Comparison of several approaches of therapeutic drug monitoring of cyclosporin A based on individual pharmacokinetics

AbstractObjective: The clinical outcome of patients after organ transplantation is correlated with cyclosporin A (CyA) exposure. It is generally accepted that the area under the concentration–time curve (AUC) provides a reliable means for drug exposure. However, in routine therapeutic drug monitoring (TDM) of CyA, trough levels are mostly used. Currently, a number of different new concepts of CyA-TDM, including approaches such as single, double or triple time-point and abbreviated AUC determinations, have been introduced. The purpose of this study was to compare the predictive value of the different strategies of TDM. Methods: Calculations were based on 40 individual concentration–time profiles after oral administration of CyA to patients who had been included into an ongoing prospective clinical trial. Non-compartmental analysis was used to calculate the AUC0–12h. Multiple linear regression was performed to describe the relationship between the different sets of blood concentrations and the respective AUC0–12h as well as to evaluate their predictive value regarding AUC. Predictive performance was assessed by prediction bias and prediction precision, which were estimated as the mean prediction error and root mean squared error, respectively. Results: When comparing the various combinations of time points, it was found that one-point approaches showed the strongest differences with regard to the predictive value; the associated r2 values differed from 0.203 to 0.792. The two and three time-point approaches showed lower differences – r2 0.802–0.972. The four-point and five-point approaches (r2 0.942–0.982) were the strongest predictors for CyA AUC0–12h. Relative bias ranged from −27.7% to 63.8% and changed significantly when multiple-point predictors were used. In those cases, the predictive performance improved. Considering the predictive performance as well as the smallest bias and highest prediction precision, C3, C1 + C3, C1 + C3 + C6 and C1 + C2 + C3 + C6 were the best predictors. Conclusion: The results of this study indicate that in kidney transplant patients a clinically sufficient precise estimation of the CyA AUC is possible using two or three concentration–time points.

[1]  D. Cooley,et al.  Analysis of pharmacokinetic profiles in 232 renal and 87 cardiac allograft recipients treated with cyclosporine. , 1986, Transplantation Proceedings.

[2]  B. Kahan,et al.  Optimization of cyclosporine therapy in renal transplantation by a pharmacokinetic strategy. , 1988, Transplantation.

[3]  R. Dahlqvist,et al.  A prospective study of cyclosporine concentration in relation to its therapeutic effect and toxicity after renal transplantation. , 1990, British journal of clinical pharmacology.

[4]  J. Kovarik,et al.  Within‐Day Consistency in Cyclosporine Pharmacokinetics from a Microemulsion Formulation in Renal Transplant Patients , 1994, Therapeutic drug monitoring.

[5]  S. Savoldi,et al.  Relationship of cyclosporine pharmacokinetic parameters to clinical events in human renal transplantation. , 1986, Transplantation proceedings.

[6]  B. Kahan,et al.  Cyclosporine Monitoring in Renal Transplantation: Area Under the Curve Monitoring Is Superior to Trough‐Level Monitoring , 1989, Therapeutic drug monitoring.

[7]  C. Marsh.  Abbreviated pharmacokinetic profiles in area-under-the-curve monitoring of cyclosporine therapy in de novo renal transplant patients treated with Sandimmune or Neoral. Neoral study group. , 1995, Therapeutic drug monitoring.

[8]  B. Kahan,et al.  Abbreviated AUC strategy for monitoring cyclosporine microemulsion therapy in the immediate posttransplant period. , 1996, Transplantation proceedings.

[9]  M. Oellerich,et al.  Lake Louise Consensus Conference on Cyclosporin Monitoring in Organ Transplantation: Report of the Consensus Panel , 1995, Therapeutic drug monitoring.

[10]  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.

[11]  R. Lechler,et al.  Do cyclosporin proffles provide useful information in the management of renal transplant recipients , 1996 .

[12]  R. Venkataramanan,et al.  Clinical Pharmacokinetics of Cyclosporin , 1986, Clinical pharmacokinetics.

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

[14]  J. Kovarik,et al.  Predicting patients’ exposure to cyclosporin , 1996 .

[15]  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.

[16]  D. Holt,et al.  A limited sampling strategy for the measurement of cyclosporine AUC. , 1990, Transplantation Proceedings.

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

[18]  N. Perico,et al.  Abbreviated kinetic profiles in area-under-the-curve monitoring of cyclosporine therapy. Technical note. , 1998, Kidney international.

[19]  D. Greenblatt.  Predicting steady state serum concentrations of drugs. , 1979, Annual review of pharmacology and toxicology.

[20]  J. Kovarik,et al.  Cyclosporine monitoring in patients with renal transplants: two- or three-point methods that estimate area under the curve are superior to trough levels in predicting drug exposure. , 1998, Therapeutic drug monitoring.

[21]  P. Keown,et al.  A Pharmacokinetic Study of Cyclosporin (Sandimmune®) , 1997 .

[22]  A Lindholm,et al.  Factors influencing the pharmacokinetics of cyclosporine in man. , 1991, Therapeutic drug monitoring.