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

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127 Citations (Scopus)


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 <0.001). AUC[0-4], capturing the drug absorption phase, represented 52% of the AUC[0-12] values across the four PK study days (mean R2>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 <0.001) from 753±202 at day 3 to 905±232 at day 7, 1080±330 at day 14 and 1521±316 by day 84, while the doseand weight-corrected AUC[0-12h] (DWC.AUC[0-12]) rose by over 80% (p <0.001) from 1477±3901 μg.h/L/ mg/kg on day 3, to 1721±426 on day 7, 2086±478 on day 14 and 2690±602 on day 84 (p <0.001). Relative CsA absorption varied over 5-fold between patients at day 3, but patients tended to remain within the same quartiles over time. Sparse-sample modeling identified optimum 3-point, 2-point and 1-point predictors for AUC[0-4] and AUC[0-12]. C2 was the most accurate and robust 1-point predictor for AUC[0-4] (mean R2: 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
Issue number2
Publication statusPublished - Feb 1 2002


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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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    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, J. P. (2002). Cyclosporine microemulsion (Neoral®) absorption profiling and sparse-sample predictors during the first 3 months after renal transplantation. American Journal of Transplantation, 2(2), 148-156.