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Therapeutic Drug Monitoring for Everolimus in Heart Transplant Recipients Based on Exposure–Effect Modeling
Author(s) -
Starling Randall C.,
Hare Joshua M.,
Hauptman Paul,
McCurry Kenneth R.,
Mayer Hartmut W.,
Kovarik John M.,
Schmidli Heinz
Publication year - 2004
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1046/j.1600-6143.2004.00601.x
Subject(s) - medicine , everolimus , therapeutic drug monitoring , drug , heart transplantation , intensive care medicine , pharmacology , transplantation
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.