The ability of pretransplant test-dose pharmacokinetic profiles to reduce early adverse events after renal transplantation.
Pretransplant test-dose pharmacokinetic profiles were used to determine individual cyclosporine drug bioavailability and clearance rates in renal transplant patients. Assuming a linear relation between dose and area under the concentration curve (AUC), starting i.v. and p.o. CsA doses were computed from the test-dose results. Target values were 400 ng/ml steady-state concentration (Css) during continuous intravenous infusion, and 500 ng/ml average drug concentration (Cavss = AUC/dosing interval) after oral administration, based upon measurements with the specific monoclonal antibody 3H-tracer radioimmunoassay. The outcomes after dose individualization with a 1-(n = 32), 2-(n = 38), or 3-(n = 41) hr i.v. infusion test dose and a p.o. test dose (n = 111) were compared with 228 historical control patients who received a uniform protocol of CsA i.v. at 2.5 mg/kg/day and p.o. at 14 mg/kg/day. The observed Css after i.v. CsA was within 10% of the target concentration in 73% of recipients tested with the 3-hr protocol, a significantly greater fraction than achieved with either the uniform dose (14%), or the 1-(34%) and 2-(25%) hr protocols. Patients in the 3-hr protocol group showed reduced incidences of delayed graft function, early graft loss, and rejection episodes, and a lower mean serum creatinine value, particularly at 7 but also at 30 days posttransplantation. Administration of the predicted oral dose produced a peak concentration of greater than or equal to 700 ng/ml drug absorption in 60% of recipients at 3 days, 90% at 5 days, and 98% at 7 days. The test-dose method less effectively predicted the appropriate oral CsA dose to produce target Cssav and failed to reduce the 90-day rejection incidence. Despite its limitations with the more-complicated p.o. route, the test-dose method successfully predicts i.v. CsA doses, thereby reducing the incidence of early adverse events.
Kahan
B D
BD
Department of Surgery, University of Texas Medical School, Houston 77030.
Welsh
M
M
Rutzky
L
L
Lewis
R
R
Knight
R
R
Katz
S
S
Napoli
K
K
Grevel
J
J
Van Buren
C T
CT
D000284:Administration, Oral; D000328:Adult; D001682:Biological Availability; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006084:Graft Rejection / Q000187:drug effects; D006801:Humans; D007275:Injections, Intravenous; D007408:Intestinal Absorption / Q000502:physiology; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D013997:Time Factors
D016572:Cyclosporine; D003404:Creatinine