Population pharmacokinetics of everolimus in de novo renal transplant patients: Impact of ethnicity and comedications

Background. Everolimus is a macrolide immunosuppressant intended for acute rejection prophylaxis after kidney transplantation. Methods: A total of 5260 blood samples were collected in the context of two randomized, double-blind, multicenter efficacy trials in 673 patients over a 6-month period after kidney transplantation. The data were evaluated in a nonlinear mixed-effects model. The influence of demographic characteristi cs (age, weight, sex, and ethnicity) and of comedications on everolimus exp osure was explored. Results: For a reference 44-year-old, 71-kg Caucasian kidney allograft reci pient receiving everolimus as part of a cyclosporine (INN, ciclosporin)-pre dnisone immunosuppressive regimen, the absorption rate constant was 6.07 h( -1) (standard error [SE], 0.70 h(-1)), the apparent clearance was 8.8 L/h ( SE, 0.2 L/h), and the apparent central distribution volume was 110 L (SE, 5 L). There were no clinically relevant influences of age, weight, or sex on clearance. No significant difference in clearance was detected for Asian p atients, whereas black patients had an average clearance that was 20% highe r than that of nonblack patients. Patients concomitantly receiving erythrom ycin or azithromycin had an average 19% lower clearance. One patient receiv ing itraconazole had a 74% reduction in clearance. After we accounted for c ovariates, the remaining interindividual variability in clearance was 27% a nd the variability for distribution volume was 36%. The combined intraindiv idual and assay/measurement residual error, in everolimus blood concentrati ons was 31%. Conclusions: Dose adjustment of everolimus on the basis of weight does not appear necessary. Black patients may need a higher dose to achieve exposure that is similar to that of nonblack patients. Concomitant administration o f potent inhibitors of the cytochrome P450 isozyme CYP3A may reduce everoli mus clearance and increase its blood concentrations.