NONMEM Population Pharmacokinetic Modeling of Orally Administered Cyclosporine From Routine Drug Monitoring Data After Heart Transplantation

Abstract

The population pharmacokinetics of cyclosporine (CsA) in adult recipients 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. Additional data included height, weight, gender, age, ethnicity, hematocrit, total bilirubin, and concurrent drug use. Population modeling was performed using NONMEM on 36 randomly selected patients, assuming a one-compartment model with first-order absorption and elimination. Improved fits were obtained by incorporating the following expression in the model to adjust oral bioavailability as a function of postoperative day (POD): F = 0.2 + 10 x ABS (POD - 7)/([POD + 10] x 60). Interpatient variability (CV%) in clearance (CL) was 20.2%. There was a mean bias of 8.5% at the average CsA concentration of 250 ng/ml when the predictive performance was assessed statistically in a reserved subset of 33 patients who received cardiac transplants. For the entire population (n = 69 patients), the average CsA CL and terminal half-life (T1/2) were, respectively: CL (l/h) = 0.256 x weight (kg); T1/2 = 11.0 hours, or CL (l/h) = 0.184 x weight (kg); T1/2 = 14.7 hours, if there was concomitant diltiazem administration. These results compared favorably with those reported elsewhere for studies of postcardiac transplant kinetics using the traditional multiple blood sampling approach.