POPULATION PHARMACOKINETICS OF SIROLIMUS IN KIDNEY-TRANSPLANT PATIENTS

Objective: To characterize the dose-related pharmacokinetics of the im munosuppressant agent sirolimus (formerly rapamycin) in kidney transpl ant patients by use of two-stage and nonlinear mixed-effect model popu lation methods. Methods: Patients (n = 36) from three centers (Germany , the United Kingdom, and Sweden) who received steady-state oral doses of cyclosporine (ciclosporin) were assessed after single oral adminis tration of sirolimus at doses of 3, 5, 10, and 15 mg/m(2). Plasma and whole blood sirolimus samples were analyzed by a high-performance liqu id chromatographic/mass spectrophotometric method, Simultaneous fittin g used biexponential functions with intercept/slope or clearance/volum e terms, as well as first-order absorption (k(a)) and a lag-time. Resu lts: The nonlinear mixed-effect model method (P-Pharm) provided a bett er characterization of sirolimus kinetics, especially for the absorpti on and distribution phases where fewer data were available per patient , Sirolimus distribution between whole blood and plasma was concentrat ion-independent, with a mean blood/plasma ratio (coefficient of variat ion) of 30.9 (48.5%), Elimination was not influenced by dose, as shown by estimates of the terminal half-life of 63 hours (27.5%) and appare nt oral blood clearance of 8.9 L/hr (38.2%), Sirolimus distribution pa rameters were influenced by body weight and surface area. Sirolimus wa s rapidly absorbed, as shown by the absorption lag-time of 0.27 hour ( 35.1%), and k(a) of 2.77 hr(-1) (48.4%), The concomitant administratio n of sirolimus and cyclosporine did not reveal any pharmacokinetic int eractions. Conclusion: This report provides an initial population phar macokinetics of sirolimus in kidney transplant recipients receiving cy closporine concurrently, Sirolimus blood and plasma pharmacokinetics w ere biexponential and linear for doses from 3 to 15 mg/m(2), No pharma cokinetic interaction was found between sirolimus and cyclosporine.