Evaluation of Performance Factors Affecting Two Formulations of Cyclosporine in Pediatric Renal Transplant Patients

Success of renal transplantation in children is largely due to improvements in immunosuppressant therapy since the introduction of calcineurin inhibitors. The aim of this study was to identify possible factors that result in formulation differences in the exposure of pediatric patients to cyclosporine (CsA). We examined the handling of the two major formulations of CsA in a group of pediatric renal transplant recipients. The pharmacokinetic profiles of both formulations were assessed, and the data stratified to assess the effects of age, gender, time posttransplant, and other concomitant drug therapy on the two CsA formulations. The microemulsified formulation (MEC) enhanced bioavailability compared to the older oil-based formulation (CYA), especially at C₂, with more predictable and consistent absorption in children. This higher bioavailability allowed a 15% reduction of dosing to achieve equal drug exposure. The concentration achieved by MEC at C₂ demonstrated a much higher correlation with area under the concentration curve (AUC) than the concentration at C₀. In the case of CYA a strong correlation was obtained between AUC and the concentrations obtained at both C₀ and C₂. Calcium channel blockers increased AUC_0-8 for both CsA formulations. Norfloxacin and pravastatin cotreatment had no effect on either of the CsA formulations. In contrast, the bioavailability of CsA was increased in boys using MEC formulation but this gender-based difference was absent during the use of CYA. This suggests that caution is required for introduction of new formulations of drugs to pediatric patients to evaluate differential effects of age, gender, and concomitant drug therapy.