Association between cyclosporine concentrations at 2 hours post-dose and clinical outcomes in de novo lung transplant recipients

Background: The objective of this study was to investigate the relationship between cyclosporine (CsA) pharmacokinetic parameters and clinical outcomes after lung transplantation. Methods: Data from 48 lung or heart/lung transplant recipients originally recruited to a randomized, prospective clinical trial of Sandimmune vs Neoral and followed for 12 months were included in this study. CsA dosing was based on the trough concentration. CsA concentrations at 0 (CO), 2 (C2), and 6 (C6) hours post-dosing were obtained at 1, 2, 3, 4, 13, 26, 39, and 52 post-operative weeks. Based on their average C2 levels in the first post-transplant month, patients were stratified retrospectively into Low C2 (< 1,000 mu g/liter, n = 18), Intermediate C2 (1,000-1,500 mu g/liter, n = 16) and High C2 (> 1,500 mu g/liter, n = 14) Groups. Results: Cyclosporine C2 was the best single-point determinant (r(2) = 0.934) for area-under-the-concentration-time curve (AUC(0-6 hours)) compared with CO (r(2) = 0.267) or C0 (r(2) = 0.304). The mean +/- SD values of CsA C2 and AUC(0 to 6 hours) in the first year post-transplant were significantly lower in patients with > 2 rejection episodes compared with those with <= 2 rejection episodes (C2: 875 +/- 546 mu g/liter vs 1,114 +/- 633 mu g/liter, p = 0.01; AUC(0-6 hours): 4,036 +/- 1,904 mu g X hour/liter vs 4,870 +/- 2,182 mu g X hour/liter; p = 0.01) whereas CO and C6 did not differ. Patients in the Intermediate C2 Group were free from rejection episodes for a significantly longer duration (p < 0.001) and had significantly higher predicted forced expiratory volume in I second (%) values (p < 0.001) compared with the Low and High C2 Groups. The percentage of increase in serum creatinine concentration by the end of first month post-transplant was significantly higher in the Intermediate C2 Group (p < 0.003). Conclusions: CsA C2 concentrations correlated better with the incidence of multiple rejections after lung transplantation than did CO or C6. C2 concentrations between 1,000 and 1,500 mu g/liter within the first post-operative month may be associated with better graft outcomes and improved pulmonary function and worsened renal function.