Pharmacokinetics of mycophenolic acid and its phenolic-glucuronide and ACYl glucuronide metabolites in stable thoracic transplant recipients

Mycophenolate mofetil is an immunosuppressant commonly used in solid organ transplantation. Its active metabolite, mycophenolic acid (MPA), is metabolized to the inactive 7-O-mycophenolic acid glucuronide (MPAG) and the active acyl glucuronide (AcMPAG). Most pharmacokinetic (PK) studies have been focused on MPA, but not its metabolites, in kidney transplant recipients. Pharmacokinetic studies of MPA and its metabolites in thoracic transplant recipients are scarce. Because neither the heart nor lung is involved in MPA metabolism or excretion, the thoracic transplant population may exhibit unique PKs. This open-label study aimed to characterize and compare PKs of MPA and its metabolites in stable lung or heart transplant recipients. Fifty thoracic (27 lung, 23 heart) transplant recipients were recruited. Subjects were also taking cyclosporine (11 lung, 14 heart) or tacrolimus (16 lung, nine heart), and prednisone (27 lung, one heart). Blood samples were obtained at 0, 20, 40, 60, and 90 minutes and 2, 4, 6, 8, 10, and 12 hours postdose. Plasma was used for drug level analysis (MPA, MPAG, and AcMPAG) by a high-performance liquid chromatography-ultraviolet detection method; in a subset of subjects, free MPA concentrations were also determined. Conventional PK parameters (dose-normalized) were determined by noncompartmental methods. There was wide interpatient variability of MPA, MPAG, and AcMPAG PKs with coefficients of variation exceeding 70% for most PK parameters measured. Other findings (P < 0.05) included: lower MPA area under the curve, maximum concentration, and minimum concentration; higher apparent clearance and MPAG/MPA metabolic ratio in the lung versus heart transplant group; lower MPA area under the curve and minimum concentration, and higher apparent clearance and MPAG/MPA metabolic ratio in lung transplant recipients concurrently taking cyclosporine versus tacrolimus; and lower minimum concentration in heart transplant recipients taking cyclosporine versus tacrolimus. Despite large interpatient variability in the PKs of MPA, MPAG, and AcMPAG among thoracic transplant recipients, there appear to be significant differences between lung and heart patients, which warrant further study.     

Pharmacokinetics of mycophenolic acid and metabolites in diabetic kidney transplant recipients

Mycophenolate mofetil (MMF), the prodrug of mycophenolic acid (MPA), is an immunosuppressive agent commonly used after organ transplantation. Because diabetes mellitus may affect disposition of pharmacologic agents, we investigated the influence of diabetes on the pharmacokinetics of MPA, unbound MPA (fMPA) and its phenyl and acyl glucuronide metabolites (MPAG and AcMPAG respectively). The study included 13 diabetic and 11 nondiabetic, stable, kidney-transplant recipients who were receiving a triple maintenance immunosuppressive regimen. Serial plasma samples were obtained predose and at regular intervals for 12 hours. Gastric emptying was assessed using an acetaminophen absorption test and glomerular filtration rate was estimated using iohexol clearance. Treatment groups were well matched. The time to maximum concentration (Tmax) of MPA was 86.4 +/- 41.4 minutes versus 52.8 +/- 31.8 minutes in D and ND patients respectively (P = 0.04) indicating a delay in MMF absorption. Neither the maximum MPA concentration nor the 0- to 12-hour area under the concentration-time curve were different. All parameters derived for fMPA and the MPA metabolites were comparable between the 2 groups, except for the metabolite ratio of MPAG and AcMPAG, which was higher for diabetic patients (P = 0.03). Delayed gastric emptying seemed to have reduced the initial rate but not the extent of MPA absorption in diabetic patients. The profiles of fMPA were similar in both patient groups. With the exception of metabolite concentration ratio, none of the other parameters associated with MPA metabolism were different between the 2 groups.     

