Therapeutic drug monitoring for everolimus in heart transplant recipients based on exposure-effect modeling

Randall C. Starling, Joshua M. Hare, Paul Hauptman, Kenneth R. McCurry, Hartmut W. Mayer, John M. Kovarik, Heinz Schmidli

Research output: Contribution to journalArticlepeer-review

70 Scopus citations


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 ≥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.

Original languageEnglish (US)
Pages (from-to)2126-2131
Number of pages6
JournalAmerican Journal of Transplantation
Issue number12
StatePublished - Dec 2004


  • Certican
  • Everolimus
  • Heart transplantation
  • Therapeutic drug monitoring

ASJC Scopus subject areas

  • Immunology


Dive into the research topics of 'Therapeutic drug monitoring for everolimus in heart transplant recipients based on exposure-effect modeling'. Together they form a unique fingerprint.

Cite this