C2 Targets and multivariate predictors of C2 levels in stable heart transplant patients immunosuppressed on a C0-based regimen

Abstract

Neoral dose monitoring in heart transplantation (HT) is based on trough levels (C0), since cyclosporine A (CsA) 2-hr peak (C2) targets have not been established. To identify C2 targets and clinical correlates of C0 and C2, we studied 314 stable HT pts (251 male, aged 50±14 yrs at HT, follow-up 6.8±4 yrs, range 1 mo-15 yrs), on a C0-based regimen. Mean C0 and C2 levels (ng/mL) were 268±80 and 1031±386 respectively for pts (n=19) in the first 3 mo; 230±49 and 955±239 in pts (n=10) between 4 and 12 mo; 157±53 and 745±235 in pts (n=285) after 1 yr. Our target C0 levels (ng/mL) are 150-400 (first 3 mo), 150-300 (4-12 mo), 100-250 (>12mo). For pts within the target C0 the corresponding C2 (ng/mL) were 600-1500 (first 3 mo), 600-1300 (4 to 12 mo), 500-1000 (>12mo). C2 correlated with C0 (Pearson, r=0.61, p=0.0001). C2 correlated better with CsA dose than C0 (r=0.50, p=0.0001 vs r=0.36, p=0.0001). Between pts CsA dose varied by a factor of 9.3; the C/dose ratio varied by a factor of 8.5 for C2 and of 15.6 for C0. Pts with higher C2 (>550) had higher rejection scores at 1 yr (p=0.04) and during whole follow-up (p=0.04) than pts with lower C2 (t-test). This did not apply to higher (>110) C0 vs. lower C0. Both C2 and C0 correlated with blood urea (r=-0.19, p=0.001; r=-0.18, p=0.002) and creatinine (r=-0.16, p=0.004; r=-0.20, p=0.0001 respectively). By logistic regression higher C2 (>550 ng/mL) was associated with higher CsA and steroid load (mg/Kg) at 1 yr (p=0.038; p=0.001 respectively), lower blood urea (p=0.003) and tended to be associated with high total severe rejection score (p=0.07). Regression analysis on higher C0 (>110 ng/mL) did not show associations. Thus, C2 showed better correlation with CsA dose, renal function, rejection profile and less variability between pts than C0. C2 may improve CsA-based immunosuppression in HT.