The expression of hepatic CYP450 enzymes is suppressed by cytokines, such as IL-6, that stimulate chronic inflammation. Thus, CYP450 expression may be reversed when potent cytokine inhibitory therapy, such as tocilizumab, is introduced. In vitro studies with cultured human hepatocytes demonstrated that IL-6 caused a reduction in CYP1A2, CYP2C9, CYP2C19 and CYP3A4 enzyme expression. Tocilizumab normalises expression of these enzymes. In a study in RA patients, levels of simvastatin (CYP3A4) were decreased by 57% one week following a single dose of tocilizumab, to the level similar to, or slightly higher than, those observed in healthy subjects. When starting or stopping therapy with tocilizumab, patients taking medicinal products which are individually adjusted and are metabolised via CYP450 3A4, 1A2 or 2C9 should be monitored as doses may need to be increased to maintain therapeutic effect. Given its long elimination half-life, the effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping therapy.

Cytochrome P450s in the liver are down-regulated by infection and inflammation stimuli including cytokines such as IL-6. Inhibition of IL-6 signalling in RA patients treated with tocilizumab may restore CYP450 activities to higher levels than those in the absence of tocilizumab leading to increased metabolism of drugs that are CYP450 substrates. In vitro studies showed that tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Its effect on CYP2C8 or transporters is unknown. Simvastatin is a CYP3A4 and OATP1B1 substrate. In 12 RA patients not treated with tocilizumab, receiving 40 mg simvastatin, exposures of simvastatin and its metabolite, simvastatin acid, was 4- to 10-fold and 2-fold higher, respectively, than the exposures observed in healthy subjects. One week following administration of a single infusion of tocilizumab (10 mg per kg), exposure of simvastatin and simvastatin acid decreased by 57% and 39%, respectively, to exposures that were similar or slightly higher than those observed in healthy subjects. Exposures of simvastatin and simvastatin acid increased upon withdrawal of tocilizumab in RA patients. Selection of a particular dose of simvastatin in RA patients should take into account the potentially lower exposures that may result after initiation of tocilizumab (due to normalization of CYP3A4) or higher exposures after discontinuation of tocilizumab.

Coadministration of simvastatin (40 mg, single dose on days 1, 15, and 43) with tocilizumab (10 mg/kg, single dose on day 8) was studied in 12 patients with rheumatoid arthritis. One week after tocilizumab, simvastatin Cmax and AUC had decreased by 57%. Five weeks after tocilizumab, simvastatin Cmax had decreased by 41% and AUC by 39%. The authors conclude that tocilizumab supressed CYP3A4 inhibition caused by high IL-6 levels as seen in rheumatic arthritis, decreasing the exposure of simvastatin.