es to the need for individualization of the dosing regimen for optimal therapy (see DOSAGE AND ADMINISTRATION). Intrasubject variability of AUC in renal transplant recipients (% CV) was 9%-21% for cyclosporine (MODIFIED) and 19%-26% for Sandimmune®. In the same studies, intrasubject variability of trough concentrations (% CV) was 17%-30% for cyclosporine (MODIFIED) and 16%-38% for Sandimmune®.
Absorption
Cyclosporine (MODIFIED) has increased bioavailability compared to Sandimmune®. The absolute bioavailability of cyclosporine administered as Sandimmune (cyclosporine) is dependent on the patient population, estimated to be less than 10% in liver transplant patients and as great as 89% in some renal transplant patients. The absolute bioavailability of cyclosporine administered as cyclosporine (MODIFIED) has not been determined in adults. In studies of renal transplant, rheumatoid arthritis and psoriasis patients, the mean cyclosporine AUC was approximately 20% to 50% greater and the peak blood cyclosporine concentration (Cmax) was approximately 40% to 106% greater following administration of cyclosporine (MODIFIED) compared to following administration of Sandimmune®. The dose normalized AUC in de novo liver transplant patients administered cyclosporine (MODIFIED) 28 days after transplantation was 50% greater and Cmax was 90% greater than in those patients administered Sandimmune®. AUC and Cmax are also increased (cyclosporine [MODIFIED] relative to Sandimmune®) in heart transplant patients, but data are very limited. Although the AUC and Cmax values are higher on cyclosporine (MODIFIED) relative to Sandimmune®, the pre-dose trough concentrations (dose-normalized) are similar for the two formulations.
Following oral administration of cyclosporine (MODIFIED), the time to peak blood cyclosporine concentrations (Tmax) ranged from 1.5 to 2.0 hours. The administration of food with cyclosporine (MODIFIED) decreases the cyclosporine AUC and Cmax. A high fat meal (669 kcal, 45 grams fat) consumed within one-half hour before cyclosporine (MODIFIED) administration decreased the AUC by 13% and Cmax by 33%. The effects of a low fat meal (667 kcal, 15 grams fat) were similar.
The effect of T-tube diversion of bile on the absorption of cyclosporine from cyclosporine (MODIFIED) was investigated in eleven de novo liver transplant patients. When the patients were administered cyclosporine (MODIFIED) with and without T-tube diversion of bile, very little difference in absorption was observed, as measured by the change in maximal cyclosporine blood concentrations from pre-dose values with the T-tube closed relative to when it was open: 6.9 ± 41% (range -55% to 68%).
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Pharmacokinetic Parameters (mean±SD) |
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1 Total daily dose was divided into two doses administered every 12 hours.
2 AUC was measured over one dosing interval.
3 Trough concentration was measured just prior to the morning cyclosporine (MODIFIED) dose, approximately 12 hours after the previous dose.
4 Assay: TDx specific monoclonal fluorescence polarization immunoassay.
5 Assay: Cyclo-trac specific monoclonal radioimmunoassay.
6 Assay: INCSTAR specific monoclonal radioimmunoassay.
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