Population pharmacokinetics of cyclosporine A in Japanese renal transplant patients: comprehensive analysis in a single center.

PURPOSE: Cyclosporine A (CyA), a potent immunosuppressive agent used in renal transplantation, has a narrow therapeutic window and a large variability in blood concentrations. This study aimed to develop a population pharmacokinetic (PPK) model of CyA in living-donor renal transplant patients at a single center and identify factors influencing CyA pharmacokinetics (PK). METHODS: A total of 660 points (preoperative) and 4785 points (postoperative) of blood concentration data from 98 patients who underwent renal transplantation were used. Pre- and postoperative CyA model structure and PPK parameters were separately estimated with a non-linear mixed-effect model, and subsequently, covariate analysis of postoperative data were comprehensively estimated, including preoperative PK parameters. RESULTS: A two-compartment model with first-order absorption and absorption lag time was selected in this study. Aspartate aminotransferase, body surface area (BSA), pretransplant area under the whole blood concentration-time curve/dose, and postoperative days were identified as the covariates on oral clearance. BSA was selected as a covariate of the distribution volume of the central compartment. In addition, diabetes mellitus was selected as a covariate of the first-order absorption rate. CONCLUSIONS: This PPK study used the largest number of blood concentration data among previous reports of living-donor renal transplant patients. Moreover, all patients received the same immunosuppressive regimen in a single center. Therefore, the validity of the selected covariates is reliable with high precision. The developed PPK model and selected covariates provide useful information about factors influencing CyA PK and greatly contributes to the identification of the most suitable dosing regimen for CyA.

Dose adjustment strategy of cyclosporine A in renal transplant patients: evaluation of anthropometric parameters for dose adjustment and C0 vs. C2 monitoring in Japan, 2001-2010.

The optimal use and monitoring of cyclosporine A (CyA) have remained unclear and the current strategy of CyA treatment requires frequent dose adjustment following an empirical initial dosage adjusted for total body weight (TBW). The primary aim of this study was to evaluate age and anthropometric parameters as predictors for dose adjustment of CyA; and the secondary aim was to compare the usefulness of the concentration at predose (C0) and 2-hour postdose (C2) monitoring. An open-label, non-randomized, retrospective study was performed in 81 renal transplant patients in Japan during 2001-2010. The relationships between the area under the blood concentration-time curve (AUC0-9) of CyA and its C0 or C2 level were assessed with a linear regression analysis model. In addition to age, 7 anthropometric parameters were tested as predictors for AUC0-9 of CyA: TBW, height (HT), body mass index (BMI), body surface area (BSA), ideal body weight (IBW), lean body weight (LBW), and fat free mass (FFM). Correlations between AUC0-9 of CyA and these parameters were also analyzed with a linear regression model. The rank order of the correlation coefficient was C0 > C2 (C0; r=0.6273, C2; r=0.5562). The linear regression analyses between AUC0-9 of CyA and candidate parameters indicated their potential usefulness from the following rank order: IBW > FFM > HT > BSA > LBW > TBW > BMI > Age. In conclusion, after oral administration, C2 monitoring has a large variation and could be at high risk for overdosing. Therefore, after oral dosing of CyA, it was not considered to be a useful approach for single monitoring, but should rather be used with C0 monitoring. The regression analyses between AUC0-9 of CyA and anthropometric parameters indicated that IBW was potentially the superior predictor for dose adjustment of CyA in an empiric strategy using TBW (IBW; r=0.5181, TBW; r=0.3192); however, this finding seems to lack the pharmacokinetic rationale and thus warrants further basic and clinical investigations.

Comparison of pharmacokinetics of cyclosporine A in cadaveric and living-related renal transplant recipients and in an experimental rat model of renal failure.

To elucidate the differences in the cyclosporine A (CyA) PK between cadaveric and living-related renal transplantation (CRT and LRT, respectively) recipients, a retrospective cohort study of clinical PK was conducted. Data from 80 patients who received LRT (n=75) and CRT (n=5) over 4 years were included. The incidence of acute rejection in CRT recipients was over 5 times higher than that in LRT recipients. On day 14 after transplantation, the area under the blood concentration versus time curve (AUC) per dose up to 4 h in CRT recipients was 65.3 % that of LRT recipients, however, there was no difference in the blood trough levels. Unlike LRT, renal failure derived from long ischemia time was observed in CRT recipients, and it is speculated that renal failure affects the PK of CyA. Moreover, we performed intravenous. (i.v.) and intraduodenal (i.d.) PK studies of CyA using renal failure model rats prepared by renal ischemia-reperfusion (RIR rats). There were no differences in PK profiles after i.v. administration of CyA between RIR and control rats; however, AUC up to infinity (1.81+/-0.18 microg.h/ml) in RIR rats after i.d. administration was significantly lower than in control rats (5.01+/-1.78 microg.h/ml). In addition, the absorption of CyA and midazolam, an ideal probe for CYP3A, from the intestinal loop in RIR rats was significantly less (69.8% and 42.8 %, respectively) than in control rats. These results suggest that the contribution of intestinal metabolism by CYP3A to decreasing CyA absorption in RIR rats is significant, namely, there is a possibility that the reason for poor absorption of CyA in CRT recipients is increasing intestinal CYP3A activity is maybe renal injury derived from long renal ischemia. The results of this study provide a useful information for therapeutic drug monitoring of CyA in CRT recipients.

