Therapeutic monitoring of calcineurin inhibitors for the nephrologist.

The calcineurin inhibitors (CNI) cyclosporine and tacrolimus remain the backbone of immunosuppression for most kidney transplant recipients. Despite many years of experience, protocols that optimize efficacy with minimal toxicity remain a subject of debate. Nevertheless, studies of the pharmacokinetic properties of the CNI, particularly cyclosporine, have led to improved dosing strategies. The purpose of this article is to review the current understanding of CNI pharmacokinetics and its relevance to proper dosing and monitoring of these medications. This article also reviews the trials that have helped to define the optimal dosages and discusses the effect of adjunctive immunosuppressive agents on CNI pharmacokinetics and dosing.

[1]  J. Hooff,et al.  Effect of breakfast on the oral bioavailability of tacrolimus and changes in pharmacokinetics at different times posttransplant in renal transplant recipients. , 1998, Transplantation proceedings.

[2]  M. Franco,et al.  Concentration‐controlled use of sirolimus associated with reduced exposure of cyclosporine in black recipients of primarily living renal allograft donors: 12‐month results , 2005, Clinical transplantation.

[3]  C. Ponticelli,et al.  Everolimus and Reduced-Exposure Cyclosporine in de novo Renal-Transplant Recipients: A Three-Year Phase II, Randomized, Multicenter, Open-Label Study , 2004, Transplantation.

[4]  Barry D Kahan,et al.  Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study , 2000, The Lancet.

[5]  S. Chadban,et al.  Efficacy and Safety Outcomes Among De Novo Renal Transplant Recipients Managed by C2 Monitoring of Cyclosporine A Microemulsion: Results of a 12-Month, Randomized, Multicenter Study , 2005, Transplantation.

[6]  A. Webster,et al.  Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomised trial data , 2005, BMJ : British Medical Journal.

[7]  Po-Huang Lee,et al.  Clinical influencing factors for daily dose, trough level, and relative clearance of tacrolimus in renal transplant recipients. , 2000, Transplantation proceedings.

[8]  M. Schnitzler,et al.  Incidence of BK with Tacrolimus Versus Cyclosporine and Impact of Preemptive Immunosuppression Reduction , 2005, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[9]  A. Richens,et al.  Letter: Thymoxamine and spasticity. , 1974, Lancet.

[10]  H. Kirchner,et al.  Delayed cytokine mRNA expression kinetics after T-lymphocyte costimulation: a quantitative measure of the efficacy of cyclosporin A-based immunosuppression. , 2002, Clinical chemistry.

[11]  B. Kahan,et al.  Influence of cyclosporine pharmacokinetics, trough concentrations, and AUC monitoring on outcome after kidney transplantation , 1993, Clinical pharmacology and therapeutics.

[12]  G. Russ,et al.  Reduced and standard target concentration tacrolimus with sirolimus in renal allograft recipients. , 2003, Transplantation proceedings.

[13]  B. Kasiske,et al.  The relationship between cyclosporine pharmacokinetic parameters and subsequent acute rejection in renal transplant recipients. , 1988, Transplantation.

[14]  B. Kiberd,et al.  Adequate Early Cyclosporin Exposure is Critical to Prevent Renal Allograft Rejection: Patients Monitored by Absorption Profiling , 2002, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[15]  CONVERSION OF STABLE KIDNEY TRANSPLANT RECIPIENTS FROM A TWICE DAILY PROGRAF BASED REGIMEN TO A ONCE DAILY MODIFIED RELEASE TACROLIMUS BASED REGIMEN , 2004, Transplantation proceedings.

[16]  F. Oppenheimer,et al.  Double-blind comparison of two corticosteroid regimens plus mycophenolate mofetil and cyclosporine for prevention of acute renal allograft rejection. , 2000, Transplantation.

[17]  J. Kovarik,et al.  CYCLOSPORINE PHARMACOKINETICS AND VARIABILITY FROM A MICROEMULSION FORMULATION—A MULTICENTER INVESTIGATION IN KIDNEY TRANSPLANT PATIENTS , 1994, Transplantation.

[18]  B. Maes,et al.  The use of an anti‐CD25 monoclonal antibody and mycophenolate mofetil enables the use of a low‐dose tacrolimus and early withdrawal of steroids in renal transplant recipients , 2003, Clinical transplantation.

