title: Pharmacokinetics of an everolimus-cyclosporine immunosuppressive regimen over the first 6 months after kidney transplantation.
abstract: The pharmacokinetics of everolimus were characterized over the first 6 months post transplant in 731 patients receiving either 0.75 or 1.5 mg bid everolimus in addition to cyclosporine and corticosteroids. Pharmacokinetic data consisted of 4014 everolimus trough concentrations (Cmin) obtained in all patients and 659 area under the concentration-time curve (AUC) -profiles obtained at months 2, 3, and 6 in a subset of 261 patients. Cmins averaged 4.3 +/- 2.4 and 7.2 +/- 4.2 ng/mL at 0.75 and 1.5 mg bid, indicating a 20% under-proportionality at the upper dose level. Cmins were 19-34% lower in the first month compared with months 2 through 6-values. AUC was dose-proportional and stable over time, averaging 77 +/- 32 and 136 +/- 57 ng.h.mL-1 at the two dose levels. Within- and between-patient variability in AUC were 27% and 31%, respectively. There was no influence of sex, age (16-66 years), or weight (42-132 kg) on AUC. Everolimus exposure was significantly lower by an average 20% in blacks. Everolimus exposure was relatively stable over the first 6 months post transplant, with no major departure from dose-proportionality over the therapeutic dose range. Weight-adjusted dosing (mg/kg) does not appear warranted. Black patients may have lower bioavailability and/or higher clearance of everolimus compared with white patients.
authors.affiliation: Novartis Pharmaceuticals, Basel, Switzerland 4002. john.kovarik@pharma.novartis.com
authors.forename: John M
authors.initials: JM
authors.lastname: Kovarik
authors.forename: Bruce
authors.initials: B
authors.lastname: Kaplan
authors.forename: Hélio Tedesco
authors.initials: HT
authors.lastname: Silva
authors.forename: Barry D
authors.initials: BD
authors.lastname: Kahan
authors.forename: Jacques
authors.initials: J
authors.lastname: Dantal
authors.forename: Louis
authors.initials: L
authors.lastname: McMahon
authors.forename: Stephane
authors.initials: S
authors.lastname: Berthier
authors.forename: Chyi-Hung
authors.initials: CH
authors.lastname: Hsu
authors.forename: Christiane
authors.initials: C
authors.lastname: Rordorf
mesh_terms: D000328:Adult; D019540:Area Under Curve; D016572:Cyclosporine / Q000493:pharmacokinetics*; D000068338:Everolimus; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D016030:Kidney Transplantation / Q000379:methods*; D008875:Middle Aged; D011897:Random Allocation; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D013997:Time Factors
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; D020123:Sirolimus