title: Therapeutic drug monitoring for everolimus in heart transplant recipients based on exposure-effect modeling.
abstract: Everolimus, a proliferation signal inhibitor, is an immunosuppressant that targets the primary causes of progressive allograft dysfunction, thus improving the long-term outcome after heart transplantation. The present study investigated whether therapeutic drug monitoring (TDM) of everolimus would benefit heart transplant patients. Data from a twelve-month phase III trial comparing everolimus (1.5 or 3 mg daily) with azathioprine were used to evaluate everolimus pharmacokinetics, exposure-efficacy/safety and TDM prognostic simulations. Everolimus trough levels were stable in the first year post-transplant and averaged 5.2 +/- 3.8 and 9.4 +/- 6.3 ng/mL in patients treated with 1.5 and 3 mg/day, respectively. Cyclosporine trough levels were similar in all treatment groups. Biopsy-proven acute rejection (BPAR) was reduced with everolimus trough levels > or =3 ng/mL. Intravascular ultrasound (IVUS) analysis showed evidence of reduced vasculopathy at 12 months with increasing everolimus exposure. Unlike cyclosporine, increasing everolimus exposure was not related to a higher rate of renal dysfunction. The TDM simulation, which was based on two everolimus dose adjustments and an initial starting dose of 1.5 mg/day, showed that the simulated BPAR rate (with TDM) was 21% versus 26% in the group with fixed dosing. Therefore, TDM in heart transplantation could optimize immunosuppressive efficacy and reduce treatment-related toxicity.
authors.affiliation: Department of Cardiovascular Medicine, Kaufman Center for Heart Failure, Cleveland, OH, USA. starlir@ccf.org
authors.forename: Randall C
authors.initials: RC
authors.lastname: Starling
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Hare
authors.forename: Paul
authors.initials: P
authors.lastname: Hauptman
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: McCurry
authors.forename: Hartmut W
authors.initials: HW
authors.lastname: Mayer
authors.forename: John M
authors.initials: JM
authors.lastname: Kovarik
authors.forename: Heinz
authors.initials: H
authors.lastname: Schmidli
mesh_terms: D001379:Azathioprine / Q000097:blood / Q000627:therapeutic use; D016903:Drug Monitoring / Q000379:methods; D000068338:Everolimus; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008657:Metabolic Clearance Rate; D011446:Prospective Studies; D015203:Reproducibility of Results; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D007166:Immunosuppressive Agents; D000068338:Everolimus; D001379:Azathioprine; D020123:Sirolimus