Population pharmacokinetics of cyclosporine in Korean adults undergoing living-donor kidney transplantation

Study Objective. To estimate the population pharmacokinetic parameters of cyclosporine in Korean adults undergoing living-donor kidney transplantation, and to identify clinical factors affecting cyclosporine pharmacokinetics. Design. Retrospective cohort study. Setting. Single, 1600-bed, tertiary care academic medical center in Seoul, South Korea. Patients. Seventy-four living-donor kidney transplant recipients (mean age 42 yrs) receiving oral cyclosporine microemulsion as an immunosuppressant between January 1, 2001, and August 31, 2006. Measurements and Main Results. Using nonlinear mixed-effects modeling (NONMEM) with first-order absorption and elimination, a total of 2394 whole-blood cyclosporine concentrations from the 74 patients were analyzed. The effects of several clinical covariates on cyclosporine pharmacokinetic parameters were evaluated over 12 months after transplantation. The absorption rate constant was fixed at 1.28 hour-1, and the following population pharmacokinetic estimates were calculated: cyclosporine clearance 43.6 L/hour, apparent volume of distribution 1990 L, and interpatient variability for clearance (coefficient of variation) 17.69%. The clinical factors (covariates) that significantly affected cyclosporine pharmacokinetics were postoperative days, prednisolone dose (in mg/day), total bilirubin level (mg/dl), current body weight (in kg), and concurrent use of amlodipine. Conclusion. This population pharmacokinetic model identified important sources of variability in cyclosporine pharmacokinetics. The model will help calculate cyclosporine dose requirements in renal transplant recipients according to specific clinical factors affecting cyclosporine clearance, and it will also be useful for therapeutic drug monitoring.