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 journalArticle

69 Citations (Scopus)

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 ≥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
Volume4
Issue number12
DOIs
StatePublished - Dec 1 2004

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Drug Monitoring
Heart Transplantation
Immunosuppressive Agents
Cyclosporine
Transplants
Biopsy
Everolimus
Transplant Recipients
Azathioprine
Allografts
Pharmacokinetics
Kidney
Safety

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

Cite this

Therapeutic drug monitoring for everolimus in heart transplant recipients based on exposure-effect modeling. / Starling, Randall C.; Hare, Joshua M.; Hauptman, Paul; McCurry, Kenneth R.; Mayer, Hartmut W.; Kovarik, John M.; Schmidli, Heinz.

In: American Journal of Transplantation, Vol. 4, No. 12, 01.12.2004, p. 2126-2131.

Research output: Contribution to journalArticle

Starling, Randall C. ; Hare, Joshua M. ; Hauptman, Paul ; McCurry, Kenneth R. ; Mayer, Hartmut W. ; Kovarik, John M. ; Schmidli, Heinz. / Therapeutic drug monitoring for everolimus in heart transplant recipients based on exposure-effect modeling. In: American Journal of Transplantation. 2004 ; Vol. 4, No. 12. pp. 2126-2131.
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