title: Pretransplant test-dose pharmacokinetic profiles: cyclosporine microemulsion versus corn oil-based soft gel capsule formulation.
abstract: The purpose of this study was to compare the accuracy of pretransplant test-dose pharmacokinetic (PK) profiling after administration of the microemulsion (CsA-ME; Neoral) versus the corn oil-based (CsA-GC; Sandimmune) gel capsule formulations of cyclosporin A (CsA) to estimate posttransplant CsA bioavailability and to individualize starting drug doses. The absolute oral bioavailability (F), clearance rate (CL), average blood concentration (C[av]), peak concentration (Cmax), and time to Cmax (tmax) values were calculated from paired intravenous and oral pretransplant PK profiles of renal transplant candidates, using CsA-GC (n = 70) or CsA-ME (n = 70) administration. The initial posttransplant oral CsA dose was estimated by linear extrapolation of the observed pretransplant value to the target concentration. Because higher mean F (P < 0.0001), but not CL, values were observed in end-stage renal disease patients after CsA-ME compared with CsA-GC treatment, the predicted starting doses for each therapy were markedly different (P < 0.01). From posttransplant days 5 to 7, 54% of patients treated with CsA-ME had a mean dose-normalized C(av) (C(av)/dose, D) value within 20% of the target concentration, compared with 42% of patients treated with CsA-GC (P = 0.03). Administration of the predicted oral dose of CsA-ME produced a Cmax > 700 ng/ml in 90% of patients from days 2 to 4, and in 97% from days 5 to 7, whereas administration of the predicted oral dose of CsA-GC produced a Cmax > 700 ng/ml in only 64 and 82% of patients during these same time periods, respectively (both P < 0.05). The mean estimated posttransplant F value of CsA-ME was significantly higher than that of CsA-GC; even at postoperative day 5 the value for CsA-GC was significantly lower than the pretransplant estimate (P < 0.01). Therefore, CsA-ME pretransplant PK profiles yield more accurate predictions for appropriate starting drug doses than those of CsA-GC.
authors.affiliation: Department of Surgery, The University of Texas-Houston Medical School, 77030, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Chueh
authors.forename: B D
authors.initials: BD
authors.lastname: Kahan
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001682:Biological Availability; D044383:Black People; D001835:Body Weight; D002214:Capsules; D016009:Chi-Square Distribution; D015331:Cohort Studies; D003314:Corn Oil; D016572:Cyclosporine / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D004655:Emulsions; D005260:Female; D006630:Hispanic or Latino; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D011300:Preoperative Care; D013997:Time Factors; D044465:White People
chemical_list: D002214:Capsules; D004655:Emulsions; D003314:Corn Oil; D016572:Cyclosporine