Cyclosporine microemulsion (Neoral®) absorption profiling and sparse-sample predictors during the first 3 months after renal transplantation

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, J. P. Wauters

Research output: Contribution to journalArticle

127 Citations (Scopus)

Abstract

Recent data suggest that optimal cyclosporine (CsA) exposure early post-transplant significantly reduces the risk of acute graft rejection. They indicate that trough level monitoring is inadequate for precise concentration-controlled therapy, and suggest that absorption profiling may offer a superior approach for guiding clinical immunosuppression with Neoral. An international, prospective, multicenter study examined the feasibility, accuracy, precision and clinical utility of cyclosporine microemulsion (Neoral®) absorption profiling in de novo renal transplant recipients receiving basiliximab immunoprophylaxis and cyclosporine microemulsion maintenance immunosuppression. The nested pharmacokinetic study reported here was conducted in 4 study centers in which full (11-point) pharmacokinetic profiles were performed on days 3, 7, 14 and 84 post-transplant to examine absorption profile and absorption efficiency, and to determine optimal sparse-sampling pharmacokinetic methods to predict Neoral exposure. Twenty-four patients had complete 12-h pharmacokinetic (PK) data on all 4 sampling days. Area under the time-concentration curve (AUC) over the first 4 h of the 12-h dosage interval (AUC[0-4]) and AUC over the entire 12-h dosage interval (AUC[0-12]) reached 3803±1033 and 7462±2120 μg.h/L, respectively, by day 3, remained stable throughout the first 2 weeks, and declined to 2310±698 and 4062±1158 μg.h/L by day 84 (p 2>0.90). Between-patient variability was highest for CO and C1 (mean coefficient of variation [c.v.] 36-47%), and lower for C2 (mean c.v. 28%) and subsequent timepoints during the dosing interval. Mean relative CsA absorption, measured by dose- and weight-adjusted AUC[0-4] and AUC[0-12], increased significantly over time. The dose- and weight-corrected AUC[0-4h] (DWC.AUC[0-4]) rose by over 100% (p 2: 0.80), while C3 was superior for AUC[0-12] (mean R2: 0.75). CO was not a good predictor of either AUC[0-4] or AUC[0-12] (mean R2: 0.13 and 0.24, respectively). Conclusion: Absorption profiling defines the heterogeneity in CsA exposure and relative absorption posttransplant. A 2-h post-dose blood sample is the most consistent, accurate and robust single-point predictor of the absorption phase measured by AUC[0-4] and should replace trough level monitoring for accurate concentration-control of Neoral therapy in the clinical setting. The use of additional samples at 1 and 3h is more complex and costly, but increases prediction accuracy and may be valuable in selected patients with erratic absorption.

Original languageEnglish
Pages (from-to)148-156
Number of pages9
JournalAmerican Journal of Transplantation
Volume2
Issue number2
DOIs
Publication statusPublished - Feb 2002

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Kidney Transplantation
Cyclosporine
Area Under Curve
Pharmacokinetics
Carbon Monoxide
Immunosuppression
Transplants
Weights and Measures
Graft Rejection
Multicenter Studies
Maintenance
Prospective Studies
Kidney

Keywords

  • Absorption profiling
  • Basiliximab
  • Cyclosporine microemulsion (Neoral®)
  • Immune suppression
  • Kidney
  • Transplantation

ASJC Scopus subject areas

  • Immunology

Cite this

Cyclosporine microemulsion (Neoral®) absorption profiling and sparse-sample predictors during the first 3 months after renal transplantation. / 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.; Wauters, J. P.

In: American Journal of Transplantation, Vol. 2, No. 2, 02.2002, p. 148-156.

