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.
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.
Mycophenolate mofetil (MMF), a morpholinoethyl ester of mycophenolic acid (MPA), is currently widely used in organ transplantation as an immunosuppressant to prevent acute and chronic rejection.1,2) MPA, a fermentation product of several Penicillium species, is a potent, noncompetitive, reversible inhibitor of eukaryotic inosine monophosphate dehydrogenases. MPA interferes with the de novo pathway of guanosine nucleotide synthesis and subsequently with DNA replication. The activity of MPA is highly specific for lymphocytes because their proliferation depends entirely on the de novo pathway for purine synthesis. 3,4) In immunosuppressive therapy after organ transplantation, therapeutic drug monitoring (TDM) of a calcineurin inhibitor, tacrolimus (FK) or cyclosporine A (CyA) is always needed, because of its narrow therapeutic range of blood concentration and various pharmacokinetic properties. However, a routine TDM for MPA after MMF dosing has not been recommended and empiric dosing was a common regimen for many institutions.Several studies concerning the relationship between MPA pharmacokinetics and clinical outcome have been performed in renal transplant patients. [5][6][7][8][9] These reports suggest that patients with low MPA AUC appeared to be at high risk for graft rejection. In Japanease renal transplant patients, Takahashi et al. reported an association between MPA AUC and the risk for acute rejection in a retrospective analysis of pharmacokinetic data.10) Recently, Okamoto, a coauthor of this article, reported a relationship between the pharmacokinetic characteristics of MPA, such as AUC MPA 0-9 , and acute rejection or the development of side effects, as observed at our institution.11) However, no reports have been published concerning the relationship between MPA pharmacokinetics and clinical outcome and the development of side effects in other Japanese renal transplant patients, to the best of our knowledge.On the other hand, many reports have examined the effects of concomitant immunosuppressants such as CyA or FK on MPA pharmacokinetics. 12-16) However, most of these reports concluded that further studies are needed to fully understand the effect of FK or CyA on MPA pharmacokinetics. In addition, such drug interaction has not been reported in Japanese transplant patients.In this study, to obtain more useful information for TDM of MPA after MMF dosing in Japanese renal transplant patients, the association between MPA pharmacokinetic characteristics and the development of side effects was investigated in detail. Moreover, the effect of other concomitant immunosupressants on MPA pharmacokinetics was also investigated.On the other hand, secondary elevation of MPA plasma level derived from enterohepatic recirculation (EHRA) has been reported [17][18][19] and this was also observed in our institution. There is a possibility that EHRA increases the exposure of drug to the intestine and elevates the trough plasma concentration of drugs during repeated administration. In addition, reduction or induction of E...
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.
The absorption of CyA was affected by plasma UA in transplant recipients and experimental rats. The contribution of intestinal metabolism by CYP3A to decreasing CyA absorption in HU rats was significant. These results suggest that transplant recipients with high UA may have poor absorption of CyA.
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