Peak cyclosporine levels (C-max) correlate with freedom from liver graft rejection - Results of a prospective, randomized comparison of neoral and sandimmune for liver transplantation (NOF-8)

Background Despite two decades of use, there are limited data on the best w ay to administer and monitor cyclosporine (CsA) for liver transplantation. The present study was undertaken (1) to determine whether treatment with a new formulation of CsA, Neoral, would improve the results of liver transpla ntation; and (2) to study the relationships between pharmacokinetic paramet ers and clinical outcomes after transplantation. Methods. A double-blind, randomized, comparison of Sandimmune (SIM) with Ne oral (NEO) was conducted at five Canadian centers in 188 consecutive adults undergoing primary orthotopic liver transplantation. Patients were induced with intravenous CsA then switched to NEO or SIM. Dose adjustments were ma de daily, or as needed, to reach a target trough CsA level of 350 ng/ml in both groups. Pharmacokinetic studies were performed on days 5, 10, 15, and 16 weeks after transplantation. Results. The NEO group was slightly younger, with a median age of 50 years (range: 23-70) versus 55 years (range: 24-71) far SIM (P=0.007); otherwise the two groups were well balanced, The NEO group stopped intravenous CsA ea rlier (5.8+/-2.6 days vs. 8.7+/-4.7 days, P<0.0001). This group required a lower median daily oral dose (7.5 mg/kg vs. 9.0 mg/kg, P<0.01) to maintain comparable trough CsA levels. Five SIM patients, but no NEO patients, disco ntinued the study due to the inability to reach target trough levels of CsA within the prescribed time (P<0.05). At 4 months, there were no difference s between the two groups with respect to patient survival (93% NEO vs. 91% SIM), graft survival (90% NEO vs. 86% SIM), and rejection-free survival (54 .1% NEO, 51.8% SIM). The incidence of serious adverse events was also simil ar and did not correlate with CsA pharmacokinetic profiles. The NEO group h ad a higher area under the drug concentration curve for the first 6 hr afte r the dosing interval (AUC(0-6)) and peak CsA levels (C-max). There was a s trong correlation between freedom from graft rejection during the first mon th after transplantation and (a) AUC(0-6) and (b) C-max at days 5 and 10 af ter transplantation, but only in the NEO group did this reach statistical s ignificance. In contrast, there was a poor correlation between trough CsA a nti graft rejection. In patients on NEO, the concentration of CsA 2 hr afte r dosing (C2) closely reflected AUC(0-6) (r(2)=0.93), whereas there was a p oorer correlation in patients on SIM (r(2)=0.73) Conclusions. C-max and/or AUC(0-6) may provide better markers than trough l evels for monitoring CsA-based immune suppression after orthotopic Liver tr ansplantation. Prospective studies are underway to determine whether dosing : to C2, which provides a good estimation of C-max, can be used to take ful l advantage of NEO's improved absorption profile.