The optimisation of cyclosporin therapy remains a challenge because of the very narrow therapeutic window and the highly variable pharmacokinetics of the drug. Therefore, there has been a concerted effort in the clinical transplant community to explore and test cyclosporin monitoring tools and techniques that will allow blood concentrations of cyclosporin to be maintained within the narrow therapeutic window in order to maximise efficacy and minimise toxicity.
Absorption profiling is a simple and accurate technique for adjusting dosages of cyclosporin microemulsion that utilises an estimation of the rate and extent of cyclosporin absorption in order to optimise immunosuppression in the individual patient. Two estimation tools in particular are an abbreviated area under the concentration-time curve (AUC) for the first 4 hours postdose and a single sampling point at 2 hours postdose. These 2 monitoring strategies have not only been validated as an accurate estimation of cyclosporin bioavailability but have been demonstrated to significantly improve clinical outcomes in patients compared with traditional trough concentration monitoring.
The evidence presented in this review demonstrates that absorption profiling results in the following clinical benefits compared with trough concentration monitoring: (i) reduced incidence of acute rejection; (ii) reduced severity of rejection episodes; (iii) reduced nephrotoxicity; and (iv) a rational basis for dosage adjustments.
The optimisation of immunosuppressive therapy continues to be a major priority in the management of the organ transplant recipient. Absorption profiling is a sensitive and practical approach for optimising the dosage of cyclosporin microemulsion, and can further extend the benefits of cyclosporin immunosuppression in the individual patient.
Lindholm A, Kahan BD. Influence of cyclosporine pharmacokinetics, trough concentrations, and AUC monitoring on outcome after kidney transplantation. Clin Pharmacol Ther 1993; 54: 205–18.PubMedCrossRefGoogle Scholar
Schroeder TJ, Hariharan S, First MR. Variations in bioavailability of cyclosporine and relationship to clinical outcome in renal transplant subpopulations. Transplant Proc 1995; 27: 837–9.PubMedGoogle Scholar
Kahan BD, Welsh M, Schoenberg L, et al. Variable oral absorption of cyclosporine: a biopharmaceutical risk factor for chronic renal allograft rejection. Transplantation 1996; 62: 599–606.PubMedCrossRefGoogle Scholar
Kahan BD. High variability of drug exposure: a biopharmaceutic risk factor for chronic rejection. Transplant Proc 1998; 30: 1639–41.PubMedCrossRefGoogle Scholar
Savoldi S, Maiorca R, Maderna M, et al. Low intrapatient variability of blood cyclosporine levels is correlated with excellent graft survival. Transplant Proc 1997; 29: 288–9.PubMedCrossRefGoogle Scholar
Best NG, Trull AK, Tan KK, et al. Pharmacodynamics of cyclosporine in heart and heart-lung transplant recipients. I: Blood cyclosporine concentrations and other risk factors for cardiac allograftrejection. Transplantation 1996; 62: 1429–35.PubMedCrossRefGoogle Scholar
Kahan BD, Dunn J, Fitts C, et al. Reduced inter- and intrasubject variability in cyclosporine pharmacokinetics in renal transplant recipients treated with a microemulsion formulation in conjunction with fasting, low-fat meals, or high-fat meals. Transplantation 1995; 59: 505–11.PubMedGoogle Scholar
Kovarik JM, Mueller EA, van Bree JB, et al. Reduced inter- and intraindividual variability in cyclosporine pharmacokinetics from a microemulsion formulation. J Pharm Sci 1994; 83: 444–6.PubMedCrossRefGoogle Scholar
