Optimal sampling time-point for cyclosporin A concentration monitoring in heart transplant recipients

Abstract

The present study was performed to determine an optimal time-point for monitoring the concentration of the immunosuppressive drug cyclosporin A (CsA) in heart transplant patients and its efficacy in the prevention of transplant rejection. A total of 32 transplant recipients were randomly assigned for three treatment approaches. Recipients in groups A (n=11), B (n=13) and C (n=8) received oral administration of CsA at doses of 3.2, 3.5 and 4.4 mg/kg, respectively. The plasma CsA concentrations were examined at 2 h intervals over 12 h. Furthermore, their correlation with the 4 h pharmacokinetic profiles as the area under the plasma CsA concentration vs. time curve (AUC_{0-4 h}) were calculated The efficacy of CsA in inhibiting cardiac allograft rejection was assessed at 2 h after oral CsA intake (C2) and adverse events of the drug were examined in the C2-monitored recipients. The plasma CsA concentration rapidly increased in most recipients with a peak level detected at ~2 h after dosing. Regression analysis revealed that among all time-points assessed, the CsA had the highest correlation with the AUC_{0-4 h} at C2. At C2, increasing CsA doses exhibited a positive association with the measure of AUC_{0-4 h}. The efficacy of increasing CsA target levels at C2 in preventing heart transplant rejection was comparable, as the survival rate was 100% in all of the treatment groups. However, the proportion of recipients with side effects in group A was obviously lower than that in the other two groups. In conclusion, C2 is an ideal time-point for monitoring plasma CsA levels with a utility for individualising the next scheduled dose for each patient to ensure that target levels are maintained and achieve a high efficacy and safety of CsA therapy in heart transplant recipients (clinical trial no. 12002610).

Keywords: AUC0-4 h; CsA concentration at 2 h; correlation coefficient; cyclosporin A; heart transplantation.

Figure 1.

Pharmacokinetic profile of CsA. The pharmacokinetic profiles of individual recipients were observed by measuring the plasma CsA concentration every 2 h over a time period of 0–12 h. The mean values for CsA levels (ng/ml) were determined to generate CsA concentration-time curves. Values are expressed as the mean ± standard deviation (n=32). CsA, cyclosporin A.

Figure 2.

(A) Correlation between the plasma CsA concentration and the AUC0-4 h (ng/h/ml) at various time-points after administration (every 2 h over 12 h). (B) Correlation scatter plot for the AUC0-4 h vs. the CsA levels at C2 in heart transplant recipients (n=32). A positive correlation between the CsA levels at C2 and the AUC0-4 h was identified with an r2 value of 0.84 (P<0.05). AUC0-4 h, area under the curve of the plot of plasma CsA concentration against the time (0–4 h); CsA, cyclosporin A; C2, 2-h time-point after CsA administration.

Figure 3.

Clinical efficacy and safety of CsA therapy. (A) The survival rate of heart transplant patients treated with CsA for preventing transplant rejection was 100% in all three groups, according to C2 monitoring. (B) The proportion of patients with adverse events (%) was obviously lower in group A compared with that in the other groups. *P<0.01 vs. groups A and B; #P<0.01 vs. group A. (C) The plasma creatinine levels were enhanced with increasing CsA concentrations at C2, with a positive correlation between the elevated creatinine content and the level of CsA at C2. CsA, cyclosporin A; C2, 2-h time-point after CsA administration.