Peak cyclosporine levels (Cmax) correlate with freedom from liver graft rejection: results of a prospective, randomized comparison of neoral and sandimmune for liver transplantation (NOF-8).

Abstract

Despite two decades of use, there are limited data on the best way 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 transplantation; and (2) to study the relationships between pharmacokinetic parameters and clinical outcomes after transplantation. A double-blind, randomized, comparison of Sandimmune (SIM) with Neoral (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 made 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. The NEO group was slightly younger, with a median age of 50 years (range: 23-70) versus 55 years (range: 24-71) for SIM (P = 0.007); otherwise the two groups were well balanced. The NEO group stopped intravenous CsA earlier (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, discontinued 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 differences 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 similar and did not correlate with CsA pharmacokinetic profiles. The NEO group had a higher area under the drug concentration curve for the first 6 hr after the dosing interval (AUC0-6) and peak CsA levels (Cmax). There was a strong correlation between freedom from graft rejection during the first month after transplantation and (a) AUC0-6 and (b) Cmax at days 5 and 10 after transplantation, but only in the NEO group did this reach statistical significance. In contrast, there was a poor correlation between trough CsA and graft rejection. In patients on NEO, the concentration of CsA 2 hr after dosing (C2) closely reflected AUC0-6 (r2 = 0.93), whereas there was a poorer correlation in patients on SIM (r2 = 0.73) Cmax and/or AUC0-6 may provide better markers than trough levels for monitoring CsA-based immune suppression after orthotopic liver transplantation. Prospective studies are underway to determine whether dosing to C2, which provides a good estimation of Cmax, can be used to take full advantage of NEO's improved absorption profile.