A Pharmacokinetic Study of Cyclosporin (Sandimmune??)

Abstract

In this study, we have investigated the absorption and elimination kinetics of cyclosporin (CsA) at once-daily and twice-daily (at 0800h and 2000h) dosage intervals from the 2 earlier dosage forms, Sandimmune® Oral Solution (OS) and Sandimmune® Soft Gel Capsules (SGC), in 11 stable renal transplant patients. Our objective was to illustrate and explain the factors that are responsible for the poor performance of trough levels in the prediction of CsA exposure and to show how these problems may be overcome in the future by the administration of a new dosage form of CSA, Sandimmune Neoral® (Neoral®). Predose trough levels for OS and SGC in the 0800- and 2000-hour intervals, and for SGC in the once-daily interval, were not significantly different. In the 0800-hour interval, the time to maximum drug concentration for the OS dosage form was significantly longer than for SGC. Analysis of the data from all patients showed no significant difference in dose-adjusted area under the concentration-time curve from zero to 12 hours (AUC0–12h) between 0800-hour and once-daily intervals; however, those results were affected by high intrasubject variability in absorption rate exhibited by a few individuals. Analysis of the data from 7 individuals with very uniform blood CsA concentration profiles revealed a significant dose-dependent effect on CsA absorption. Diurnal fluctuations in SGC absorption rate and extent had significant effects on postdose trough levels: in the 2000-hour interval, postdose trough concentration (Cmin12) was significantly higher than predose trough concentration (Cmin0). This change reflected both delays in absorption as well as increases in absorption extent. The assessment of the predictive potential of CsA trough levels from SGC 12- (0800-hour) and 24-hour (once-daily) intervals revealed poor correlations between: (1) dose vs AUC0–12h (r = 0.17) and AUC0–24h (r = 0.21), (2) dose vs pre- and postdose 12-hour trough concentrations (r < 0.2 in all cases), and (3) AUC0–12hvs predose (r = 0.16) and postdose (r = 0.49) 12-hour trough concentrations. Better correlations were observed with AUC0–24hvs 24-hour predose (r = 0.85) and postdose (r = 0.88) trough concentrations. The results in this study thus serve to illustrate the complexity underlying the use of predose trough concentrations to either predict the AUC, or calculate a dose, for a subsequent dosage interval.