Efficacy of area under the curve cyclosporine monitoring in renal transplantation.
Previous studies suggest that area-under-the-curve (AUC) pharmacokinetic monitoring is superior to trough level monitoring for proper cyclosporin A (CSA) dosing, but AUC monitoring is expensive and unwieldy. The utility of a simplified AUC monitoring method was evaluated for predicting AUC on the basis of three timed levels. CSA pharmacokinetic profiles were studied in 27 renal transplant patients at steady state early (days), late (months), and in some patients, serially posttransplantation. Whole-blood RIA levels were obtained at 2, 4, 6, 10, 12, 14, and 24 h after a once-daily CSA dose. The 6- and 24-h levels were the best single-level predictors of AUC (r = 0.77 and 0.76, respectively). The best model predictive of AUC curves used three time points at 2, 6, and 24 h postdose: AUC predicted = 8.6 x (24 h) + 1.4 x (2 h) + 6.2 x (6 h) + 1.57 mg x h/L; r2 = 0.986, P = 0.00001. The greatest pharmacokinetic variability occurred between 0 and 10 h postdose (absorption and distribution) between patients and even within individual patients monitored serially over time. The 12- to 24-h postdose portion (elimination) of the curve was consistently flat and uniform among patients. AUC were not consistent in individual patients over time. An AUC of more than 13 mg x h/L correlated with nephrotoxicity, whereas a value of 8 mg x h/L correlated with protection from rejection in first-transplant recipients. This AUC, however, was not able to prevent rejection in reengrafted or highly sensitized patients.
Meyer
M M
MM
Division of Nephrology, Hypertension and Clinical Pharmacology, Oregon Health Sciences University, Portland.
Munar
M
M
Udeaja
J
J
Bennett
W
W
D000328:Adult; D001774:Blood Chemical Analysis / Q000191:economics; D003365:Costs and Cost Analysis; D016572:Cyclosporine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D006084:Graft Rejection / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D016030:Kidney Transplantation / Q000009:adverse effects / Q000276:immunology / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D012086:Reoperation; D013997:Time Factors
D016572:Cyclosporine