Longitudinal assessment of everolimus in de novo renal transplant recipients over the first post-transplant year: Pharmacokinetics, exposure-response relationships, and influence on cyclosporine

• Published in: Clinical pharmacology and therapeutics Vol. 69; no. 1; pp. 48 - 56
• Main Authors: Kovarik, John M., Kahan, Barry D., Kaplan, Bruce, Lorber, Marc, Winkler, Michael, Rouilly, Marisel, Gerbeau, Christophe, Cambon, Natalie, Boger, Robert, Rordorf, Christiane, Cockfield, S., Hricik, D., Rigg, K., Shehata, M., Land, W., Mueller, E., Schmidt, A. G., Wehr, S., Wilkie, M. M., Wong, R. L.
• Format: Journal Article
• Language: English
• Published: New York, NY Nature Publishing 01-01-2001
• Subjects: Administration, Oral; Adolescent; Adult; Aged; Area Under Curve; Biological and medical sciences; Cyclosporine - pharmacokinetics; Cyclosporine - therapeutic use; Dose-Response Relationship, Drug; Double-Blind Method; Drug Interactions; Everolimus; Female; Humans; Hypercholesterolemia - chemically induced; Hypertriglyceridemia - chemically induced; Immunomodulators; Immunosuppressive Agents - pharmacokinetics; Immunosuppressive Agents - therapeutic use; Kidney Transplantation; Longitudinal Studies; Male; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Sirolimus - adverse effects; Sirolimus - analogs & derivatives; Sirolimus - pharmacokinetics; Sirolimus - therapeutic use; Thrombocytopenia - chemically induced; Human; Kidney disease; Drug combination; Urinary system disease; Oral administration; Transplantation; Kidney; Dose activity relation; Activity concentration relation; Ciclosporin; Drug interaction; Immunosuppressive agent; Pharmacokinetics
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1067/mcp.2001.112969

Objective
Our objective was to characterize the steady‐state pharmacokinetics of everolimus and cyclosporine (INN, ciclosporin) when coadministered in de novo kidney allograft recipients during the first year after transplantation.
Methods
This study was a multicenter randomized double‐blind study of 101 patients who were randomly assigned 1:1:1 to receive everolimus tablets at doses of 0.5 mg, 1 mg, or 2 mg twice daily with cyclosporine and prednisone. Blood sampling for the pharmacokinetics of everolimus and cyclosporine was performed on day 1, on weeks 1, 2, 3, and 4, and on months 2, 3, 6, 9, and 12. Everolimus dose‐proportionality and stability over time were assessed in the context of linear regression and ANOVA models. Everolimus exposure‐response relationships between area under the blood concentration‐time curve (AUC) and changes in platelets, leukocytes, and lipids were explored with the median‐effect model. Potential differences in cyclosporine dosing and pharmacokinetics at different levels of everolimus exposure were assessed in the context of ANOVA.
Results
Everolimus steady state was reached on or before day 7, with a median 3‐fold accumulation of drug exposure compared with that after the first postoperative dose. Both steady‐state maximum concentration and AUC were dose proportional over the full dose range when assessed on day 1, as well as for the full duration of the study at steady state. There was evidence for longitudinal stability in AUC of everolimus during the course of the study. The interindividual pharmacokinetic variability for AUC was 85.4% and intraindividual, interoccasion variability was 40.8%. Age (range, 17–69 years), weight (range, 49–106 kg), and sex (65 men and 36 women) were not significant contributors to variability. There was an increasing incidence of transient thrombocytopenia (≤100 × 109/L) with increasing everolimus AUC (P = .03). Cyclosporine doses, trough concentrations, and AUC exhibited similar temporal patterns during the course of the study regardless of the co‐administered everolimus dose level (P = .13, .82, and .76, respectively).
Conclusions
Everolimus exhibited dose‐proportional, stable exposure during the first post‐transplant year. For a 4‐fold range of everolimus doses there were no differential effects on cyclosporine dosing or pharmacokinetics.
Clinical Pharmacology & Therapeutics (2001) 69, 48–56; doi: 10.1067/mcp.2001.112969