Low intraindividual variability of cyclosporin A exposure reduces chronic rejection incidence and health care costs.
The present study applied a receiver operating characteristic (ROC) analysis to assess the role of intraindividual variability of cyclosporin A (CsA) drug exposure in predisposing renal transplant recipients to the occurrence of chronic rejection, as well as to increased health care costs using a resource-based economic analysis. Two hundred and four adult renal transplant recipients were treated with tapering doses of prednisone (Pred) and with a concentration-controlled strategy that selected doses of the olive oil-based formulations of CsA (Sandimmune(R)) that achieved target concentrations based on serial pharmacokinetic profiles. The ROC analysis revealed an inflection point of plots of the coefficient of variation (%CV) of CsA exposure versus the risk of chronic rejection at >/=28.4% for the average concentration (C(av)), i.e., the dosing interval-corrected area under the concentration-time curves, and >/=36% for the trough concentration (C(0)). The incidence of chronic rejection over a period of 5 yr was 24% among the less variable (LV) versus 40% among the variable (V) cohort. The economic analysis revealed that the total mean facility and physician costs per patient were $48,789 versus $60,998, respectively (P < 0.01). The degree of variability displayed by any individual could only be predicted by serial measurements of CsA concentrations, and not by demographic features, laboratory determinations, clinical characteristics, individual or mean values of any observed CsA concentration, or other pharmacokinetic parameters calculated following a single drug exposure. Thus, strategies that reduce intrapatient variability of CsA exposure over time may lead to reductions in chronic allograft loss and in treatment costs.
Kahan
Barry D
BD
Division of Immunology and Organ Transplantation, Department of Surgery, University of Texas Houston Health Science Center - Medical School, Houston, Texas.
Welsh
Maria
M
Division of Immunology and Organ Transplantation, Department of Surgery, University of Texas Houston Health Science Center - Medical School, Houston, Texas.
Urbauer
Diana L
DL
Biometrics Consulting, Houston, Texas.
Mosheim
Melinda B
MB
Division of Immunology and Organ Transplantation, Department of Surgery, University of Texas Houston Health Science Center - Medical School, Houston, Texas.
Beusterien
Kathleen M
KM
Covance Health Economics and Outcomes Services, Inc., Washington, DC.
Wood
Martha R
MR
Covance Health Economics and Outcomes Services, Inc., Washington, DC.
Schoenberg
Linda P
LP
Division of Immunology and Organ Transplantation, Department of Surgery, University of Texas Houston Health Science Center - Medical School, Houston, Texas.
Dicesare
Joseph
J
Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
Katz
Stephen M
SM
Division of Immunology and Organ Transplantation, Department of Surgery, University of Texas Houston Health Science Center - Medical School, Houston, Texas.
VAN Buren
Charles T
CT
Division of Immunology and Organ Transplantation, Department of Surgery, University of Texas Houston Health Science Center - Medical School, Houston, Texas.
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D019540:Area Under Curve; D015331:Cohort Studies; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006084:Graft Rejection / Q000188:drug therapy* / Q000378:metabolism*; D017048:Health Care Costs; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D011182:Postoperative Care / Q000191:economics*; D011241:Prednisone / Q000008:administration & dosage; D012372:ROC Curve; D012306:Risk; D012680:Sensitivity and Specificity; D018709:Statistics, Nonparametric
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D011241:Prednisone