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.

Tocilizumab is a humanized anti-interleukin-6 (IL-6) receptor monoclonal antibody that has demonstrated efficacy in the treatment of rheumatoid arthritis (RA). A population pharmacokinetic (PK) model was developed using nonlinear mixed effect modeling to describe the PK profile of tocilizumab and used to estimate interindividual variability and assess the influence of covariates on PK parameters. The model was constructed based on data collected from 1793 patients with moderate to severe RA who received tocilizumab (4 or 8 mg/kg), via intravenous infusion every 4 weeks, during 4 phase III clinical trials. Serum concentration-time profiles of tocilizumab were adequately described by a 2-compartment disposition model with parallel linear and nonlinear elimination kinetics. The 8-mg/kg dose of tocilizumab, compared with the 4-mg/kg dose, resulted in a more pronounced saturation of the nonlinear clearance pathway over the dosing interval, and this nonlinear clearance was representative of target-mediated elimination due to tocilizumab binding to the IL-6 receptor.

The reversible monoamine oxidase A inhibitor moclobemide was given in single (300 mg) and multiple doses (600 mg/day) to 11 male and four female healthy volunteers (age range, 23 to 27) who were either poor metabolizers of S-mephenytoin (n = 7) or extensive metabolizers of S-mephenytoin (n = 8). All were extensive metabolizers of sparteine. Poor metabolizers of S-mephenytoin had lower moclobemide clearance values (median, single dose: 16.1 versus 43.2 L.hr-1; steady state: 13.4 versus 22.1 L.hr-1) and longer moclobemide half-life values (median, single dose: 4.0 versus 1.8 hours; steady state: 5.1 versus 2.7 hours) than extensive metabolizers of S-mephenytoin. The plasma levels of a metabolite formed by C-hydroxylation (Ro 12-8095) were lower in poor metabolizers of S-mephenytoin than in extensive metabolizers of S-mephenytoin. Moclobemide thus partially undergoes oxidative metabolism by way of the polymorphic CYP2C19. A combined mephenytoin, sparteine, and caffeine test performed before, during, and after multiple dosing of moclobemide showed changes in the metabolic indexes compatible with a reversible inhibition of oxidation by way of the corresponding CYP enzymes--CYP2C19, CYP2D6, and CYP1A2--during moclobemide treatment.

No clinically relevant differences in the pharmacokinetics of capecitabine and its key metabolites 5'-DFUR, 5'-DFCR, and 5-FU were found between Japanese and Caucasian patients. Plasma concentrations of FBAL were higher in Caucasian than in Japanese patients but this difference is not clinically relevant as FBAL has no antiproliferative activity and systemic exposure to FBAL does not correlate with the tolerability of capecitabine.