Clinical pharmacokinetics of mycophenolate mofetil in Japanese renal transplant recipients: A retrospective cohort study in a single center.

Mycophenolate mofetil (MMF), a morpholinoethyl ester of mycophenolic acid (MPA), is currently widely used in organ transplantation as an immunosuppressant. The usefulness of therapeutic drug monitoring (TDM) of MPA after MMF dosing is not clear in Japanese renal transplant patients. In this study, to obtain more information for TDM of MPA, the association between MPA pharmacokinetic characteristics and the development of the side effects, and the effect of other concomitant immunosupressants such as cyclospoline A (CyA), tacrolimus (FK) and predonisolone (PSL) on MPA pharmacokinetics were investigated in detail. Moreover, the effects of enterohepatic recirculation (EHRA) on pharmacokinetic characteristics of MPA and the development of the side effects were also investigated. AUC(MPA)(0-9) with FK medication was 1.3-1.9 times higher than that with CyA medication, and the contribution to the plasma level of MPA of FK might be smaller than that of CyA, because EHRA inhibition by CyA was 2 times greater than that by FK. AUC(MPA)(0-9) was not influenced by PSL. The association between AUC(MPA)(0-9) and the development of the side effects was not observed; however, the development of side effects (leukopenia and diarrhea) in the EHRA group was 2 times higher than that in the non-EHRA group. These results suggested that TDM for MPA after MMF dosing was desirable in Japanease transplant patients. However, though not frequently, AUC obtained by multiple blood sampling after MMF dosing was needed. In addition, EHRA has led to increasing interest in MMF medication.

Effect of plasma lipid on pharmacokinetics of ciclosporin and its relationship with plasma prednisolone level in renal transplant patients.

Ciclosporin (cyclosporine A, CyA) is a potent immunosuppressant used after organ transplantation. The pharmacokinetic properties of CyA vary widely and lipoproteins are the major complexing constituents for CyA in the plasma. Therefore, a change in lipoprotein level may influence the pharmacokinetic properties of CyA. Prednisolone (PSL) is concomitantly used with CyA as an immunosuppressant. After organ transplantation, hyperlipidaemia resulting from PSL therapy has been mostly observed and PSL increased the plasma lipoprotein level. Therefore, in this study, to obtain more useful information of the therapeutic drug monitoring (TDM) of CyA, the relationship between the plasma PSL level, plasma lipoprotein level and blood CyA level was investigated in detail. An open-label, non-randomized, retrospective study was performed. Data from 21 male and 11 female patients (age 11-65 years) who received a living-related renal transplantation from 2002 to 2004 were included. On postoperative days (PODs) 7, 14 and 28, the area under the plasma concentration-time curve until 9 h after 40 mg of PSL administration (AUCPSL40(0-9)) correlated well with total cholesterol (T-cho) (r=0.558, 0.768, 0.660, all P<0.05) and high-density lipoprotein (HDL) (r=0.688, P<0.05; 0.835, P<0.01; 0.508, p<0.05), and correlated negatively with very-low-density lipoprotein (VLDL) (r=-0.486, p<0.01; -0.776, p<0.01; -0.967, p<0.01). In addition, AUC until 9 h after CyA administration (AUCCyA0-9) also correlated with T-cho (r=0.797, p<0.01; 0.577, p<0.05; 0.901, p<0.01), HDL (r=0.514, p<0.05; 0.614, p<0.05; 0.893, p<0.01) and low-density lipoprotein (LDL) (r=0.906, p<0.01; 0.573, p<0.05; 0.537, p<0.05), and there was a negative correlation with VLDL (r=-0.480, -0.630, -0.632, all p<0.05). Moreover, AUCCyA0-9 correlated well with AUCPSL40(0-9) (r=0.728, p<0.01; 0.482, p<0.05; 0.688, p<0.05); namely, it was considered that the variety of plasma PSL concentrations influenced the pharmacokinetic properties of CyA through the change in lipoprotein levels. These results suggested that monitoring of the biochemical parameters of the plasma lipid and plasma PSL level might be useful for the TDM of CyA.

Estimation of minimum whole-blood tacrolimus concentration for therapeutic drug monitoring with plasma prednisolone concentration: A retrospective cohort study in Japanese kidney transplant recipients.

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. OBJECTIVES: 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.