[19]  M. Castagneto,et al.  Results of a Three-Year Prospective Study of C2 Monitoring in Long-Term Renal Transplant Recipients Receiving Cyclosporine Microemulsion , 2005, Transplantation.

[20]  J. Gaynor,et al.  A Randomized Long-Term Trial of Tacrolimus/Sirolimus versus Tacrolimums/Mycophenolate versus Cyclosporine/Sirolimus in Renal Transplantation: Three-Year Analysis , 2006, Transplantation.

[21]  A. Monaco,et al.  Multicenter Randomized Prospective Trial of Steroid Withdrawal in Renal Transplant Recipients Receiving Basiliximab, Cyclosporine Microemulsion and Mycophenolate Mofetil , 2003, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[22]  N. Giannetti,et al.  Best single time points to predict the area-under-the-curve in long-term heart transplant patients taking mycophenolate mofetil in combination with cyclosporine or tacrolimus. , 2005, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[23]  P. Halloran,et al.  The temporal profile of calcineurin inhibition by cyclosporine in vivo. , 1999, Transplantation.

[24]  J. Schold,et al.  Sirolimus in Combination with Tacrolimus Is Associated with Worse Renal Allograft Survival Compared to Mycophenolate Mofetil Combined with Tacrolimus , 2005, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[25]  G. Knoll,et al.  Randomized, International Study of Cyclosporine Microemulsion Absorption Profiling in Renal Transplantation with Basiliximab Immunoprophylaxis , 2002, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[26]  B. Kiberd,et al.  Approaching the therapeutic window for cyclosporine in kidney transplantation: a prospective study. , 2001, Journal of the American Society of Nephrology : JASN.

[27]  Daniel C. Brennan,et al.  A Randomized, Prospective, Pharmacoeconomic Trial of Tacrolimus versus Cyclosporine in Combination with Thymoglobulin in Renal Transplant Recipients , 2005, Transplantation.

[28]  G. Borm,et al.  Steroid‐Withdrawal at 3 Days After Renal Transplantation with Anti‐IL‐2 Receptor α Therapy: A Prospective, Randomized, Multicenter Study , 2004, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[29]  A. Johnston,et al.  Pharmacokinetic validation of neoral absorption profiling. , 2000, Transplantation proceedings.

[30]  C. Shek,et al.  Abbreviated tacrolimus area-under-the-curve monitoring for renal transplant recipients. , 2000, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[31]  J. Barkun,et al.  Comparison of neoral dose monitoring with cyclosporine through levels versus 2-hr postdose levels in stable liver transplant patients. , 1998, Transplantation.

[32]  Joshua Miller,et al.  A Comparison Of Tacrolimus (fk506) And Cyclosporine For Immunosuppression After Cadaveric Renal Transplantation1 , 1997 .

[33]  M. Pescovitz,et al.  The safety and tolerability of cyclosporine emulsion versus cyclosporine in a randomized, double-blind comparison in primary renal allograft recipients , 1996 .

[34]  W. Weimar,et al.  Three‐Year Efficacy and Safety Results from a Study of Everolimus Versus Mycophenolate Mofetil in de novo Renal Transplant Patients , 2005, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[35]  J. McMichael,et al.  Stimulated response of peripheral lymphocytes may distinguish cyclosporine effect in renal transplant recipients receiving a cyclosporine+rapamycin regimen. , 2000, Transplantation.

[36]  U. Christians,et al.  Alternative cyclosporine metabolic pathways and toxicity. , 1995, Clinical biochemistry.

[37]  A. Forrest,et al.  The clinical impact of 1:1 conversion from Neoral to a generic cyclosporine (Gengraf) in renal transplant recipients with stable graft function , 2006, Clinical transplantation.

[38]  Julio Pascual,et al.  Everolimus with Optimized Cyclosporine Dosing in Renal Transplant Recipients: 6‐Month Safety and Efficacy Results of Two Randomized Studies , 2004, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[39]  D. Dunn,et al.  CYCLOSPORIN A INITIALLY AS THE ONLY IMMUNOSUPPRESSANT IN 34 RECIPIENTS OF CADAVERIC ORGANS: 32 KIDNEYS, 2 PANCREASES, AND 2 LIVERS , 1979, The Lancet.

