The relationship between serum infliximab concentrations and clinical response was tested in the ATTRACT trial for rheumatoid arthritis. Doses of 3 mg/kg or 10 mg/kg infliximab resulted in maximal maximum serum concentrations that were directly proportional to the intravenous dose; serum concentrations of 68.8 |g/ml and 219.1 |g/mlwere detected 1 hpost-infu-sion (St Clair et al. 2002). The trough concentration was also dependent on the amount and frequency of dose. Patients receiving 10 mg/kg every 4 weeks had the highest trough levels, while patients receiving 3 mg/kg every 8 weeks had the lowest trough levels. The median trough levels were comparable in patients receiving 10 mg/kg every 8 weeks and 3 mg/kg every 4 weeks (Kavanaugh et al. 2000; St Clair et al. 2002).
When the trough serum levels of infliximab at week 54 were correlated with clinical response it became apparent that a higher ACR-N response was significantly associated with a higher trough serum concentration of infliximab. While no significant difference in the ACR20 response was detected for patients receiving 3 mg/kg or 10 mg/kg infliximab at either 4- or 8-week intervals, the ACR50 response rates were significantly lower in the group receiving 3 mg/kg every 8 weeks compared to the other groups. This suggested that clinical response relates to trough serum concentrations of infliximab.
Indeed, when clinical responses were correlated with trough serum concentrations, most patients with a response of less than ACR20 had undetectable trough serum levels of infliximab, while the highest proportion of ACR50 and ACR70 responders had the highest trough serum levels (St Clair et al. 2002).
In another open label study the relationship between infliximab levels and clinical response to infliximab treatment in RA was confirmed. Patients received 3-mg/kg inflixmab infusions at weeks 0, 2, 6 and 14. At week 2 the median serum trough level for inflixi-
mab was 22.3 (15.3-29.4) |g/ml, at week six 14.6 (7.2 - 22) |g/ml, and at week fourteen 2.8 (0.6 - 6.8) |g/ ml. While trough serum concentrations varied considerably between patients, a better clinical response was associated with higher median trough serum concentrations (Wolbink et al. 2006). In general, in RA, a trough concentration of > 1.0 |g/ml is associated with a good therapeutic response (St Clair et al. 2002) and the clinical response declines rapidly after serum inflixi-mab levels drop below this threshold (Markham and Lamb 2000).
The relationship between trough infliximab serum concentrations and clinical response was also determined in a 1-year psoriasis study. Patients were receiving 5 mg/kg inflixmab treatment every 8 weeks after induction therapy. Between week 22 and week 46 the median pre-infusion inflixmab concentration stabilized between 2.8 |g/ml and 3.7 |g/ml. Patients who maintained their clinical response through week 50 had trough infliximab serum concentrations above 1 |g/ml, while in about 25 % of patients who lost the response the median pre-infusion infliximab concentrations dropped below 1 |g/ml (Reich et al. 2005).
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