Mahalati K, Belitsky P, Sketris I, et al. Neoral® monitoring by simplified sparse sampling area under the concentration-time curve: its relationship to acute rejection and cyclosporine nephrotoxicity early after kidney transplantation. Transplantation 1999; 68: 55–62.PubMedCrossRefGoogle Scholar
Mahalati K, Belitsky P, Kiberd B, et al. Absorption profiling: a novel method for monitoring Neoral in kidney transplantation that reduces rejection and nephrotoxicity [abstract]. Transplantation 2000; 69: S114.CrossRefGoogle Scholar
Barama AA, Yilmaz S, Gough J, et al. Lower cyclosporine exposure increases the risk for sub-clinical rejection in renal transplant recipients [abstract]. Transplantation 2000; 69: S225.CrossRefGoogle Scholar
Grant D, Kneteman N, Tchervenkov J, et al. Peak cyclosporine levels (Cmax) correlated with freedom from liver graft rejection: results of a prospective, randomized comparison of Neoral® and Sandimmune® for liver transplantation (NOF-8). Transplantation 1999; 67: 1133–7.PubMedCrossRefGoogle Scholar
Levy GA, Lake JR, Beauregard-Zollinger L, et al. Improved clinical outcomes for liver transplant recipients using cyclosporine blood level monitoring based on two-hour postdose levels. Transplantation 2000; 69: S387.CrossRefGoogle Scholar
Cantarovich M, Elstein E, de Varennes B, et al. Clinical benefit of Neoral® dose monitoring with cyclosporine 2-hr post-doselevels compared with trough levels in stable heart transplant patients [abstract]. Transplantation 1999; 68: 1839–42.PubMedCrossRefGoogle Scholar
Keiles A, Herman J, Tjandra-Maga TB, et al. Sandimmune® to Neoral® conversion and value of abbreviated AUC monitoring in stable pediatric kidney transplant recipients. Pediatr Transplant 1999; 3: 282–7.CrossRefGoogle Scholar
Cantarovich M, Besner J, Barkun J, et al. Two-hour cyclosporine level determination is the appropriate tool to monitor Neoral therapy. Clin Transplant 1998; 12: 243–9.PubMedGoogle Scholar
Halloran P. Calcineurin inhibition: relationship to cyclosporin blood concentration. In: Halloran PF, editor. New strategies for therapeutic drug monitoring of Neoral®. London: Blackwell Science Ltd, 1998: 15–8.Google Scholar
Halloran PF, Helms LM, Kung L, et al. The temporal profile of calcineurin inhibition by cyclosporine in vivo. Transplantation 1999; 68: 1356–61.PubMedCrossRefGoogle Scholar
Sindhi R, LaVia MF, Paulling E, et al. Stimulated response of peripheral lymphocytes may distinguish cyclosporine effect in renal transplant recipients receiving a cyclosporine + rapamycin regimen. Transplantation 2000; 69: 432–6.PubMedCrossRefGoogle Scholar
Johnston A, David OJ, Cooney GF. Pharmacokinetic validation of neoral absorption profiling. Transplant Proc 2000 May; 32(3A Suppl.): S53–6.CrossRefGoogle Scholar
Mendez R, Abboud H, Burdick J, et al. Reduced intrapatient variability of cyclosporine pharmacokinetics in renal transplant recipients switched from oral Sandimmune® to Neoral®. Clin Ther 1999; 21: 160–71.PubMedCrossRefGoogle Scholar
Cooney GF, Jeevanandam V, Choudhury S, et al. Comparative bioavailability of Neoral® and Sandimmune® in cardiac transplant recipients over 1 year. Transplant Proc 1998;30: 1892–4.PubMedCrossRefGoogle Scholar
Cantarovich M, Barkun JS, Tchervenkov JI, et al. Comparison of Neoral® dose monitoring with cyclosporine trough levels versus 2-hr postdose levels in stable liver transplant patients. Transplantation 1998; 66: 1621–7.PubMedCrossRefGoogle Scholar
Bilitsky T, Levy GA, Johnston A. Neoral absorption profiling: an evolution in effectiveness. Transplant Proc 2000; 32 Suppl. 3A: 45S–52S.CrossRefGoogle Scholar