The new microemulsion formulation of CSA (Neoral) has supplanted conventional Sandimmune, with little formal evaluation of Neoral kinetics in the pediatric population. CSA kinetics and area under the curve(AUC) were measured in 19 children receiving both Neoral and diltiazem following either renal (n=13) or hepatic (n=6) transplantation. The following parameters (mean + 1SD) were observed in 15 children taking Neoral on a bid schedule: dose (mg/kg/d): 5.8+2.1; trough (ng/ml): 204+76; daily AUC (h× ng/ml): 11045+2398; Tmax (hrs): 1.37+0.48; Cmax (ng/ml): 1227+263. Although the correlation between trough levels and AUC is said to be improved with Neoral in adults, this was not the case in our experience (r=0.46, p=0.08). The best correlation was noted with the 2 hr CSA level (r=0.84, p< 0.0001) or the 6 hour level (r=0.77, p<0.001). In 9 children (4 renal, 5 hepatic), kinetic studies and iothalamate clearance (GFR) were also available on both Sandimmune and Neoral following dose adjustment to maintain a constant trough. Conversion from Sandimmune to Neoral was associated with an increase in AUC and Cmax despite maintenance of constant trough levels. There was also a trend toward a lower dose, more rapid peak, and a lower GFR (p=0.06).
Conclusion: Since AUC is the best predictor of both CSA efficacy and nephrotoxicity, the break down of the relationship between trough levels and AUC poses a problem for the routine monitoring of CSA. The explanation for this finding is not clear, but it may reflect either the young age of our patients or the effects of diltiazem on the elimination phase of CSA metabolism. This observation may require a change in the method employed to monitor CSA dosing, with the 2 hour level providing the most reliable single measure of CSA AUC. Following conversion to Neoral, increased CSA AUC despite maintenance of constant trough levels is worrisome, but longer term studies will be needed to clarify any associated toxicity.