Pharmacokinetic role of protein binding of mycophenolic acid and its glucuronide metabolite in renal transplant recipients

Mycophenolic acid (MPA), the active compound of mycophenolate mofetil (MMF), is used to prevent graft rejection in renal transplant recipients. MPA is glucuronidated to the metabolite MPAG, which exhibits enterohepatic recirculation (EHC). MPA binds for 97% and MPAG binds for 82% to plasma proteins. Low plasma albumin concentrations, impaired renal function and coadministration of cyclosporine have been reported to be associated with increased clearance of MPA. The aim of the study was to develop a population pharmacokinetic model describing the relationship between MMF dose and total MPA (tMPA), unbound MPA (fMPA), total MPAG (tMPAG) and unbound MPAG (fMPAG). In this model the correlation between pharmacokinetic parameters and renal function, plasma albumin concentrations and cotreatment with cyclosporine was quantified. tMPA, fMPA, tMPAG and fMPAG concentration–time profiles of renal transplant recipients cotreated with cyclosporine (n = 48) and tacrolimus (n = 45) were analyzed using NONMEM. A 2- and 1-compartment model were used to describe the pharmacokinetics of fMPA and fMPAG. The central compartments of fMPA and fMPAG were connected with an albumin compartment allowing competitive binding (bMPA and bMPAG). tMPA and tMPAG were modeled as the sum of the bound and unbound concentrations. EHC was modeled by transport of fMPAG to a separate gallbladder compartment. This transport was decreased in case of cyclosporine cotreatment (P < 0.001). In the model, clearance of fMPAG decreased when creatinine clearance (CrCL) was reduced (P < 0.001), and albumin concentration was correlated with the maximum number of binding sites available for MPA and MPAG (P < 0.001). In patients with impaired renal function cotreated with cyclosporine the model adequately described that increasing fMPAG concentrations decreased tMPA AUC due to displacement of MPA from its binding sites. The accumulated MPAG could also be reconverted to MPA by the EHC, which caused increased tMPA AUC in patients cotreated with tacrolimus. Changes in CrCL had hardly any effect on fMPA exposure. A decrease in plasma albumin concentration from 0.6 to 0.4 mmol/l resulted in ca. 38% reduction of tMPA AUC, whereas no reduction in fMPA AUC was seen. In conclusion, a pharmacokinetic model has been developed which describes the relationship between dose and both total and free MPA exposure. The model adequately describes the influence of renal function, plasma albumin and cyclosporine co-medication on MPA exposure. Changes in protein binding due to altered renal function or plasma albumin concentrations influence tMPA exposure, whereas fMPA exposure is hardly affected.     

Pharmacokinetics and protein adduct formation of the pharmacologically active acyl glucuronide metabolite of mycophenolic acid in pediatric renal transplant recipients

The acyl glucuronide metabolite (AcMPAG) of mycophenolic acid (MPA) has been found to possess both immunosuppressive and pro-inflammatory activity in vitro. In this study its pharmacokinetics were determined in pediatric renal transplant recipients receiving cyclosporine, steroids, and mycophenolate mofetil. Twelve-hour concentration-time profiles for AcMPAG, MPA, and the phenolic glucuronide (MPAG) were determined by high-performance liquid chromatography (HPLC) in the initial (1-3 wk; n = 16) and stable (3-12 mo; n = 22) phases after transplantation. In addition, the formation of covalent adducts between AcMPAG and plasma albumin (AcMPAG-Alb) was investigated using Western Blot analysis. AcMPAG-AUC(12h) showed significant (p < 0.05) correlations with MPA-AUC(12h) (r = 0.78) and MPAG-AUC(12h) (r = 0.78). In molar equivalents the median AcMPAG-AUC(12h) was 10.3% (range, 4.6%-45.5%) of MPA-AUC(12h). Values (median [range]) of AcMPAG-AUC(12h) (10.1 [3.30-30.1] mg.h/L), AcMPAG-C(0) (0.48 [0.08-1.43] mg/L), and AcMPAG-C(max) (1.95 [0.88-5.35] mg/L) were significantly (p < 0.05) higher in the stable phase than in the initial phase: 3.54 [2.07-20.0] mg.h/L for AUC(12h); 0.25 [<0.04-0.97] mg/L for C(0), and 1.12 [0.32-2.44] mg/L for C(max). The increases in the AcMPAG pharmacokinetic variables were paralleled by significant increases in the corresponding MPA variables. In addition, a strong negative correlation (r = -0.69; p < 0.05) was found between AcMPAG concentrations and the creatinine clearance. AcMPAG-Alb adducts were detected in all patient samples. They showed considerable interindividual variation and increased significantly with time from the initial phase to the stable phase. AcMPAG-Alb correlated significantly (p < 0.05) with AcMPAG-AUC(12h) (r = 0.70) and plasma albumin (r = 0.40). AcMPAG plasma concentrations are dependent on renal function, MPA disposition, and glucuronidation. The pharmacokinetics of AcMPAG is characterized by broad interindividual variation. In some patients AcMPAG may significantly contribute to the immunosuppression during mycophenolate mofetil therapy. AcMPAG-Alb adduct formation may serve as a marker for extended AcMPAG exposure. The association of AcMPAG with adverse effects must be further investigated.     

