Disease–Drug–Drug Interaction Involving Tocilizumab and Simvastatin in Patients With Rheumatoid Arthritis

Abstract

In rheumatoid arthritis (RA), interleukin-6 (IL-6) concentration is elevated, which may cause reduced cytochrome P450 (CYP) activity and increased exposure (peak plasma concentration and area under the plasma concentration-vs.-time curve (AUC)) to certain drugs. Tocilizumab may reverse IL-6-induced suppression of CYP3A4 activity. In this study, exposure to simvastatin was significantly reduced at 1 and 5 weeks after tocilizumab infusion in 12 patients with RA. The mean effect ratio for simvastatin AUC(last) was 43% (90% confidence interval (CI), 34-55%) at 1 week after tocilizumab infusion (day 15) and 61% (90% CI, 47-78%) at 5 weeks after tocilizumab infusion, as compared with baseline (day 1); both ratios were significantly lower than the bioequivalence boundary (80-125%). Mean plasma C-reactive protein (CRP) levels normalized within 1 week after tocilizumab was initiated; the time course of tocilizumab's CRP-reducing effect paralleled that of simvastatin pharmacokinetics. The study findings suggest that caution should be exercised when starting tocilizumab in RA patients who are taking simvastatin.

Inflammation-Induced Phenoconversion of Polymorphic Drug Metabolizing Enzymes: Hypothesis with Implications for Personalized Medicine

“…Within the context of the pharmacokinetic effects of inflammation and its relief, exposure to simvastatin, a CYP3A4 substrate, is 4-to 10-fold higher in patients with rheumatoid arthritis, compared with exposures observed in healthy subjects-and a single infusion of tocilizumab reduces this by 57% (Schmitt et al, 2011). In this study, mean plasma CRP levels normalized within 1 week after tocilizumab was initiated and the time course of the CRP-reducing effect of tocilizumab paralleled that of simvastatin pharmacokinetics.…”

ICH E14 Q&A(R2) document: commentary on the further updated recommendations on thorough QT studies

“…The interaction between simvastatin and tocilizumab illustrates our point. Clinical studies by Schmitt et al [13] showed significantly decreased simvastatin exposure in rheumatoid arthritis patients receiving tocilizumab, an anti-human IL-6 receptor monoclonal antibody. The decreased exposure was linked to changes in CYP3A4 expression reported by the same group following anti-IL-6R treatment in the presence and absence of tocilizumab in cultured human hepatocytes [14].…”

Therapeutic Protein Drug–Drug Interactions: Navigating the Knowledge Gaps–Highlights from the 2012 AAPS NBC Roundtable and IQ Consortium/FDA Workshop

“…In the tocilizumab-simvastatin clinical drug-disease interaction study (2), CRP levels in RA patients dropped from relatively high values (40-50 mg/L) to near the upper limit of normal value of 3 mg/L. IL-6 is an important cytokine in the human liver (14) and one of its primary effects is the secretion of CRP by hepatocytes (15).…”

“…IL-6 is an important cytokine in the human liver (14) and one of its primary effects is the secretion of CRP by hepatocytes (15). Supplementary genomic data (5,16) and some clinical studies (2,(17)(18)(19)(20) have all revealed a relationship between CYP3A and CRP or IL-6. Data were presented where CRP changes in 19 selected inflammatory disease clinical studies were compared to CRP changes observed in the tocilizumab-simvastatin study in patients with RA.…”

“…This results in decreased clearance of SM substrates of the affected CYPs (1). Recently, treatment of rheumatoid arthritis (RA) patients with tocilizumab, a monoclonal anti-IL-6 receptor antibody was shown to desuppress (or normalize) CYP3A4-mediated clearance of simvastatin by just over 2-fold (2).…”