Randomized, international study of cyclosporine microemulsion absorption profiling in renal transplantation with basiliximab immunoprophylaxis

Paul Keown, E. Cole, N. Muirhead, T. Romanet, F. Citterio, L. Bäckman, D. Del Castillo, Robert Balshaw, Hans Prestele, Lyse Beauregard-Zollinger, Sophie Fornairon, Gerard Murphy, F. Perner, A. Barama, E. Ancona, Tufveson, J. M. Tabernero, F. Ortega, M. Castagneto, P. RigottiG. Boschiero, P. Vialtel, G. Ancona, D. Casadei, Horvath, J. P. Wauters, P. Szenohradszky, G. Knoll, D. Uehlinger, D. Ludwin, C. Pouteil-Noble

Research output: Contribution to journalArticle

77 Citations (Scopus)

Abstract

Increasing information suggests that absorption profiling may be superior to trough level monitoring for optimal concentration control of cyclosporine microemulsion (Neoral™) therapy, and that CsA exposure early post-transplant may correlate significantly with reduced risk of acute graft rejection. This randomized, prospective, multicenter international concentration-controlled study was conducted in 21 renal transplant centers in 8 countries to test and compare the clinical feasibility, functionality, accuracy, precision and prediction of rejection by cyclosporine microemulsion absorption profiling to conventional trough-level drug monitoring. Primary or second renal allograft recipients treated with basiliximab, cyclosporine microemulsion and prednisone immunosuppression were randomized to two study groups in which cyclosporine microemulsion therapy was monitored using a multipointalgorithm or by trough levels. The two study arms were comparable in terms of baseline characteristics, treatment and clinical outcomes. Treatment failure, consisting of acute rejection, graft loss or death, occurred with equal incidence in the two groups (30% and 33%, respectively). Diagnostic feasibility, measured as the proportion of samples obtained within the designated time window, was marginally lower in area under the time-concentration curve (AUC) than in trough groups, but the therapeutic accuracy and precision were comparable or superior in the AUC group. Cox regression analysis performed across study groups showed a highly significant correlation between the predicted probability of acute rejection and cyclosporine (CsA) exposure measured by AUC over the entire 12-h dosage interval (AUC[0-12]) (p = 0.0068), AUC over the first 4 h of the 12-h dosage interval (AUC[0-4]) (p =0.0014) or 2 h post-dose (C2) CsA level (p =0.0027). Day 3 dose- and weight-corrected C2 values (EMIT equivalent) separated patients into low (350μg/L/mg/kg dose), defining those at greatest risk. Within these categories, C2 values above approximately 1500μg/L by day 3 post-transplant were associated with the lowest predicted probability of rejection. Comparable analysis by Cox regression using CO levels did notreach statistical significance. Absorption profiling is a feasible, accurate and precise method for monitoring cyclosporine microemulsion therapy in clinical practice and, as shown in the companion article, may be simplified by the use of single-point C2 concentrations which accurately predict individual AUC[0-4] exposure levels. Both cyclosporine microemulsion relative absorption (i.e. dose- and weight-corrected exposure) and CsA exposure (measured by predicted AUC or C2 levels) are closely correlated with the risk of rejection, and define patients at high and low risk of acute graft rejection. Trough (CO) levels are not closely correlated with either CsA exposure or rejection risk, and should not be considered reliable for monitoring cyclosporine microemulsion therapy.

Original languageEnglish
Pages (from-to)157-166
Number of pages10
JournalAmerican Journal of Transplantation
Volume2
Issue number2
DOIs
Publication statusPublished - Feb 2002

Fingerprint

Kidney Transplantation
Cyclosporine
Area Under Curve
Graft Rejection
Carbon Monoxide
Transplants
Regression Analysis
Implosive Therapy
Kidney
basiliximab
Weights and Measures
Drug Monitoring
Therapeutics
Prednisone
Treatment Failure
Immunosuppression
Allografts
Arm
Incidence

Keywords

  • Absorption profiling
  • Basiliximab
  • Cyclosporine microemulsion
  • Immune suppression
  • Kidney
  • Transplantation

ASJC Scopus subject areas

  • Immunology

Cite this

Randomized, international study of cyclosporine microemulsion absorption profiling in renal transplantation with basiliximab immunoprophylaxis. / Keown, Paul; Cole, E.; Muirhead, N.; Romanet, T.; Citterio, F.; Bäckman, L.; Del Castillo, D.; Balshaw, Robert; Prestele, Hans; Beauregard-Zollinger, Lyse; Fornairon, Sophie; Murphy, Gerard; Perner, F.; Barama, A.; Ancona, E.; Tufveson; Tabernero, J. M.; Ortega, F.; Castagneto, M.; Rigotti, P.; Boschiero, G.; Vialtel, P.; Ancona, G.; Casadei, D.; Horvath; Wauters, J. P.; Szenohradszky, P.; Knoll, G.; Uehlinger, D.; Ludwin, D.; Pouteil-Noble, C.

