Approaching the therapeutic window for cyclosporine in kidney transplantation: a prospective study.
Neoral dosing is traditionally based on cyclosporine (CyA) trough levels (C(0)). Four-h area under the curve (AUC(0-4)) for Neoral in the early posttransplantation period was shown previously to have a better correlation to acute rejection (AR) and CyA nephrotoxicity (CyANT), compared with C(0). An AUC(0-4) range of 4400 to 5500 microg/h per L during the first week was associated with the lowest AR and CyANT. This article describes a prospective study to assess the feasibility, safety, and efficacy of dosing Neoral solely by AUC(0-4) monitoring, regardless of C(0), in the first 3 mo after kidney transplantation. Fifty-nine kidney transplant recipients received Neoral-based triple immunosuppression. AUC(0-4) was measured on days 3, 5, 7, 10, and 14 and weeks 3, 4, 6, and 8, then monthly. Target AUC(0-4) was 4400 to 5500 microg/h per L. Dose was adjusted by percentage difference from target AUC(0-4). Ninety-four percent of AUC were performed on the scheduled day or close to it. No patients had CyANT while AUC(0-4) was in target range. Four patients had reversible CyANT with AUC(0-4) > 5500. Only 1 of 33 patients (3%) who achieved and maintained AUC(0-4) > 4400 by day 3 posttransplantation had AR, whereas 10 of 22 (45%) of those with day 3 to 5 AUC(0-4) < 4400 had AR (P: = 0.0002). In logistic regression analysis, higher early AUC(0-4) was the only significant variable associated with lower serum creatinine at 3 mo. Neoral dose monitoring by AUC(0-4) is a potentially valuable tool for optimizing Neoral immunosuppression. Attainment of a target range of 4400 to 5500 microg/h per L for AUC(0-4) early after transplantation has been demonstrated to reduce significantly the risk of AR and CyANT.
Kidney Transplant Program and the Department of Urology, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada.
Kamran
K
Mahalati
Kidney Transplant Program and the Department of Urology, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada.
Philip
P
Belitsky
Kidney Transplant Program and the Department of Medicine, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada.
Kenneth
K
West
Kidney Transplant Program and the Department of Medicine, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada.
Bryce
B
Kiberd
Kidney Transplant Program and the Department of Pathology, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada.
Albert
A
Fraser
Kidney Transplant Program and the Department of Pharmacy, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada.
Ingrid
I
Sketris
Kidney Transplant Program and the Department of Surgery, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada.
Alan S
AS
Macdonald
Kidney Transplant Program and the Department of Surgery, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada.
Vivian
V
McAlister
Kidney Transplant Program and the Department of Urology, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada.
Joseph
J
Lawen
D000328:Adult; D019540:Area Under Curve; D016572:Cyclosporine / Q000009:adverse effects / Q000627:therapeutic use*; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects; D016030:Kidney Transplantation; D008099:Liver / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009420:Nervous System / Q000187:drug effects; D011184:Postoperative Period; D011446:Prospective Studies; D012449:Safety; D016896:Treatment Outcome
D007166:Immunosuppressive Agents; D016572:Cyclosporine