control during maintenance treatment.

The 458 patients enrolled in NOR-DRUM B had been diagnosed with rheumatoid arthritis, spondyloarthritis, psoriasis, psoriatic arthritis, ulcerative colitis, or Crohn’s disease and were being treated with infliximab (originator or biosimilar) for up to 3 years.

For patients in the TDM group, the dose of infliximab or interval between doses was adjusted according to an algorithm intended to maintain drug levels within the therapeutic range of 3-8 mg/L, with measurement of serum levels and antidrug antibodies at the time of each infusion.

Patients’ mean age was 45, and the most common diagnoses were spondyloarthritis and rheumatoid arthritis. Disease duration averaged 6 years, and more than half of patients were receiving concomitant immunosuppressive treatment.

On one secondary outcome, disease worsening, standard therapy was inferior to TDM, with a hazard ratio of 2.1 (95% CI 1.5-2.9). No significant differences were seen on other secondary outcomes such as remission status and patient-reported outcomes at week 52.

The mean infliximab dose during the 52 weeks of the trial was 4.8 mg/kg in both groups, but an increase in the dose occurred more often after disease worsening in the standard therapy group.

A total of 15% of patients in each group stopped their infliximab treatment. In the TDM group, 17 patients discontinued because of the appearance of antidrug antibodies, while in the standard therapy group, 22 discontinued as a result of worsening disease.

The median serum level of infliximab in both groups was 5.8 mg/L. Serum levels remained within the therapeutic range in 30% of the TDM group compared with 17% of the standard therapy group.

Low infliximab levels — 2 mg/L or lower — were observed at least once in 19% of the TDM group but in 27% of the standard therapy group. Clinically significant levels of antidrug antibodies — 50 µg/L or greater — were detected in 9.2% of the TDM group and 15% of the standard group.

With regard to safety, some types of infection such as herpes virus infection and pneumonia occurred more often in the TDM group. No patients in the TDM group developed infusion reactions, while three in the standard group experienced these reactions.

The findings that significant benefits for TDM were seen for maintenance therapy in NOR-DRUM B but not for induction therapy in NOR-DRUM A “are probably related to different mechanisms underlying lack of response/primary treatment failure during the induction period and loss of response/secondary treatment failure during maintenance therapy,” the investigators wrote.

In an editorial accompanying the study, Zachary S. Wallace, MD, of Massachusetts General Hospital in Boston, and Jeffrey A. Sparks, MD, of Brigham and Women’s Hospital in Boston, noted that the prevention of secondary failure, as was seen during maintenance therapy in NOR-DRUM B, “is an important therapeutic goal because disease flares are associated with irreversible tissue damage, glucocorticoid exposure, lost productivity, and worsened quality of life.”

Wallace and Sparks also called for additional studies focusing on specific subgroups of disease.

“In the meantime, addressing barriers to implementing proactive TDM may help introduce a new era in treatment approach to maintenance therapy for patients with immune-mediated inflammatory diseases,” the editorialists wrote.

A limitation of the study, the researchers said, was the open-label design.