[40]  S. Chadban,et al.  Clinical outcomes during the first three months posttransplant in renal allograft recipients managed by C2 monitoring of cyclosporine microemulsion , 2003, Transplantation.

[41]  H. Meier‐Kriesche,et al.  Sirolimus with Neoral Versus Mycophenolate Mofetil with Neoral is Associated with Decreased Renal Allograft Survival , 2004, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[42]  J. Wauters,et al.  Cyclosporine Microemulsion (Neoral®) Absorption Profiling and Sparse‐sample Predictors During the First 3 Months after Renal Transplantation , 2002, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[43]  F. Delmonico,et al.  A prospective, randomized clinical trial of cyclosporine reduction in stable patients greater than 12 months after renal transplantation , 2003, Transplantation.

[44]  C. Cantarell,et al.  Evaluation of a Limited Sampling Strategy to Estimate Area Under the Curve of Tacrolimus in Adult Renal Transplant Patients , 2005, Therapeutic drug monitoring.

[45]  J. Pringle,et al.  Differential effects of cyclosporin and tacrolimus on the expression of fibrosis‐associated genes in isolated glomeruli from renal transplants , 2000, The British journal of surgery.

[46]  U. Kunzendorf,et al.  Efficacy and safety of tacrolimus compared with cyclosporin A microemulsion in renal transplantation: 2 year follow-up results. , 2005, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[47]  J. D. de Fijter,et al.  Molecular comparison of calcineurin inhibitor-induced fibrogenic responses in protocol renal transplant biopsies. , 2006, Journal of the American Society of Nephrology : JASN.

[48]  B. Myers,et al.  Cyclosporine-associated chronic nephropathy. , 1984, The New England journal of medicine.

[49]  S. Busque,et al.  Canadian multicentre trial of tacrolimus/azathioprine/steroids versus tacrolimus/mycophenolate mofetil/steroids versus neoral/mycophenolate mofetil/steroids in renal transplantation. , 2001, Transplantation proceedings.

[50]  P. Halloran,et al.  Symphony - Comparing Standard Immunosuppression to Low-Dose Cyclosporine, Tacrolimus or Sirolimus in Combination With Mmf, Daclizumab and Corticosteroids in Renal Transplantation , 2006 .

[51]  J. D. de Fijter,et al.  AUC-guided dosing of tacrolimus prevents progressive systemic overexposure in renal transplant recipients. , 2005, Kidney international.

[52]  P. Fauchald,et al.  C2 monitoring in maintenance renal transplant recipients: is it worthwhile? , 2003, Transplantation.

[53]  S. Keam,et al.  Tacrolimus: a further update of its use in the management of organ transplantation. , 2003, Drugs.

[54]  C. Perry,et al.  Cyclosporin , 2012, Drugs.

[55]  M. Pescovitz,et al.  Two‐hour post‐dose cyclosporine level is a better predictor than trough level of acute rejection of renal allografts , 2002, Clinical transplantation.

[56]  J. Pirsch,et al.  A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 Kidney Transplant Study Group. , 1997, Transplantation.

[57]  L. Shaw,et al.  THERAPEUTIC DRUG MONITORING OF CYCLOSPORINE AND TACROLIMUS , 1998 .

[58]  C. Cardella,et al.  Clinical benefits of neoral C2 monitoring in the long-term management of renal transplant recipients1 , 2003, Transplantation.

[59]  N. Sinclair,et al.  IMMUNOLOGICAL AND PHARMACOLOGICAL MONITORING IN THE CLINICAL USE OF CYCLOSPORIN A , 1981, The Lancet.

[60]  J. Lake,et al.  Patient management by Neoral C2 monitoring: An international consensus statement1 , 2002, Transplantation.

[61]  J. Squifflet,et al.  Efficacy and cardiovascular safety of daclizumab, mycophenolate mofetil, tacrolimus, and early steroid withdrawal in renal transplant recipients: a multicenter, prospective, pilot trial , 2005, Clinical transplantation.

[62]  M. Schnitzler,et al.  Cyclosporine Minimization and Cost Reduction in Renal Transplant Recipients Receiving a C2-Monitored, Cyclosporine-Based Quadruple Immunosuppressive Regimen , 2004, Transplantation.

[63]  D. Urbauer,et al.  Variable oral absorption of cyclosporine. A biopharmaceutical risk factor for chronic renal allograft rejection. , 1996, Transplantation.