Time-dependent clearance of mycophenolic acid in renal transplant recipients

AIMS: Pharmacokinetic studies of the immunosuppressive compound mycophenolic acid (MPA) have shown a structural decrease in clearance (CL) over time after renal transplantation. The aim of this study was to characterize the time-dependent CL of MPA by means of a population pharmacokinetic meta-analysis, and to test whether it can be described by covariate effects. METHODS: One thousand eight hundred and ninety-four MPA concentration-time profiles from 468 renal transplant patients (range 1-9 profiles per patient) were analyzed retrospectively by nonlinear mixed effect modelling. Sampling occasions ranged from day 1-10 years after transplantation. RESULTS: The pharmacokinetics of MPA were described by a two-compartment model with time-lagged first order absorption, and a first-order term for time-dependent CL. The model predicted the mean CL to decrease from 35 l h(-1) (CV = 44%) in the first week after transplantation to 17 l h(-1) (CV = 38%) after 6 months. In a covariate model without a term for time-dependent CL, changes during the first 6 months after transplantation in creatinine clearance from 19 to 71 ml min(-1), in albumin concentration from 35 to 40 g l(-1), in haemoglobin from 9.7 to 12 g dl(-1) and in cyclosporin predose concentration from 225 to 100 ng ml(-1) corresponded with a decrease of CL from 32 to 19 l h(-1). Creatinine clearance, albumin concentration, haemoglobin and cyclosporin predose concentration explained, respectively, 19%, 12%, 4% and 3% of the within-patient variability in MPA CL. CONCLUSIONS: By monitoring creatinine clearance, albumin concentration, haemoglobin and cyclosporin predose concentration, changes in MPA exposure over time can be predicted. Such information can be used to optimize therapy with mycophenolate mofetil.     

霉酚酸在肝移植病人体内的药代动力学研究

目的研究免疫抑制剂霉酚酸酯(MMF)的活性代谢物霉酚酸(MPA)在肝移植病人体内的药代动力学。方法38例肝移植病人(男30例，女8例)术后早期按推荐剂量(每次1.0 g，每天两次)口服MMF达稳态，在给予一个早晨的剂量(1.0 g)后，在1个给药间隔内，于给药前及给药后不同时间点采血，用HPLC法测定MPA血药浓度，用3P97软件计算药代动力学参数。结果病人口服MMF后，血浆MPA浓度在给药后0.5～6.0 h内达峰值，部分病人在给药后4～12 h出现第2个小峰，血药峰浓度(C_max)和药-时曲线下面积(AUC_{0-12 h})均值分别为(12±7) μg·mL^-1和(44±16) μg·h·mL^-1，病人个体间存在较大差异。结论MPA在肝移植病人体内的药代动力学存在较大个体差异，提示在临床用药时需要监测MPA血药浓度，进行个体化给药。     

