title: 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.
authors.affiliation: Pharmacy Department, The Prince Charles Hospital, Brisbane, Queensland, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Parke
authors.forename: B G
authors.initials: BG
authors.lastname: Charles
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001682:Biological Availability; D016572:Cyclosporine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D016903:Drug Monitoring / Q000379:methods* / Q000706:statistics & numerical data*; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D012189:Retrospective Studies; D013997:Time Factors
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine