Inflammatory conditions tend to downregulate the activity and expression of CYP 450 isozymes (in this case CYP3A4 is of particular concern). Patients with RA tend to have decreased CYP3A4 activity and therefore higher plasma concentrations of simvastatin compared to the average healthy patient. Tocilizumab is an antihuman IL-6 receptor antibody that ameliorates inflammatory effects of patients with RA. Administration of Tocilizumab with simvastatin appears to decrease plasma simvastatin concentration and normalize the CYP3A4 activity level of a RA patient to appear like that of a healthy person.
Disease-drug-drug interaction involving tocilizumab and simvastatin in patients with rheumatoid arthritis
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Study Design
This study was a multicenter, open-label, randomized, disease-drug-drug interaction study of patients with RA. There were 12 participants (4 caucasian men and 8 caucasian women) in the study, given simvastatin 40mg as a single dose on days 1, 15, and 43 and a single infusion of tocilizumab at 10mg/kg on day 8. Blood samples were collected to measure simvastatin and its beta-hydroxy-simvastatin acid metabolite before each dose and then at 0.5, 1,2,3,4,8,12, and 24 hours after each dose. Blood samples for the plasma concentration of tocilizumab were collected before the infusion and then at 1,4, and 12 hours after the start of the infusion and at 1,3,7,8,12,21,28,35,36,56, days after the start of the infusion.
Study Results
All 12 subjects were able to complete the study. Both Cmax and AUC for simvastatin and beta-hydroxy-simvastatin acid were significantly reduced at week 1 (day 15) and 5 weeks (day 43) after tocilizumab infusion, compared with simvastatin administration alone. The day 15 AUC for simvastatin was reported as 45 18 ng x h/ml in patients with RA which has an overlap in reported AUCs in a healthy person taking simvastatin, which is 1750 1022 ng x h/ml. The same thing could be said about beta-hydroxy-simvastatin AUCs reported to be 25 18 ng x h/ml in RA patients and 1829 920 ng x h/ml in healthy patients.
Study Conclusions
Patients with RA who are taking tocilizumab have a decreased simvastatin plasma concentration compared to other patients with RA who are taking simvastatin without tocilizumab.
References
Schmitt C. Disease-drug-drug interaction involving tocilizumab and simvastatin in patients with rheumatoid arthritis. Clin Pharmacol Ther.. 2011; 5: 735-40.
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