Lack of an effect of oral iron administration on mycophenolic acid pharmacokinetics in stable renal transplant recipients

STUDY OBJECTIVES: To determine if coadministration of polysaccharide iron complex and slow-release ferrous sulfate alter the absorption of mycophenolic acid (MPA), and to examine the potential influence of dosing relative to mycophenolate mofetil (MMF) administration and the effect of immediate- versus sustained-release iron products on the steady-state pharmacokinetics of MPA. DESIGN: Prospective, open-label, three-phase, crossover, steady-state pharmacokinetic study. SETTING: National Institutes of Health-sponsored General Clinical Research Center at a university medical center. PATIENTS: Twelve adult (mean age 50 yrs) renal transplant recipients who were receiving concomitant iron and MMF maintenance therapy. INTERVENTION: Oral iron therapy was coadministered with MMF on days -6-0, MMF was administered alone on days 1-8 (control phase), then oral iron therapy was administered 2 hours after MMF administration on days 9-16. MEASUREMENTS AND MAIN RESULTS: Baseline demographics, concurrent drug regimens, and clinical laboratory values were assessed. Blood samples were obtained at baseline and at 1, 2, 3, 4, 6, 8, and 12 hours after MMF administration on days 0, 8, and 16. The MPA levels were measured by high-performance liquid chromatography. We found no significant differences in the dose-standardized area under the concentration-time curve from 0-12 hours (AUC(0-12)) for MPA between the control phase (39.66 +/- 8.70 mg mg x hr/L) and the concomitant ferrous sulfate or dose-separated ferrous sulfate (37.56 +/- 9.95 or 32.84 +/- 8.43 mg x hr/L, respectively, p>0.05) phases. Dose-standardized AUC(0-12) values for MPA did not significantly differ after the concomitant administration of polysaccharide iron complex from that of the control phase (48.46 +/- 9.68 and 43.80 +/- 9.46 mg x hr/L, respectively, p=0.065). However, the AUC(0-12) for MPA significantly increased when polysaccharide iron complex was administered 2 hours after MMF (53.41 +/- 11.75 mg x hr/L, p=0.012). Maximum concentrations and times to reach maximum concentrations remained consistent across all study phases in each arm of the trial (p>0.05). CONCLUSION: Multiple doses of iron therapy-slow-release ferrous sulfate, or polysaccharide iron complex-did not significantly reduce systemic exposure to MMF, as measured by using AUC(0-12) values.     

霉酚酸在肝移植受者的药代动力学与药效学相关性研究

目的研究肝移植受者早期口服霉酚酸(免疫抑制剂)药代动力学与药效学的相关性。方法20例肝移植受者口服霉酚酸酯前、后,用酶增强免疫法测定患者血浆霉酚酸浓度。服药前(0h)及服药后1,2h,用患者血清处理人急性淋巴细胞白血病T淋巴(CEM)细胞,检测CEM细胞的增殖情况。结果口服霉酚酸酯前,CEM细胞增殖率显著高于服药后1,2h(P<0.05);服药后1,2h霉酚酸浓度与相应的CEM细胞增殖率呈负相关(P<0.05)。结论肝移植受者口服霉酚酸酯后,血清对CEM细胞的增殖产生显著抑制作用,其作用和霉酚酸浓度呈显著负相关。     

Pharmacokinetics and bioavailability of mycophenolic acid after intravenous administration and oral administration of mycophenolate mofetil to heart transplant recipients

