title: A predictive model for area under the concentration versus time curve of cyclosporin A using several routine monitoring results in renal transplant patients.
abstract: We created a predictive model for the area under the concentration versus time curve (AUC) of cyclosporin A (CsA) using routine monitoring results, and examined its clinical utility. Based on 48 clinical time courses accumulated from renal transplant patients, the AUC predictive model was created. An estimate of the AUC0-8 (integrated from time zero to 8 h) was then given as follows: AUC0-8 = 5673.1 x log(TL) + 9342.8 x log(OB) + 64.1 x Dprd x 869.4 x DTK - 168.9 x HCT - 161.2 x SCr - 11.3 x GPT + 3.0 x PL - 588.6 x SEX - 24794.5. In this model, the AUC0-8(ng.h/ml) is given as a function of the CsA through levels (TL, ng/ml), obesity (OB, %), daily dose of prednisolone (Dprd, mg/d), donor type of kidney (DTK), hematocrit (HCT, %), serum creatinine (SCr, mg/dl), glutamate-pyruvate transaminase activity (GPT, IU/l), plasma lipids (PL, mg/dl) and sex distinction (SEX). The Statistical significance of the multiple regression was p < 0.00001 (R2 = 0.862, n = 48), and the day after transplantation, neither the administered oral dose of CsA, or the patient's age had any contribution to the regression. The predictive performance of this model was almost equal to that of the existing method which used 3-point data on the concentration versus time curve. In clinical adaptation for renal transplant patients, the steady-state concentration of CsA (Css) based on the AUC0-8 predictive model was significantly decreased during acute gastroenteritis or before acute rejection, whereas nephrotoxicity was increased, even though CsA trough levels were within a normal therapeutic range (100-200 ng/ml). These findings suggest that the created AUC0-8 predictive model using routine monitoring results, i.e., the trough level of CsA, biochemical tests, a daily dose of predorinsolone (PRD), and basic patient information, is convenient as a monitoring device for CsA therapy, and is satisfactory in clinical practice.
authors.affiliation: Department of Hospital Pharmacy, Shiga University of Medical Science Seta Tsukinowa Otsu, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Shibata
authors.forename: T
authors.initials: T
authors.lastname: Hayakawa
authors.forename: N
authors.initials: N
authors.lastname: Hoshino
authors.forename: T
authors.initials: T
authors.lastname: Minouchi
authors.forename: A
authors.initials: A
authors.lastname: Yamaji
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D016572:Cyclosporine / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics*; D016030:Kidney Transplantation / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D015999:Multivariate Analysis; D011237:Predictive Value of Tests; D011239:Prednisolone / Q000494:pharmacology
chemical_list: D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D011239:Prednisolone