Estimation of Abbreviated Cyclosporine A Area under the Concentration-Time Curve in Allogenic Stem Cell Transplantation after Oral Administration

Abstract

Measurements of Cyclosporine (CsA) systemic exposure permit its dose adjustment in allogenic stem cell transplantation recipients to prevent graft-versus-host disease. CsA LSSs were developed and validated from 60 ASCT patients via multiple linear regressions. All whole-blood samples were analyzed by fluorescence polarization immunoassay (FPIA-Axym). The 10 models that have used CsA concentrations at a single time point did not have a good fit with AUC(0-12) (R(2) < 0.90). C(2) and C(4) were the time points that correlated best with AUC(0-12 h), R(2) were respectively 0.848, and 0.897. The LSS equation with the best predictive performance (bias, precision and number of samples) utilized three sampling concentrations was AUC(0-12 h) = 0.607 + 1.569 × C(0.5) + 2.098 × C(2) + 3.603 × C(4) (R(2) = 0.943). Optimal LSSs equations which limited to those utilizing three timed concentrations taken within 4 hours post-dose developed from ASCT recipient's patients yielded a low bias <5% ranged from 1.27% to 2.68% and good precision <15% ranged from 9.60% and 11.02%. We propose an LSS model with equation AUC(0-12 h) = 0.82 + 2.766 × C(2) + 3.409 × C(4) for a practical reason. Bias and precision for this model are respectively 2.68% and 11.02%.

Figure 1

Individual blood concentration-time curves of patients administered CsA (n = 30).

Figure 2

Comparison of the full cyclosporine (CsA) AUC_0–12 h and values estimated using 6 regression models: (a) model using trough concentration (R ^² = 0.391), (b) model using concentration at 2 hours after dosing (R ² = 0.848), (c) model using concentration at 4 hours after dosing (R ² = 0.897), (d) model using concentrations at 2 and 4 hours after dosing (R ² = 0.930), (e) model using concentrations at 0.5, 2 and 4 hours after dosing (R ² = 0.943), and (f) model using concentrations at 2, 4, 6 and 8 hours after dosing (R ² = 0.965).

Figure 3

Evolution of Correlation coefficients R ² according selected models. (a) Correlation coefficients between AUC_0–12 h and CsA concentration at each time point. (b) Correlation coefficients between AUC_0–12 h estimated and concentrations at full hours.