In: American Journal of Transplantation, Vol. 2, No. 2, 02.2002, p. 157-166.

Research output: Contribution to journalArticle

Keown, P, Cole, E, Muirhead, N, Romanet, T, Citterio, F, Bäckman, L, Del Castillo, D, Balshaw, R, Prestele, H, Beauregard-Zollinger, L, Fornairon, S, Murphy, G, Perner, F, Barama, A, Ancona, E, Tufveson, Tabernero, JM, Ortega, F, Castagneto, M, Rigotti, P, Boschiero, G, Vialtel, P, Ancona, G, Casadei, D, Horvath, Wauters, JP, Szenohradszky, P, Knoll, G, Uehlinger, D, Ludwin, D & Pouteil-Noble, C 2002, 'Randomized, international study of cyclosporine microemulsion absorption profiling in renal transplantation with basiliximab immunoprophylaxis', American Journal of Transplantation, vol. 2, no. 2, pp. 157-166. https://doi.org/10.1034/j.1600-6143.2002.020207.x
Keown, Paul ; Cole, E. ; Muirhead, N. ; Romanet, T. ; Citterio, F. ; Bäckman, L. ; Del Castillo, D. ; Balshaw, Robert ; Prestele, Hans ; Beauregard-Zollinger, Lyse ; Fornairon, Sophie ; Murphy, Gerard ; Perner, F. ; Barama, A. ; Ancona, E. ; Tufveson ; Tabernero, J. M. ; Ortega, F. ; Castagneto, M. ; Rigotti, P. ; Boschiero, G. ; Vialtel, P. ; Ancona, G. ; Casadei, D. ; Horvath ; Wauters, J. P. ; Szenohradszky, P. ; Knoll, G. ; Uehlinger, D. ; Ludwin, D. ; Pouteil-Noble, C. / Randomized, international study of cyclosporine microemulsion absorption profiling in renal transplantation with basiliximab immunoprophylaxis. In: American Journal of Transplantation. 2002 ; Vol. 2, No. 2. pp. 157-166.
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T1 - Randomized, international study of cyclosporine microemulsion absorption profiling in renal transplantation with basiliximab immunoprophylaxis

AU - Keown, Paul

AU - Cole, E.

AU - Muirhead, N.

AU - Romanet, T.

AU - Citterio, F.

AU - Bäckman, L.

AU - Del Castillo, D.

AU - Balshaw, Robert

AU - Prestele, Hans

AU - Beauregard-Zollinger, Lyse

AU - Fornairon, Sophie

AU - Murphy, Gerard

AU - Perner, F.

AU - Barama, A.

AU - Ancona, E.

AU - Tufveson,

AU - Tabernero, J. M.

AU - Ortega, F.

AU - Castagneto, M.

AU - Rigotti, P.

AU - Boschiero, G.

AU - Vialtel, P.

AU - Ancona, G.

AU - Casadei, D.

AU - Horvath,

AU - Wauters, J. P.

AU - Szenohradszky, P.

AU - Knoll, G.

AU - Uehlinger, D.

AU - Ludwin, D.

AU - Pouteil-Noble, C.