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 & Wauters, JP 2002, 'Cyclosporine microemulsion (Neoral®) absorption profiling and sparse-sample predictors during the first 3 months after renal transplantation', American Journal of Transplantation, vol. 2, no. 2, pp. 148-156. https://doi.org/10.1034/j.1600-6143.2002.020206.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. ; Wauters, J. P. / Cyclosporine microemulsion (Neoral®) absorption profiling and sparse-sample predictors during the first 3 months after renal transplantation. In: American Journal of Transplantation. 2002 ; Vol. 2, No. 2. pp. 148-156.
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abstract = "Recent data suggest that optimal cyclosporine (CsA) exposure early post-transplant significantly reduces the risk of acute graft rejection. They indicate that trough level monitoring is inadequate for precise concentration-controlled therapy, and suggest that absorption profiling may offer a superior approach for guiding clinical immunosuppression with Neoral. An international, prospective, multicenter study examined the feasibility, accuracy, precision and clinical utility of cyclosporine microemulsion (Neoral{\circledR}) absorption profiling in de novo renal transplant recipients receiving basiliximab immunoprophylaxis and cyclosporine microemulsion maintenance immunosuppression. The nested pharmacokinetic study reported here was conducted in 4 study centers in which full (11-point) pharmacokinetic profiles were performed on days 3, 7, 14 and 84 post-transplant to examine absorption profile and absorption efficiency, and to determine optimal sparse-sampling pharmacokinetic methods to predict Neoral exposure. Twenty-four patients had complete 12-h pharmacokinetic (PK) data on all 4 sampling days. Area under the time-concentration curve (AUC) over the first 4 h of the 12-h dosage interval (AUC[0-4]) and AUC over the entire 12-h dosage interval (AUC[0-12]) reached 3803±1033 and 7462±2120 μg.h/L, respectively, by day 3, remained stable throughout the first 2 weeks, and declined to 2310±698 and 4062±1158 μg.h/L by day 84 (p 2>0.90). Between-patient variability was highest for CO and C1 (mean coefficient of variation [c.v.] 36-47{\%}), and lower for C2 (mean c.v. 28{\%}) and subsequent timepoints during the dosing interval. Mean relative CsA absorption, measured by dose- and weight-adjusted AUC[0-4] and AUC[0-12], increased significantly over time. The dose- and weight-corrected AUC[0-4h] (DWC.AUC[0-4]) rose by over 100{\%} (p 2: 0.80), while C3 was superior for AUC[0-12] (mean R2: 0.75). CO was not a good predictor of either AUC[0-4] or AUC[0-12] (mean R2: 0.13 and 0.24, respectively). Conclusion: Absorption profiling defines the heterogeneity in CsA exposure and relative absorption posttransplant. A 2-h post-dose blood sample is the most consistent, accurate and robust single-point predictor of the absorption phase measured by AUC[0-4] and should replace trough level monitoring for accurate concentration-control of Neoral therapy in the clinical setting. The use of additional samples at 1 and 3h is more complex and costly, but increases prediction accuracy and may be valuable in selected patients with erratic absorption.",
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T1 - Cyclosporine microemulsion (Neoral®) absorption profiling and sparse-sample predictors during the first 3 months after renal transplantation

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 - Wauters, J. P.