The aim of this prospective study was to characterize the multiple-dose pharmacokinetics of mycophenolic acid (MPA) after administration of a 3-hour intravenous (IV) infusion of mycophenolate mofetil (MMF, CellCept) at a dose level of 1.5 g every 12 hours for 5 full days to cardiac allograft recipients and to compare the bioavailability of MPA after a switch from the IV infusion to an oral dose of 1.5 g every 12 hours from day 6. In addition to MMF, patients received cyclosporine and prednisolone. Blood (EDTA) samples for full pharmacokinetic profiles were obtained for 9 patients on days 3 and 5 (IV MMF) and on days 6 and 10 (oral MMF). They were centrifuged within 45 minutes of collection, and plasma was stabilized by addition of ortho-phosphoric acid to prevent in vitro conversion of MMF to MPA. Plasma concentrations of MPA were determined using a validated HPLC procedure. The median MPA AUC on day 6 (29.7 mg.h/L) after the first oral dose was slightly lower than the AUCs on the other study days (34.2, 33.8, and 33.8 mg.h/L on days 3, 5, and 10, respectively). Pairwise comparison of the individual days revealed statistically significant (P<0.05) differences between day 6 and day 3 and between day 5 and day 3. The Cmax on day 6 was significantly lower than that on study days 3 and 5. The bioavailability of MPA from the oral MMF formulation was estimated as the ratio of the AUC on day 6 or 10 to the AUC on day 5 when steady state was presumed to have been reached with the IV formulation. The mean ratios (expressed as percentage) for the log-transformed AUCs were 91.6% and 107.8% on days 6 and 10, respectively, relative to day 5. The 90% confidence interval (CI) on day 6 (79.3% to 105.8%) was marginally below the range (80%-125%) required to conclude that the formulations are bioequivalent, whereas on day 10 the 90% CI (93.3% to 124.7%) was within this range. In the case of the Cmax values, however, the 90% confidence intervals fell outside of this range (day 6, 57.2% to 92.8%; day 10, 70.6% to 114.9%). The results of this study show that heart transplant recipients receiving the IV formulation of MMF (1.5 g BID) are not subject to a greater drug exposure than that seen with the oral formulation (1.5 g BID) and that the oral MMF formulation shows excellent, high, and consistent bioavailability (mean 95%) based on comparison with the IV formulation.     

Population pharmacokinetics of mycophenolic acid and its glucuronide metabolite in lung transplant recipients with and without cystic fibrosis

1.?Cystic fibrosis (CF) is a disease affecting multiple organs that may reduce the systemic exposure of some drugs. The objective of this work was to characterize and compare the population pharmacokinetics (PK) of the immunosuppressant mycophenolic acid (MPA), and its glucuronide metabolite (MPAG) in adult lung transplant recipients with and without CF (NCF) following repeated oral administration of the prodrug mycophenolate mofetil (MMF).

2.?A population PK model was developed, with simultaneous modeling of MPA and MPAG, using nonlinear mixed effects modeling. MPA and MPAG serum concentration-time data were adequately described by a compartmental model including enterohepatic recirculation (EHR). Both MPA and MPAG apparent clearance values were significantly elevated (>65%) in patients with CF (24.1 and 1.95?L/h, respectively) compared to the values in the NCF patients (14.5 and 1.12?L/h, respectively), suggesting a notable influence of CF on MPA absorption and disposition.

3.?The population PK model developed from our study successfully characterized the absorption, distribution, elimination and EHR of MPA and the metabolite MPAG in lung transplant recipients with or without CF. This model may help to further understand the impact of CF to the overall clinical effects of MPA therapy including immunosuppression and gastrointestinal side effects.     

霉酚酸在肾移植病人术后首次给药和稳态后的药代动力学

目的 研究免疫抑制剂霉酚酸酯(MMF)的活性代谢产物霉酚酸(MPA)在肾移植病人首次给药和稳态后的药代动力学,评价其蓄积情况。方法选择肾移植病人8例(男3例,女5例),在术后第1天首剂服用MMF1g,按每次1g,每12h给药1次,连续服药7天达稳态,用高效液相色谱法测定MPA血药浓度,血药浓度数据用3P87药代动力学软件,按两室模型拟合并计算药代动力学参数。结果 首次服药及稳态后的药代动力学参数t1/2β分别为12.78±7.29和12.30±5.57 h(P>0.05);Cmax分别为14.29±6.85和19.72±5.83 mg·L-1(P<0.01);AUC0-12h分别为44.57±9.61和64.26±16.59 mg·h·L-1(P<0.01);CL(s)分别为15.51±2.53和11.16±3.53 L·h-1(P<0.01);稳态后,Cmax和AU0-12h与首次服药的比值分别为1.54±0.56和1.48±0.36,均增加了50％。结论MMF连续给药后,MPA在体内存在明显蓄积现象,临床用药时需要对MPA的血药浓度进行常规监测。     