PY - 2002/2

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N2 - Increasing information suggests that absorption profiling may be superior to trough level monitoring for optimal concentration control of cyclosporine microemulsion (Neoral™) therapy, and that CsA exposure early post-transplant may correlate significantly with reduced risk of acute graft rejection. This randomized, prospective, multicenter international concentration-controlled study was conducted in 21 renal transplant centers in 8 countries to test and compare the clinical feasibility, functionality, accuracy, precision and prediction of rejection by cyclosporine microemulsion absorption profiling to conventional trough-level drug monitoring. Primary or second renal allograft recipients treated with basiliximab, cyclosporine microemulsion and prednisone immunosuppression were randomized to two study groups in which cyclosporine microemulsion therapy was monitored using a multipointalgorithm or by trough levels. The two study arms were comparable in terms of baseline characteristics, treatment and clinical outcomes. Treatment failure, consisting of acute rejection, graft loss or death, occurred with equal incidence in the two groups (30% and 33%, respectively). Diagnostic feasibility, measured as the proportion of samples obtained within the designated time window, was marginally lower in area under the time-concentration curve (AUC) than in trough groups, but the therapeutic accuracy and precision were comparable or superior in the AUC group. Cox regression analysis performed across study groups showed a highly significant correlation between the predicted probability of acute rejection and cyclosporine (CsA) exposure measured by AUC over the entire 12-h dosage interval (AUC[0-12]) (p = 0.0068), AUC over the first 4 h of the 12-h dosage interval (AUC[0-4]) (p =0.0014) or 2 h post-dose (C2) CsA level (p =0.0027). Day 3 dose- and weight-corrected C2 values (EMIT equivalent) separated patients into low (350μg/L/mg/kg dose), defining those at greatest risk. Within these categories, C2 values above approximately 1500μg/L by day 3 post-transplant were associated with the lowest predicted probability of rejection. Comparable analysis by Cox regression using CO levels did notreach statistical significance. Absorption profiling is a feasible, accurate and precise method for monitoring cyclosporine microemulsion therapy in clinical practice and, as shown in the companion article, may be simplified by the use of single-point C2 concentrations which accurately predict individual AUC[0-4] exposure levels. Both cyclosporine microemulsion relative absorption (i.e. dose- and weight-corrected exposure) and CsA exposure (measured by predicted AUC or C2 levels) are closely correlated with the risk of rejection, and define patients at high and low risk of acute graft rejection. Trough (CO) levels are not closely correlated with either CsA exposure or rejection risk, and should not be considered reliable for monitoring cyclosporine microemulsion therapy.

AB - Increasing information suggests that absorption profiling may be superior to trough level monitoring for optimal concentration control of cyclosporine microemulsion (Neoral™) therapy, and that CsA exposure early post-transplant may correlate significantly with reduced risk of acute graft rejection. This randomized, prospective, multicenter international concentration-controlled study was conducted in 21 renal transplant centers in 8 countries to test and compare the clinical feasibility, functionality, accuracy, precision and prediction of rejection by cyclosporine microemulsion absorption profiling to conventional trough-level drug monitoring. Primary or second renal allograft recipients treated with basiliximab, cyclosporine microemulsion and prednisone immunosuppression were randomized to two study groups in which cyclosporine microemulsion therapy was monitored using a multipointalgorithm or by trough levels. The two study arms were comparable in terms of baseline characteristics, treatment and clinical outcomes. Treatment failure, consisting of acute rejection, graft loss or death, occurred with equal incidence in the two groups (30% and 33%, respectively). Diagnostic feasibility, measured as the proportion of samples obtained within the designated time window, was marginally lower in area under the time-concentration curve (AUC) than in trough groups, but the therapeutic accuracy and precision were comparable or superior in the AUC group. Cox regression analysis performed across study groups showed a highly significant correlation between the predicted probability of acute rejection and cyclosporine (CsA) exposure measured by AUC over the entire 12-h dosage interval (AUC[0-12]) (p = 0.0068), AUC over the first 4 h of the 12-h dosage interval (AUC[0-4]) (p =0.0014) or 2 h post-dose (C2) CsA level (p =0.0027). Day 3 dose- and weight-corrected C2 values (EMIT equivalent) separated patients into low (350μg/L/mg/kg dose), defining those at greatest risk. Within these categories, C2 values above approximately 1500μg/L by day 3 post-transplant were associated with the lowest predicted probability of rejection. Comparable analysis by Cox regression using CO levels did notreach statistical significance. Absorption profiling is a feasible, accurate and precise method for monitoring cyclosporine microemulsion therapy in clinical practice and, as shown in the companion article, may be simplified by the use of single-point C2 concentrations which accurately predict individual AUC[0-4] exposure levels. Both cyclosporine microemulsion relative absorption (i.e. dose- and weight-corrected exposure) and CsA exposure (measured by predicted AUC or C2 levels) are closely correlated with the risk of rejection, and define patients at high and low risk of acute graft rejection. Trough (CO) levels are not closely correlated with either CsA exposure or rejection risk, and should not be considered reliable for monitoring cyclosporine microemulsion therapy.

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KW - Transplantation

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