PY - 2002/2

Y1 - 2002/2

N2 - Recent data suggest that optimal cyclosporine (CsA) exposure early post-transplant significantly reduces the risk of acute graft rejection. They indicate that trough level monitoring is inadequate for precise concentration-controlled therapy, and suggest that absorption profiling may offer a superior approach for guiding clinical immunosuppression with Neoral. An international, prospective, multicenter study examined the feasibility, accuracy, precision and clinical utility of cyclosporine microemulsion (Neoral®) absorption profiling in de novo renal transplant recipients receiving basiliximab immunoprophylaxis and cyclosporine microemulsion maintenance immunosuppression. The nested pharmacokinetic study reported here was conducted in 4 study centers in which full (11-point) pharmacokinetic profiles were performed on days 3, 7, 14 and 84 post-transplant to examine absorption profile and absorption efficiency, and to determine optimal sparse-sampling pharmacokinetic methods to predict Neoral exposure. Twenty-four patients had complete 12-h pharmacokinetic (PK) data on all 4 sampling days. Area under the time-concentration curve (AUC) over the first 4 h of the 12-h dosage interval (AUC[0-4]) and AUC over the entire 12-h dosage interval (AUC[0-12]) reached 3803±1033 and 7462±2120 μg.h/L, respectively, by day 3, remained stable throughout the first 2 weeks, and declined to 2310±698 and 4062±1158 μg.h/L by day 84 (p 2>0.90). Between-patient variability was highest for CO and C1 (mean coefficient of variation [c.v.] 36-47%), and lower for C2 (mean c.v. 28%) and subsequent timepoints during the dosing interval. Mean relative CsA absorption, measured by dose- and weight-adjusted AUC[0-4] and AUC[0-12], increased significantly over time. The dose- and weight-corrected AUC[0-4h] (DWC.AUC[0-4]) rose by over 100% (p 2: 0.80), while C3 was superior for AUC[0-12] (mean R2: 0.75). CO was not a good predictor of either AUC[0-4] or AUC[0-12] (mean R2: 0.13 and 0.24, respectively). Conclusion: Absorption profiling defines the heterogeneity in CsA exposure and relative absorption posttransplant. A 2-h post-dose blood sample is the most consistent, accurate and robust single-point predictor of the absorption phase measured by AUC[0-4] and should replace trough level monitoring for accurate concentration-control of Neoral therapy in the clinical setting. The use of additional samples at 1 and 3h is more complex and costly, but increases prediction accuracy and may be valuable in selected patients with erratic absorption.

AB - Recent data suggest that optimal cyclosporine (CsA) exposure early post-transplant significantly reduces the risk of acute graft rejection. They indicate that trough level monitoring is inadequate for precise concentration-controlled therapy, and suggest that absorption profiling may offer a superior approach for guiding clinical immunosuppression with Neoral. An international, prospective, multicenter study examined the feasibility, accuracy, precision and clinical utility of cyclosporine microemulsion (Neoral®) absorption profiling in de novo renal transplant recipients receiving basiliximab immunoprophylaxis and cyclosporine microemulsion maintenance immunosuppression. The nested pharmacokinetic study reported here was conducted in 4 study centers in which full (11-point) pharmacokinetic profiles were performed on days 3, 7, 14 and 84 post-transplant to examine absorption profile and absorption efficiency, and to determine optimal sparse-sampling pharmacokinetic methods to predict Neoral exposure. Twenty-four patients had complete 12-h pharmacokinetic (PK) data on all 4 sampling days. Area under the time-concentration curve (AUC) over the first 4 h of the 12-h dosage interval (AUC[0-4]) and AUC over the entire 12-h dosage interval (AUC[0-12]) reached 3803±1033 and 7462±2120 μg.h/L, respectively, by day 3, remained stable throughout the first 2 weeks, and declined to 2310±698 and 4062±1158 μg.h/L by day 84 (p 2>0.90). Between-patient variability was highest for CO and C1 (mean coefficient of variation [c.v.] 36-47%), and lower for C2 (mean c.v. 28%) and subsequent timepoints during the dosing interval. Mean relative CsA absorption, measured by dose- and weight-adjusted AUC[0-4] and AUC[0-12], increased significantly over time. The dose- and weight-corrected AUC[0-4h] (DWC.AUC[0-4]) rose by over 100% (p 2: 0.80), while C3 was superior for AUC[0-12] (mean R2: 0.75). CO was not a good predictor of either AUC[0-4] or AUC[0-12] (mean R2: 0.13 and 0.24, respectively). Conclusion: Absorption profiling defines the heterogeneity in CsA exposure and relative absorption posttransplant. A 2-h post-dose blood sample is the most consistent, accurate and robust single-point predictor of the absorption phase measured by AUC[0-4] and should replace trough level monitoring for accurate concentration-control of Neoral therapy in the clinical setting. The use of additional samples at 1 and 3h is more complex and costly, but increases prediction accuracy and may be valuable in selected patients with erratic absorption.

KW - Absorption profiling

KW - Basiliximab

KW - Cyclosporine microemulsion (Neoral®)

KW - Immune suppression

KW - Kidney

KW - Transplantation

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