Comparison of Trough, 2-Hour, and Limited AUC Blood Sampling for Monitoring Cyclosporin (Neoral®) at Day 7 Post–Renal Transplantation and Incidence of Rejection in the First Month

Abstract

The use of alternative strategies to the traditional pre-dose/trough (C0) blood sampling for cyclosporine (CsA) therapeutic drug monitoring has the potential to revolutionize analytical practices which have, in many centers, been established for some 20 years. While the C0 sample has previously been recommended, current attitudes are increasingly proposing alternatives for assessing CsA exposure, including various limited sampling strategies of the AUC (lssAUC) in the early postdose period, or alternative single-point nontrough samples, such as a 2-hour postdose sample (C2). The present study has reviewed a series of consecutive renal transplant recipients over 18 months where CsA was the primary immunosuppressant. The lssAUC performed at around day 7 posttransplantation included drawing blood at 0, 2, and 4 hours postdose, giving AUC(0-4). The aim of this study was to review the occurrence of acute biopsy-proven rejection in the first month and consider which of (simultaneously measured) C0, C2 or AUC(0-4) was a better early indicator of this adverse outcome. The result was best described by comparing the data from rejectors (n = 13) and nonrejectors (n = 42) for these 3 indices of CsA exposure (i.e., C0, C2 or AUC(0-4)). There was no evidence that C0 predicted the likelihood of such adverse clinical outcomes. In contrast, rejectors tended to have lower mean C2 CsA concentrations, and the incidence of rejection was 0.0 when C2 exceeded 1200 microg/L (n = 10). While the data are limited in the higher C2 CsA concentration range, it is nevertheless consistent with more recent recommendations suggesting that the CsA at C2 should target 1700 microg/L in this first month posttransplantation. As 64% of the patients were also receiving a CsA-sparing agent (diltiazem [DTZ]), the relationships were also investigated to determine whether any affect of concomitant DTZ therapy could be demonstrated. However, in this small sample, no significant affect of DTZ was seen.

Optimizing the use of cyclosporin in allogeneic stem cell transplantation

“…This was illustrated by data showing that the rates of acute rejection and nephrotoxicity in patients with trough CsA concentrations within a defined therapeutic range remained 59 and 63%, respectively. 42 Subsequent work showed that trough CsA levels did not correlate with drug exposure as estimated by the area under the concentration time curve (AUC) 43 and others demonstrated that the correlation between trough levels and clinical outcomes was relatively poor 42,[44][45][46][47][48][49][50] in the settings of renal, liver and heart transplantation.…”

CsA 2-h concentration correlates best with area under the concentration–time curve after allo-SCT compared with trough CsA

“…[5][6][7] In solid organ transplantation, the use of C0 monitoring has been associated with a high incidence of renal dysfunction. 8 In these patients, levels taken 2 h after a dose (C2) appear to correlate best with C max and area under the concentration-time curve 0-4 h (AUC 0À4h ), 9 and monitoring and dose adjustments based on C2 levels has been associated generally with improved renal function without an increased risk of graft rejection after heart, 10 liver 11 and renal transplantation, 12 although not all studies have demonstrated benefit with this approach. 13,14 Alterations in GI motility and mucosal integrity by conditioning regimens or GVHD mean that observations in solid organ transplantation may not apply to recipients of allo-SCT.…”

Cyclosporine A (CsA) 2-h concentrations vary between patients without correlation to graft-versus-host disease after allogeneic haematopoietic stem cell transplantation

“…3 Thus, concentration sampling 2 h after dose intake (C2) has been suggested as a better measure of both total drug exposure and effect in kidney, heart and liver transplant patients. [4][5][6][7] In other series of liver and heart transplant patients, no clinical superiority (lower incidence of acute graft rejections) was demonstrated using C2 levels. 8,9 A definite drawback of C2 measures is that they are sensitive to minor deviations in sampling time.…”