TY - JOUR
T1 - Therapeutic drug monitoring for everolimus in heart transplant recipients based on exposure-effect modeling
AU - Starling, Randall C.
AU - Hare, Joshua M.
AU - Hauptman, Paul
AU - McCurry, Kenneth R.
AU - Mayer, Hartmut W.
AU - Kovarik, John M.
AU - Schmidli, Heinz
PY - 2004/12
Y1 - 2004/12
N2 - 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.
AB - 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.
KW - Certican
KW - Everolimus
KW - Heart transplantation
KW - Therapeutic drug monitoring
UR - http://www.scopus.com/inward/record.url?scp=10044246181&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=10044246181&partnerID=8YFLogxK
U2 - 10.1046/j.1600-6143.2004.00601.x
DO - 10.1046/j.1600-6143.2004.00601.x
M3 - Article
C2 - 15575918
AN - SCOPUS:10044246181
SN - 1600-6135
VL - 4
SP - 2126
EP - 2131
JO - American Journal of Transplantation
JF - American Journal of Transplantation
IS - 12
ER -