Infliximab Blood Levels, Clinical Responses and Dosing Schedules

[Guest guest]

Dr. Lee's latest Rheumatoid Arthritis Viewpoint (from

VeritasMedicine.com):

Infliximab Blood Levels, Clinical Responses and Dosing Schedules

08/30/2002

The advent of anti-tumor necrosis factor (anti-TNF) agents in the

therapy of rheumatoid arthritis (RA) has provided powerful new

therapeutic options over the past three years. However, despite the

large number of patients already using these medications, our clinical

experience with them remains limited, especially relative to other drugs

that have been used to treat RA for years. Infliximab (Remicade), one

of the anti-TNF agents, is a monoclonal antibody that is delivered by

intermittent intravenous infusions. The clinical trials that tested

infliximab delivered the medication either every 4 or every 8 weeks at

various doses. Lingering issues regarding the use of infliximab include

determining the appropriate dosing schedule in long term use, as well as

the appropriate dose escalations in the event of inadequate or

diminishing responses to the medication.

A recent publication in the journal Arthritis & Rheumatism (1)

investigates the possibility that inadequate clinical responses result

from decreased blood levels of infliximab, and provides evidence

regarding dosing schedules designed to improve blood levels of the

medication. A group of investigators from the ATTRACT trial, which

initially defined the effectiveness of infliximab in RA therapy, (2)

examined serum levels of infliximab in patients from their clinical

trial. In particular, they studied the lowest, or trough, concentration

of medication in patients' blood. They then correlated these levels

with the effectiveness of infliximab. They found that the greatest

percentage of patients with inadequate clinical responses were present

in the groups of patients with the lowest trough levels of infliximab in

their bloodstream. Conversely, the greatest percentage of patients with

very good clinical responses to infliximab was found in the group of

patients with high trough levels of the medication.

Knowing that a correlation exists between clinical response and

blood levels of infliximab, the investigators then developed ways of

administering infliximab to increase the blood levels of the medication.

In one approach, they found that decreasing the dosing interval from

every 8 weeks to every 6 weeks significantly increased the trough level

of the medication. They also found that increasing the dosage of

infliximab with each infusion also increased trough levels of the drug.

From these results, these investigators suggest that physicians

and patients consider more frequent infusions and/or increased dosing of

infliximab for those patients with sub-optimal responses to infliximab.

Their model predicts that decreasing the dosing interval will be more

efficient than raising the dosage. They recommend these increases in an

empiric, or " try it and see if it helps " fashion, and do not advocate

measuring blood levels of the medication. It should be noted that these

findings and recommendations are based on correlations and experimental

models. Increasing the response to medication by increasing how often

the medication is administered has not been validated in a clinical

trial. These authors recommend further trials to define both

effectiveness and safety of dose escalation of infliximab over time.

References:

(1) St. Clair, E.W. et. al. " The relationship of serum infliximab

concentrations to clinical improvement in rheumatoid arthritis. " 2002.

Arthritis & Rheumatism 46:1451-1459.

(2) Lipsky, P.E. et. al. " Infliximab and methotrexate in the

treatment of rheumatoid arthritis. " 2000. New England Journal of

Medicine 343:1594-1602.