title: Estimation of minimum whole-blood tacrolimus concentration for therapeutic drug monitoring with plasma prednisolone concentration: A retrospective cohort study in Japanese kidney transplant recipients.
abstract: BACKGROUND
  In immunosuppressive therapy administered after organ transplantation, therapeutic drug monitoring (TDM) of tacrolimus must be performed frequently because of the large variation in its pharmacokinetic properties and a progressive decrease in dose requirements. An indicator for estimating the target minimum whole-blood tacrolimus concentration (Cmin TAC) would be useful to minimize the number of blood samplings required for tacrolimus TDM.
  
  
  OBJECTIVE
  The primary objective of this study was to investigate whether plasma prednisolone concentration, postoperative days (POD) and AUC 0 to 9 hours before transplantation (AUC0-9int) are useful indicators of tacrolimus TDM. The secondary objective was to determine the usefulness of blood tacrolimus concentration as an indicator of the development of nontraumatic, glucocorticoid-induced necrosis of the femoral head, an adverse event that has been associated with the use of prednisolone in vivo.
  
  
  METHODS
  This open-label, nonrandomized, retrospective study was conducted at the Department of Transplantation and Regenerative Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan. Data from 43 male and 22 female patients (mean age, 38 years [range, 9-64 years]) who received a living-related kidney transplant from 2001 to 2004 were included. Multiple blood samplings were performed to determine AUC0-9int, AUC 0 to 9 hours after drug administration and after transplantation (AUC0-9), Cmin TAC, Cmax, and Tmax after transplantation. The correlations between each parameter were determined. The correlation between POD and the changes in tacrolimus bioavailability was investigated using the indicator, defined as the tacrolimus dose required to maintain the target (10-15 ng/mL) Cmin TAC (dose/C10-15). Correlations between dose/C10-15 and AUC0-9int (3 AUC0-9int groups, defined as follows: low, medium, and high [<93, ≧93-≤152, and ≧152 ng·h/mL, respectively]) were determined. Correlations between mean Cmin values of prednisolone at a dose of 40 mg on PODs 4 to 11 (Cmin PSL40) and Cmin TAC, or AUC0-9int were determined. A subanalysis was used to determine the relationship between dose/C10-15 and the prevalence of nontraumatic, glucocorticoid-induced necrosis of the femoral head.
  
  
  RESULTS
  Cmin TAC was found to be significantly correlated with AUC0-9int (r=0.554; P<0.001) and Cmin PSL40 (r=0.336; P<0.001). In the low-AUC0-9int group, dose/C10-15 was higher than that of the other groups (P<0.001). AUC0-9int was significantly correlated with Cmin PSL40 (r=0.445; P<0.001)). Dose/C10-15 in the patient group that had necrosis of the femoral head was lower than that of the group without necrosis (n=6; P<0.01).
  
  
  CONCLUSIONS
  The results of this small, retrospective study suggest that Cmin PSL40, AUC0-9int, and POD were significant predictors of Cmin TAC. These parameters were found to be a useful indicator of tacrolimus TDM in these Japanese transplant recipients. Our results also suggest that dose/C10-15 and AUC0-9int might be useful indicators for estimating the risk for nontraumatic, steroid-induced necrosis of the femoral head. (Curr Ther Res Clin Exp. 2006;67: 103-117) Copyright © 2006 Excerpta Medica, Inc.
authors.affiliation: Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto, Japan ; Department of Hospital Pharmacy, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Sugioka
authors.affiliation: Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Matsushita
authors.affiliation: Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Kokuhu
authors.affiliation: Department of Hospital Pharmacy, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.lastname: Bpharm
authors.affiliation: Department of Transplantation and Regenerative Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Okamoto
authors.affiliation: Department of Transplantation and Regenerative Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Yoshimura
authors.affiliation: Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: Yukako
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Department of Biopharmaceutics, Faculty of Pharmaceutical Science, Doshisha Women's College of Liberal Arts, Kyoto, Japan.
authors.forename: Nobuhito
authors.initials: N
authors.lastname: Shibata
authors.affiliation: Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: Kanji
authors.initials: K
authors.lastname: Takada
keywords: blood concentration; prednisolone; tacrolimus; therapeutic drug monitoring