Conversion of patients with rheumatoid arthritis from the conventional to a microemulsion formulation of cyclosporine: A double blind comparison to screen for differences in safety, efficacy, and pharmacokinetics

Objective. To assess whether patients with rheumatoid arthritis (RA) may be converted, on a milligram-to-milligram basis, from conventional cyclospori n A (CyA, Sandimmun) to the microemulsion formulation (Neoral) with mainten ance of longterm safety, and to compare cyclosporin A (CyA) pharmacokinetic s between formulations. Methods. In this double blind, multicenter, parallel group study, 51 patien ts receiving stable conventional CyA maintenance treatment were randomized to continue conventional CyA (n = 27) or to convert to CyA microemulsion (n = 24) and were monitored for 52 weeks. Trough blood CyA levels were measur ed before and at intervals after conversion. CyA steady-state area under th e curve was assessed one week before and 2 and 6 weeks after randomization in 15 patients in each treatment arm. CyA trough levels and pharmacokinetic results remained unknown to investigators throughout the study. CyA doses were titrated as necessary on the basis of clinical evaluation and disease activity assessments. Results. initial mean daily doses were 3.5 mg/kg/day (conventional CyA) and 3.3 mg/kg/day (CyA microemulsion) and did not change significantly during the study. The mean bioavailability of CyA from the microemulsion formulati on was 23% higher than from conventional CyA. Replicate assessments indicat ed a more reproducible pharmacokinetic profile with CyA microemulsion. The overall incidence and nature of adverse events and changes in vital signs a nd laboratory variables were similar in both groups. No clinically relevant differences in efficacy were found between treatments. No loss of efficacy and no tolerability problems occurred after conversion from conventional t o microemulsion CyA. Conclusion. Existing CyA dosing guidelines, formulated for conventional CyA , are suitable for longterm CyA microemulsion therapy of patients with RA. These results indicate the pharmacokinetic advantages of the microemulsion formulation.