St. Clair et al. (Arthr and Rheum. 6:1451-1459; 2002) evaluated the relationship of the serum concentration of infliximab to the clinical efficacy of RA in subjects who had participated in the ATTRACT clinical trial, a double-blinded, placebo-controlled trial of infliximab and methotrexate compared to methotrexate alone.
Methods:
428 patients with active RA taking stable doses of methotrexate (>12.5 mg), NSAIDS, and prednisone (< 10mg) were randomized to placebo, 3mg/kg or 10 mg/kg of infliximab on a every 4 or 8 week dosing regimen following an induction phase at weeks 0, 2, and 6. Assessments of the ACR clinical response were completed prior to dosing and included the ACR-N which is used to assess continuous measurement of clinical response. Serum concentrations were also obtained prior to dosing and one hour post-dosing. Infliximab levels were measured by ELISA (lowest detectable level = 0.1 μg/ml). Modeling serum profiles for each of the dosing regimens were used to determine the benefit of a dose increase versus a change in dosing interval frequency to achieve adequate clinical response.
Results:
Trough serum levels of infliximab corresponded with the magnitude of ACR response. There was no significant difference in observed ACR20 response rates across the infliximab treatment groups, however, ACR50 and ACR70 response rates increased with increased serum trough levels. Thus, an ACR50 response rate of 21.5% observed in the 3mg/kg every 8 weeks which was significantly lower than that observed in the 10 mg/kg groups at every 4 weeks (34.1%) and 10mg/kg every 8 weeks (40%). The greatest percentage (26%) of ACR20 non-responders at week 54 displayed serum trough levels of <0.1mg/ml observed in the group receiving 3mg/kg of infliximab every 8 weeks which was significant in comparison to the other 3 treatment groups (P<0.001). Importantly, greater reductions in baseline serum CRP levels correlated with the higher serum trough levels of infliximab (P<0.001) and likewise with less radiographic progression of joint damage (p<0.004). Finally, pharmacokinetic modeling demonstrated that for patients with undetectable trough levels, decreasing the dosing interval from 8 weeks to 6 weeks raised serum trough levels to a greater extent than increasing the dose by 1 vial of drug (100mg).
Conclusion:
Significantly greater improvement in ACR responses, reduction of CRP levels, and less radiographic progression of joint damage observed with higher trough serum infliximab concentrations, corresponding with increased doses of infliximab, suggests that clinical efficacy is dose dependent. Therefore, patients who demonstrate a lack of treatment response may benefit from dose escalation, and/or decreasing the interval between doses, to increase trough serum concentrations of infliximab.
Editorial Comments:
Many patients have noted a breakthrough in their joint pain and swelling during the last 2 weeks of their 8-week intervals between infliximab dosing. This study provides some scientific rationale for this “breakthrough” and some guidance for altering the dosing regimen in individual patients. However, it is important to note that some patients in this study had dramatic clinical (ACR 70 and ACR 90) responses even with undetectable serum levels of infliximab. Correlation of serum levels and clinical response is still imprecise, and this study does not help us predict who will be a “good responder” vs. a “non-responder”.
