IMPROVED DOSE LINEARITY OF CYCLOSPORINE PHARMACOKINETICS FROM A MICROEMULSION FORMULATION

The pharmacokinetic dose proportionality and relative bioavailability of cyclosporine from a microemulsion formulation (Sandimmune Neoral) w ere compared to those of the commercial formulation (Sandimmune) over the dosage range 200 to 800 mg. Single oral administrations were given as soft gelatin capsules in an open randomized study with 48 healthy volunteers. Whole-blood cyclosporine concentrations were determined by a specific monoclonal radioimmunoassay. In comparison to Sandimmune, the absorption rate (maximum concentration) and systemic availability (area under the curve) of cyclosporine were greater for Sandimmune Neo ral at all dose levels investigated. The area under the curve for Sand immune increased in a less than proportional manner with respect to do se, whereas that for Sandimmune Neoral was consistent with linear phar macokinetics. Because of this difference, no global assessment of rela tive bioavailability could be performed. The relative bioavailability of cyclosporine from Sandimmune Neoral ranged from 174 to 239% compare d to Sandimmune, depending on the dose level. The improvements in oral bioavailability and dose linearity of cyclosporine exposure after adm inistration as Sandimmune Neoral should facilitate more accurate dosag e titration in the clinical setting.