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

Abstract

Cyclosporine A (CsA) therapy based on 2-h concentrations (C2) after oral administration has demonstrated low acute rejection rates after solid organ transplantation. We analysed the correlation between C2 and trough (C0) levels of oral CsA therapy in samples obtained twice in consecutive weeks from 58 patients during their first admission for allogeneic haematopoietic stem cell transplantation. Also 8-h concentration curves were obtained from 23 patients. The mean (range) CsA dose was 332 (167-763) and 255 (113-575) mg/day for patients with matched unrelated donor (MUD) and human leukocyte antigen identical sibling donor (Sib), respectively. Median (range) C0 and C2 were 254 (145-332) and 898 (419-1466) ng/ml in MUD patients, and 130 (93-265) and 554 (196-988) ng/ml in Sib patients. In MUD patients with either aGVHD grade oII or XII, the median C2 were 915 (419-1466) and 890 (519-1399) ng/ ml, respectively. In Sib patients with aGVHD grade oII or grade XII, the median C2 were 552 (404-718) and 539 (196-988) ng/ml, respectively. The median C2 levels were comparable in patients with or without severe infections. Interindividual variations in CsA uptake and metabolism may explain the wide variation of C2 levels without prediction for increased risk for severe aGVHD or infectious complication when C0 guided the CsA dosing.

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

“…16 Importantly, C0 does not appear to be a good predictor of AUC 0À4h , AUC 0À8h and AUC 0À12h when compared with CsA concentrations sampled at other time points (for example C2, C3 and C4). In the early transplant period, C2 values seemed to be most reliable in predicting AUC, but at later post transplant intervals, C3 and C4 values were equally predictive if not superior.…”

“…CsA, is required for maximal efficacy and correlates well with transplant-associated complications, 15 but another analysis, albeit with a modest sample size and using orally administered CsA, found no correlation between C2 and the development of adverse events such as acute GVHD and infections. 16 The current study was not designed nor powered to correlate CsA concentrations with the development of transplant-associated complications and patient outcome.…”

“…15 A Swedish study found wide inter-individual variations in C2 levels in patients taking oral CsA, and that both C0 and C2 levels correlated well (r 2 ¼ 0.77 and 0.86, respectively) with the estimated AUC 0-12 h (AUC 0À12h ), although the dose of CsA and timing of post-transplant monitoring was not specified. 16 To date, information on the influence of factors such as age, MDR-1 polymorphism and concomitant use of steroid on the relationship between CsA blood levels and AUC in allo-SCT remains limited, despite evidence suggesting that these factors influence CsA clearance [17][18][19] and therefore potentially the relationship between CsA levels and AUCs.…”

CsA exposure is associated with acute GVHD and relapse in children after SCT

“…20 In HSCT, however, C2 concentrations did not show any correlation with acute GVHD in adults. 21 To further complicate CsA therapy after HSCT, it has been suggested that a high CsA dose is related to relapse of original disease. 22 Although this implicates a relationship between dosage and actual systemic exposure, it is known Table 3 Prognostic impact of CsA exposure (trough level4100 mcg/l vs o100 mcg/l) during the early post-SCT period on OS, RR and TRM in all 91 SCT patients and those transplanted for ALL and AML separately Abbreviations: CI ¼ confidence interval; HR ¼ hazard ratio; RR ¼ relapse risk.…”

Determination of initial i.v. CYA dosage to achieve target AUC values in pediatric hematopoietic stem cell transplant patients

“…CYA administration and the incidence of aGVHD though there recently has been interest in this concept. [7][8][9][10][11] The objective of this study was to develop a guideline for the initial i.v. CYA dose for pediatric HSCT patients that would achieve the target AUC values recommended for solid organ transplant patients.…”