Background: In SONIC (NCT00094458), pts with moderate-severe CD treated with infliximab (IFX) in combination with azathioprine (AZA) achieved higher corticosteroid-free remission at wk26 (CSFR26) vs IFX monotherapy (Colombel et al, 2010). It has been hypothesized that the enhanced benefit of combination therapy occurs via influence of AZA on the pharmacokinetics (PK) of IFX, & a shared mechanism of apoptosis for the 2 drugs. To better understand the value of combination therapy in the presence of different levels of IFX in pts with CD, the exposure-response (ER) relationships within serum IFX concentration (SIC) ranges were evaluated, with & without concomitant AZA.
Methods: Data from 206 pts with trough SIC at wk30 were analyzed; 97 received IFX monotherapy & 109 received combination therapy with AZA.SIC were categorized into quartiles & proportion of pts achieving efficacy outcomes (CSFR26; mucosal healing at wk26 [MH26]) in each quartile were compared between the 2 treatment grps. Pt characteristics & presence of ATI in these quartiles were assessed. Receiver operating characteristics (ROC)of ER relationships were also compared.
Results: While pts on combination therapy were enriched in higher SIC quartiles, proportions of pts achieving CSFR26 were not significantly greater among those receiving combination therapy vs monotherapy within the same quartile (Fig. 1). Contrary to what may be expected of an independent interaction, proportions of pts with CSFR26 while on monotherapy were almost twice those who achieved this endpoint on combination therapy in the lowest SIC quartile. Consistent with a drug-sensitive assay, ATI were found only in the lowest SIC quartile across both IFX treatment grps& within this quartile the incidence of ATI was higher among those on monotherapy (35.9%) vs. combination therapy (8.3%). No other notable differences in pt characteristics were seen among SIC quartile groups. In subgrp of pts evaluable for MH26 (n=123), numerically higher proportions of pts achieved MH26 in the combination grp relative to monotherapy particularly in lower two SIC quartiles; however, these differences were not statistically significant. Differences in ROC characteristics between both treatment grps could not be established.
Conclusions: Within similar trough SIC ranges, clinical efficacy was not consistently greater with the addition of AZA to IFX. While there was some benefit seen with addition of AZA in MH, this was only notable in the 2 lower SIC quartiles. Overall, data suggests that the benefit of combination therapy is primarily due to AZA's influence on the PK of IFX.