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ABSTRACT: Everolimus is a macrolide immunosuppressant intended for acute rejection prophylaxis after kidney transplantation.
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 characteristics (age, weight, sex, and ethnicity) and of comedications on everolimus exposure was explored.
For a reference 44-year-old, 71-kg Caucasian kidney allograft recipient receiving everolimus as part of a cyclosporine (INN, ciclosporin)-prednisone 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 patients, whereas black patients had an average clearance that was 20% higher than that of nonblack patients. Patients concomitantly receiving erythromycin or azithromycin had an average 19% lower clearance. One patient receiving itraconazole had a 74% reduction in clearance. After we accounted for covariates, the remaining interindividual variability in clearance was 27% and the variability for distribution volume was 36%. The combined intraindividual and assay/measurement residual error in everolimus blood concentrations was 31%.
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 of potent inhibitors of the cytochrome P450 isozyme CYP3A may reduce everolimus clearance and increase its blood concentrations.
Clinical Pharmacology & Therapeutics 10/2001; 70(3):247-54. · 7.39 Impact Factor