Pharmacokinetics of mycophenolic acid and determination of area under the curve by abbreviated sampling strategy in Chinese liver transplant recipients

OBJECTIVES: This study aimed to: (i) define the clinical pharmacokinetics of mycophenolic acid (MPA) in Chinese liver transplant recipients; and (ii) develop a regression model best fitted for the prediction of MPA area under the plasma concentration-time curve from 0 to 12 hours (AUC(12)) by abbreviated sampling strategy. METHODS: Forty liver transplant patients received mycophenolate mofetil 1g as a single dose twice daily in combination with tacrolimus. MPA concentrations were determined by high-performance liquid chromatography before dose (C(0)) and at 0.5 (C(0.5)), 1 (C(1)), 1.5 (C(1.5)), 2 (C(2)), 4 (C(4)), 6 (C(6)), 8 (C(8)), 10 (C(10)) and 12 (C(12)) hours after administration on days 7 and 14. A total of 72 pharmacokinetic profiles were obtained. MPA AUC(12) was calculated with 3P97 software. The trough concentrations (C(0)) of tacrolimus and hepatic function were also measured simultaneously. Multiple linear regression analysis was used to establish the models for estimated MPA AUC(12). The agreement between predicted MPA AUC(12) and observed MPA AUC(12) was investigated by Bland-Altman analysis. RESULTS: The pattern of MPA concentrations during the 12-hour interval on day 7 was very similar to that on day 14. In the total of 72 profiles, the mean maximum plasma concentration (C(max)) and time to reach C(max) (t(max)) were 9.79 +/- 5.26 mg/L and 1.43 +/- 0.78 hours, respectively. The mean MPA AUC(12) was 46.50 +/- 17.42 mg . h/L (range 17.99-98.73 mg . h/L). Correlation between MPA C(0) and MPA AUC(12) was poor (r(2) = 0.300, p = 0.0001). The best model for prediction of MPA AUC(12) was by using 1, 2, 6 and 8 hour timepoint MPA concentrations (r(2) = 0.921, p = 0.0001). The regression equation for estimated MPA AUC(12) was 5.503 + 0.919 . C(1) + 1.871 . C(2) + 3.176 . C(6) + 3.664 . C(8).This model had minimal mean prediction error (1.24 +/- 11.19%) and minimal mean absolute prediction error (8.24 +/- 7.61%). Sixty-three of 72 (88%) estimated MPA AUC(12) were within 15% of MPA AUC(12). Bland-Altman analysis also revealed the best agreement of this model compared with the others and a mean error of +/-9.89 mg . h/mL. CONCLUSION: This study showed the wide variability in MPA AUC(12) in Chinese liver transplant recipients. Single timepoint MPA concentration during the 12-hour dosing interval cannot reflect MPA AUC(12). MPA AUC(12) could be predicted accurately using 1, 2, 6 and 8 hour timepoint MPA concentrations by abbreviated sampling strategy.     

Trough levels of mycophenolic acid and its glucuronidated metabolite in renal transplant recipients

