Bd. Kahan et al., VARIABLE ORAL ABSORPTION OF CYCLOSPORINE - A BIOPHARMACEUTICAL RISK FACTOR FOR CHRONIC RENAL, ALLOGRAFT-REJECTION, Transplantation, 62(5), 1996, pp. 599-606
The inter- and intrapatient variability in cyclosporine (CsA) pharmaco
kinetics obfuscates the relationship between therapeutic outcome and a
dministered dose, thereby impeding the development of secure algorithm
s for CsA therapy, In an attempt to understand these variabilities, we
previously performed serial pharmacokinetic profiles on 160 renal tra
nsplant recipients during the first 3 posttransplant months, Drug expo
sure was estimated by the average CsA concentration (C-av), which was
defined as a time-corrected (tau, hours) expression of the area under
the concentration-time curve (AUC), i.e., C-av = (AUC/tau). Low C-av v
alues correlated with an increased occurrence of acute rejection episo
des and 1-year rate of renal transplant loss, The present study examin
es the results of serial pharmacokinetic profiling of a cohort of 204
patients treated for up to 5 years with CsA doses selected to achieve
target C-av values. Multivariate analyses correlated demographic facto
rs, laboratory values, clinical parameters, and CsA pharmacokinetic pa
rameters with the occurrence of chronic rejection. The factors that pr
edisposed to chronic rejection included a previous acute rejection epi
sode, initial acute tubular necrosis, diastolic blood pressure above 8
5 mmHg, and African-American race, Once regression models were adjuste
d to account for the impact of these factors, we examined the associat
ion between the incidence of chronic rejection and individual pharmaco
kinetic parameters, including the mean values of the absolute and dose
-corrected trough, peak, and C-av concentrations, as well as the perce
nt coefficient of variation of each of these values, Receiver operatin
g characteristic curves documented that 27% of the total risk for the
occurrence of chronic rejection was attributable to a greater than 20%
coefficient of variation of the dose-corrected C-av, namely, AUC/(tau
. mg). This study suggests that variable oral bioavailability of CsA
represents a biopharmaceutical risk factor for the occurrence of chron
ic rejection.