[64]  S. Roger,et al.  Assessment of the Bioequivalence of a Generic Cyclosporine A by a Randomized Controlled Trial in Stable Renal Recipients , 2006, Transplantation.

[65]  J. Barkun,et al.  Two-hour cyclosporine level determination is the appropriate tool to monitor Neoral therapy. , 1998, Clinical transplantation.

[66]  D. Hricik,et al.  Improved Renal Function after Conversion from Tacrolimus/Sirolimus to Tacrolimus/Mycophenolate Mofetil in Kidney Transplant Recipients , 2006, Transplantation.

[67]  N. Undre Pharmacokinetics of tacrolimus-based combination therapies. , 2003, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[68]  David B. Evans,et al.  Effect of dietary fat on the pharmacokinetics and pharmacodynamics of cyclosporine in kidney transplant recipients , 1995, Clinical pharmacology and therapeutics.

[69]  J. D. de Fijter,et al.  No difference in degree of interstitial Sirius red-stained area in serial biopsies from area under concentration-over-time curves-guided cyclosporine versus tacrolimus-treated renal transplant recipients at one year. , 2005, Journal of the American Society of Nephrology : JASN.

[70]  J. Alexander,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. , 1995, Transplantation.

[71]  N. Honcharik,et al.  The effect of food on cyclosporine absorption. , 1991, Clinical biochemistry.

[72]  A. Macdonald A WORLDWIDE, PHASE III, RANDOMIZED, CONTROLLED, SAFETY AND EFFICACY STUDY OF A SIROLIMUS/CYCLOSPORINE REGIMEN FOR PREVENTION OF ACUTE REJECTION IN RECIPIENTS OF PRIMARY MISMATCHED RENAL ALLOGRAFTS , 2001, Transplantation.

[73]  K. West,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. , 1999, Transplantation.

[74]  A. Angelini,et al.  C2 is superior to C0 as predictor of renal toxicity and rejection risk profile in stable heart transplant recipients , 2005, Transplant international : official journal of the European Society for Organ Transplantation.

[75]  A. Glanville,et al.  Cyclosporine C2 monitoring improves renal dysfunction after lung transplantation. , 2004, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[76]  R. Loertscher,et al.  Safety and tolerability of cyclosporine and cyclosporine microemulsion during 18 months of follow-up in stable renal transplant recipients: a report of the Canadian Neoral Renal Study Group. , 1998, Transplantation.

[77]  J. Squifflet,et al.  A three-arm study comparing immediate tacrolimus therapy with antithymocyte globulin induction therapy followed by tacrolimus or cyclosporine A in adult renal transplant recipients1 , 2003, Transplantation.

[78]  M. Pescovitz,et al.  The pharmacokinetics of a microemulsion formulation of cyclosporine in primary renal allograft recipients. The Neoral Study Group. , 1996, Transplantation.

[79]  P. Keown,et al.  Potential clinical implications of substitution of generic cyclosporine formulations for cyclosporine microemulsion (Neoral) in transplant recipients , 2004, European Journal of Clinical Pharmacology.

[80]  S. Chueh,et al.  Clinical application of sirolimus in renal transplantation: an update , 2005, Transplant international : official journal of the European Society for Organ Transplantation.

[81]  C. Shekhar,et al.  Comparison of generic cyclosporine microemulsion versus neoral in de novo renal transplant recipients managed by 2-hour postdose monitoring. , 2006, Transplantation proceedings.

[82]  B. Dréno,et al.  Effect of long-term immunosuppression in kidney-graft recipients on cancer incidence: randomised comparison of two cyclosporin regimens , 1998, The Lancet.

[83]  S. Mulgaonkar,et al.  Everolimus versus Mycophenolate Mofetil in the Prevention of Rejection in De Novo Renal Transplant Recipients: A 3-Year Randomized, Multicenter, Phase III Study , 2005, Transplantation.

[84]  J. Joh,et al.  Steroid withdrawal in living donor renal transplant recipients using tacrolimus and cyclosporine: a randomized prospective study * , 2006, Transplant international : official journal of the European Society for Organ Transplantation.

[85]  J. Rogers,et al.  Does Bioequivalence Between Modified Cyclosporine Formulations Translate into Equal Outcomes? , 2005, Transplantation.