OBJECTIVE: The prophylactic use of the immunosuppressant prodrug, mycophenolate mofetil (MMF) to prevent graft rejection in renal transplant patients is continuing to increase. We measured trough levels of the active metabolite, mycophenolic acid (MPA) and its inactive glucuronide (MPAG) in renal recipients with the aim of characterizing individual variability and of ascertaining factors influencing trough levels, in particular the effect of differences in renal function and the effect of drugs given concurrently. METHODS: Laboratory and clinical data obtained in 35 renal recipients treated with triple therapy (MMF, cyclosporin A (CsA), steroids) were included in this retrospective study. Trough levels of MPA and MPAG were obtained after transplantation and up to 16 months post transplantation where the mean observation period was 5.7 months. Plasma levels were measured using a validated HPLC assay. RESULTS: A total of 212 plasma concentrations of MPA and 209 of MPAG were measured. There was considerable intra- and interindividual variability in MPA and MPAG trough levels especially in the early post-transplantation phase. At a fixed dose of 2 g/d MMF, the mean MPA level during the first 30 days averaged 1.46 +/- 1.31 microg/ml vs. 1.87 +/- 0.89 microg/ml after 30 days and later (p = 0.130) and the mean MPAG concentration averaged 188.1 = 142.8 [microg/ml vs. 98.09 +/- 52.4 microlg/ml (p 0.003). The MPAG levels were positively correlated with the serum creatinine concentrations (r = 0.815, p < 0.001), and in the case of MPA there was a correlation with the serum protein concentrations (r = 0.258, p = 0.001). Concomitant drug treatment using CsA, steroids and furosemide were without effect of the measured plasma concentrations, but in the case of xipamide (+) and diltiazem (-) an effect on MPA and MPAG levels and a co-effect depending on the serum creatinine could not be excluded. Neither CsA trough levels nor hemoglobin levels were related to MPA and MPAG trough levels. CONCLUSIONS: The data of this study demonstrate that there is substantial individual variability in the trough levels of MPA and MPAG after renal transplantation which may be associated with the functional status of the graft and the serum protein level. Whether comedication with xipamide and diltiazem affects the plasma levels of MPA and MPAG remains to be clarified in further investigations.     

Adverse effects of mycophenolic acid in renal transplant recipients: gender differences

Background Mycophenolic acid is widely used immunosuppressive drug, associated with adverse effects which increase patient morbidity and decrease medication adherence. Objective To evaluate the adverse effects in renal transplant recipients under mycophenolate treatment with respect to gender. Setting University Clinical Centre of Nis, Clinic of Nephrology, Serbia. Method This research included 96 renal transplant recipients, who received immunosuppressive regimen, based on tacrolimus or cyclosporin A, prednisone and mycophenolic acid. The high-performance liquid chromatography method combined with protein precipitation was used for the analysis of mycophelate concentration in human plasma. Drug concentration and dose-adjusted concentration were determined with respect to the patients’ gender. An adverse effect scoring system developed by nephrologists within the University of Buffalo Nephrology/Transplant Program was used to monitor adverse effects of therapy. Main outcome measure Individual and scores of adverse effects in relation to the dosing regimen and gender. Results Results showed statistically lower dose and concentrations in men compared to the women in our investigation group. Also, female patients demonstrated higher mean scores (cumulative and subscores) within the same dosing regimens of mycophenolic acid. The gastrointestinal score was significantly higher in women who received a dose greater than 720 mg compared to men (0.20?±?0.12 vs 0.12?±?0.12). Women demonstrated higher individual adverse effects such as diarrhea and skin changes (41.7 vs 17.0; p?=?0.038 and 62.5 vs 30.2; p?=?0.037, respectively). Conclusions The results of our research showed that recipients’ gender may play an important role in pharmacokinetic profile of mycophenolic acid, suggesting that women had higher concentration of mycophenolic acid and more serious side effects.

     

Free mycophenolic acid should be monitored in renal transplant recipients with hypoalbuminemia

