title: Influence of everolimus on steady-state pharmacokinetics of cyclosporine in maintenance renal transplant patients.
abstract: To investigate possible interactions of the novel immunosuppressant everolimus with cyclosporine, a multicenter, randomized, double-blind, placebo-controlled, dose-escalating phase I study was performed. Everolimus regimens (0.75-10 mg/d) were administered for 28 days to stable renal allograft recipients receiving the microemulsion form of cyclosporine. Steady-state cyclosporine profiles were assessed at baseline on day 0 (cyclosporine alone) and on day 21 with everolimus on steady state. By day 21, mean dose-normalized cyclosporine AUC0-12 increased by 15% in patients receiving placebo. In everolimus-treated patients, mean increases in cyclosporine AUC0-12 ranged from 7% to 43%, which were not significantly different across all dosing cohorts including placebo. Linear regression of everolimus AUC on day 21 versus the increase in cyclosporine AUC0-12 yielded a slope not significantly different from a horizontal line (P = ns). In conclusion, these results suggest that steady-state everolimus exposure over the wide range assessed in this study did not affect steady-state cyclosporine pharmacokinetics.
authors.affiliation: University Clinic Charité, Berlin, Germany.
authors.forename: Klemens
authors.initials: K
authors.lastname: Budde
authors.forename: Gustav
authors.initials: G
authors.lastname: Lehne
authors.forename: Michael
authors.initials: M
authors.lastname: Winkler
authors.forename: Lutz
authors.initials: L
authors.lastname: Renders
authors.forename: Arno
authors.initials: A
authors.lastname: Lison
authors.forename: Lutz
authors.initials: L
authors.lastname: Fritsche
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Soulillou
authors.forename: Per
authors.initials: P
authors.lastname: Fauchald
authors.forename: Hans-Hellmut
authors.initials: HH
authors.lastname: Neumayer
authors.forename: Jaques
authors.initials: J
authors.lastname: Dantal
mesh_terms: D000328:Adult; D000368:Aged; D002214:Capsules; D016572:Cyclosporine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D000068338:Everolimus; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D013607:Tablets
chemical_list: D002214:Capsules; D007166:Immunosuppressive Agents; D013607:Tablets; D016572:Cyclosporine; D000068338:Everolimus; D020123:Sirolimus