title: Therapeutic drug monitoring for everolimus in kidney transplantation using 12-month exposure, efficacy, and safety data.
abstract: The aims of the current study were to determine whether therapeutic drug monitoring (TDM) might benefit kidney transplant recipients receiving everolimus, and to establish dosage recommendations when everolimus is used in combination with cyclosporine and corticosteroids. The analysis was based on data from 779 patients enrolled in two 12-month trials. Everolimus trough concentrations >/=3 ng/mL were associated with a reduced incidence in biopsy-proven acute rejection (BPAR) in the first month (p = 0.0001) and the first 6 months (p = 0.0001), and reduced graft loss compared with lower concentrations (4% vs. 20%, respectively). By contrast, cyclosporine in the standard concentration range had no impact on BPAR within the same timeframes. Most patients receiving everolimus 1.5 or 3 mg/d achieved trough concentrations above the therapeutic threshold of 3 ng/mL, regardless of reductions in cyclosporine dose. TDM simulation showed that just two dose adjustments would achieve median everolimus trough values >/=3 ng/mL in 95% of patients during the first 6 months. This investigation indicates that improved efficacy is likely when TDM is considered as an integral component of the immunosuppressive strategy of everolimus.
authors.affiliation: Yale University School of Medicine, New Haven, CT, USA. marc.lorber@yale.edu
authors.forename: Marc I
authors.initials: MI
authors.lastname: Lorber
authors.forename: Claudio
authors.initials: C
authors.lastname: Ponticelli
authors.forename: John
authors.initials: J
authors.lastname: Whelchel
authors.forename: Hartmut W
authors.initials: HW
authors.lastname: Mayer
authors.forename: John
authors.initials: J
authors.lastname: Kovarik
authors.forename: Yulan
authors.initials: Y
authors.lastname: Li
authors.forename: Heinz
authors.initials: H
authors.lastname: Schmidli
mesh_terms: D001706:Biopsy; D016572:Cyclosporine / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use; D004311:Double-Blind Method; D016903:Drug Monitoring; D000068338:Everolimus; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D016030:Kidney Transplantation; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011239:Prednisolone / Q000008:administration & dosage / Q000627:therapeutic use; D012449:Safety; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; D011239:Prednisolone; D009173:Mycophenolic Acid; D020123:Sirolimus