NONMEM POPULATION PHARMACOKINETIC MODELING OF ORALLY-ADMINISTERED CYCLOSPORINE FROM ROUTINE DRUG-MONITORING DATA AFTER HEART-TRANSPLANTATION

The population pharmacokinetics of cyclosporine (CsA) in adult recipie nts of cardiac transplants were determined from sparse, retrospective drug monitoring data accumulated for at least 3 months after surgery. All were receiving oral CsA twice daily, and morning trough levels in whole-blood were measured by high-performance liquid chromatography. A dditional data included height, weight, gender, age, ethnicity hematoc rit, total bilirubin, and concurrent drug use. Population modeling was performed using NONMEM on 36 randomly selected patients, assuming a o ne-compartment model with first-order absorption and elimination, Impr oved fits were obtained by incorporating the following expression in t he model to adjust oral bioavailability as a function of postoperative day (POD): F = 0.2 + 10 x ABS (POD - 7)/([POD + 10] x 60), Interpatie nt variability (CV%) in clearance (CL) was 20.2%. There was a mean bia s of 8.5% at the average CsA concentration of 250 ng/ml when the predi ctive performance was assessed statistically in a reserved subset of 3 3 patients who received cardiac transplants. For the entire population (n = 69 patients), the average CsA CL and terminal half-life (T-1/2) were, respectively: CL (l/h) = 0.256 x weight (kg)/T-1/2 = 11.0 hours, or CL (l/h) = 0.184 x weight (kg); T-1/2 = 14.7 hours, if there was c oncomitant diltiazem administration. These results compared favorably with those reported elsewhere for studies of postcardiac transplant ki netics using the traditional multiple blood sampling approach.