Relationships of serum levels of tocilizumab to interleukin-6 and endogenous markers of CYP3A activity in patients with rheumatoid arthritis.

Abstract

Background Tocilizumab co-administration and inflammatory conditions potentially alter the activity of cytochrome P450 (CYP) 3A4 by modulating the interleukin-6 (IL-6) signaling pathway in patients with rheumatoid arthritis (RA). This study aimed to evaluate the correlations of serum levels of tocilizumab with IL-6 and CYP3A activity in RA. Methods RA patients (n = 35) with controllable disease activity using intravenous or subcutaneous tocilizumab were enrolled. Serum tocilizumab was monitored at the trough point after reaching steady-state. Serum levels of IL-6, its soluble receptor (sIL-6R), 4β-hydroxycholesterol (4β-OHC), and 25-hydroxyvitamin D (25-OHD) and CYP3A5 genotype were determined. Results The RA patients had a wide variation of serum tocilizumab level (interquartile range, 9.8-24.6 µg/mL). Tocilizumab treatment led to abnormally high levels of serum IL-6 and sIL-6R. The serum level of tocilizumab was correlated with that of IL-6, but not sIL-6R. In the tocilizumab-treated RA patients, the median serum levels of 4β-OHC and 25-OHD were 36.7 and 17.7 ng/mL, respectively, and no correlations with the serum level of tocilizumab were observed. CYP3A5 genetic polymorphisms were not also associated with the serum level of 4β-OHC. RA patients with the CYP3A5*1 allele exhibited a correlation between serum levels of tocilizumab and 4β-OHC, while those with CYP3A5*3/*3 did not. Conclusions Tocilizumab treatment raised the serum IL-6 level in a concentration-dependent manner. In the RA patients with functional CYP3A5 protein, the serum tocilizumab level partially explained the interindividual variation in CYP3A activity.