[86]  J. Hooff,et al.  Low systemic exposure to tacrolimus correlates with acute rejection. , 1999, Transplantation proceedings.

[87]  P. Keown,et al.  Cyclosporine microemulsion increases drug exposure and reduces acute rejection without incremental toxicity in de novo renal transplantation. International Sandimmun Neoral Study Group. , 1998, Kidney international.

[88]  R. Margreiter Efficacy and safety of tacrolimus compared with ciclosporin microemulsion in renal transplantation: a randomised multicentre study , 2002, The Lancet.

[89]  B. Kiberd,et al.  Basiliximab lowers the cyclosporine therapeutic threshold in the early post‐kidney transplant period , 2005, Clinical transplantation.

[90]  L. Shaw,et al.  Therapeutic drug monitoring of cyclosporine and tacrolimus. Update on Lake Louise Consensus Conference on cyclosporin and tacrolimus. , 1998, Clinical biochemistry.

[91]  M. Borzi,et al.  C2 single-point sampling to evaluate cyclosporine exposure in long-term renal transplant recipients. , 2001, Transplantation proceedings.

[92]  I. Bekersky,et al.  Demographic considerations in tacrolimus pharmacokinetics. , 1998, Transplantation proceedings.

[93]  B. Dimitrov,et al.  Mycophenolate mofetil versus azathioprine for prevention of acute rejection in renal transplantation (MYSS): a randomised trial , 2004, The Lancet.

[94]  J. Murray,et al.  Inhibition of stimulated interleukin-2 production in whole blood: a practical measure of cyclosporine effect. , 1999, Clinical chemistry.

[95]  C. Cardella,et al.  A Comparison of the Effects of C2-Cyclosporine and C0-Tacrolimus on Renal Function and Cardiovascular Risk Factors in Kidney Transplant Recipients , 2006, Transplantation.

[96]  D. Rush,et al.  A randomized, prospective multicenter pharmacoepidemiologic study of cyclosporine microemulsion in stable renal graft recipients. Report of the Canadian Neoral Renal Transplantation Study Group. , 1996, Transplantation.

[97]  T. Giese,et al.  Pharmacodynamic Monitoring of Cyclosporine A in Renal Allograft Recipients Shows a Quantitative Relationship Between Immunosuppression and the Occurrence of Recurrent Infections and Malignancies , 2006, Transplantation.

[98]  D. Abramowicz,et al.  Tacrolimus Combined with Two Different Dosages of Sirolimus in Kidney Transplantation: Results of a Multicenter Study , 2006, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[99]  R. Moore,et al.  Prospective randomised study comparing tacrolimus (Prograf) and cyclosporin (Neoral) as primary immunosuppression in cadaveric renal transplants at a single institution: interim report of the first 80 cases , 1998, Transplant international : official journal of the European Society for Organ Transplantation.

[100]  B D Kahan,et al.  INDIVIDUALIZATION OF CYCLOSPORINE THERAPY USING PHARMACOKINETIC AND PHARMACODYNAMIC PARAMETERS , 1985, Transplantation.

[101]  M. Nicholson,et al.  Randomized clinical trial of the effect of microemulsion cyclosporin and tacrolimus on renal allograft fibrosis , 2003, The British journal of surgery.

[102]  M. Büchler,et al.  Review of the clinical experience with a modified release form of tacrolimus [FK506E (MR4)] in transplantation , 2006, Clinical transplantation.

[103]  K. Budde,et al.  Corticosteroid-Free Immunosuppression with Tacrolimus, Mycophenolate Mofetil, and Daclizumab Induction in Renal Transplantation , 2005, Transplantation.

[104]  R. Kershner,et al.  Relationship of FK506 whole blood concentrations and efficacy and toxicity after liver and kidney transplantation. , 1996, Transplantation.

[105]  G. Klintmalm,et al.  RESULTS OF LIS2T, A MULTICENTER, RANDOMIZED STUDY COMPARING CYCLOSPORINE MICROEMULSION WITH C2 MONITORING AND TACROLIMUS WITH C0 MONITORING IN DE NOVO LIVER TRANSPLANTATION , 2004, Transplantation.

[106]  D Talbot,et al.  Multicenter randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of renal allograft rejection: a report of the European Tacrolimus Multicenter Renal Study Group. , 1997, Transplantation.