VARIABLE ORAL ABSORPTION OF CYCLOSPORINE - A BIOPHARMACEUTICAL RISK FACTOR FOR CHRONIC RENAL, ALLOGRAFT-REJECTION

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.