The current approach for therapeutic drug monitoring in renal transplant recipients receiving mycophenolate mofetil (MMF) is measurement of total mycophenolic acid (MPA) concentration. Because MPA is highly bound, during hypoalbuminemia the total concentration no longer reflects the free (pharmacologically active) concentration. The authors investigated what degree of hypoalbuminemia causes a significant change in protein binding and thus percentage free MPA. Forty-two renal transplant recipients were recruited for the study. Free and total concentrations of MPA (predose, and 1, 3, and 6 hours post-MMF dose samples) and plasma albumin concentrations were determined on day 5 posttransplantation. Six-hour area under the concentration-time curve (AUC(0-6)) values were calculated for free and total MPA, and percentage free MPA was determined for each patient. The authors found a significant relationship between low albumin concentrations and increased percentage free MPA (Spearman correlation = -0.54, P < 0.0001). Receiver operating characteristic (ROC) curve analysis was performed on the albumin versus percentage free MPA data. The cutoff value of albumin determined from the ROC analysis that differentiated normal from elevated percentage free MPA (defined as > or = 3%) in this patient population was 31 g/L. At this cutoff value albumin was found to be a good predictor of altered free MPA percentage, with a sensitivity and specificity of 0.75 and 0.80, respectively, and an area under the ROC curve of 0.79. To rationalize MMF dosing regimens in hypoalbuminemic patients (plasma albumin < or = 31 g/L), clinicians should consider monitoring the free MPA concentration.     

CEDIA mycophenolic acid assay compared with HPLC-UV in specimens from transplant recipients

Routine monitoring of mycophenolic acid (MPA) has been accepted as an essential tool in the management of this therapy in transplant recipients. The availability of simple, sensitive assays that measure MPA in plasma permits individualization of dosing regimens according to pharmacokinetic principles. We report the results of an evaluation of the CEDIA Mycophenolic Acid Immunoassay (Microgenics Corporation, Fremont, California) for the measurement of plasma MPA concentrations in a range of transplant indications and compare its performance and specificity to an established HPLC/UV method. Precision and accuracy were determined both within and between runs using the quality control materials provided with the CEDIA MPA assay, which produced within run (n = 21) coefficients of variation (CV%) and biases of less than 5%. The between run analyses, performed over consecutive days following daily calibration of the assay, showed CVs and biases of less than 7%. Routine patient samples (n = 298) from 142 patients of varying transplant type were analyzed using the CEDIA MPA kit and HPLC/UV methods. Regression analysis of the patient samples gave an equation of CEDIA = 1.18 HPLC/UV + 0.45 (r = 0.83). According to the manufacturer's product information, there is 192% cross reactivity with the active mycophenolate acyl glucuronide. The data presented suggest that the CEDIA MPA immunoassay, run on the Hitachi 911 analyzer, over-estimates plasma MPA concentrations with a magnitude that is influenced by transplant type. Hence, users must interpret the immunoassay results with caution and not assume that the metabolite fraction is constant in recipients of the same organ type or in different organ transplant populations.     

Limited sampling strategy for predicting area under the concentration-time curve of mycophenolic acid in adult lung transplant recipients

STUDY OBJECTIVE: To develop limited sampling strategies for estimation of mycophenolic acid exposure (by determining area under the concentration-time curve [AUC]) in lung transplant recipients by using sampling times within 2 hours after drug administration and a maximum of three plasma samples. DESIGN: Prospective, open-label clinical study. SETTING: Lung transplant clinic in Vancouver, British Columbia, Canada. PATIENTS: Nineteen adult (mean age 48.3 yrs) lung transplant recipients who were receiving mycophenolate mofetil therapy along with cyclosporine (9 patients) or tacrolimus (10 patients). INTERVENTION: Eleven blood samples were collected from each of the 19 patients over 12 hours: immediately before (0 hr) and 0.3, 0.6, 1, 1.5, 2, 4, 6, 8, 10, and 12 hours after administration of mycophenolate mofetil. MEASUREMENTS AND MAIN RESULTS: Mycophenolic acid levels in plasma were determined by a high-performance liquid chromatography-ultraviolet detection method. The 19 patients were randomly divided into index (10 patients) and validation (9 patients) groups. Limited sampling strategies were developed with multiple regression analysis by using data from the index group. Data from the validation group were used to test each strategy. Bias and precision of each limited sampling strategy were determined by calculating the mean prediction error and the root mean square error, respectively. The correlation between AUC and single concentrations was generally poor (r2= 0.18-0.73). Two single-concentration strategies, eight two-concentration strategies, and eight three-concentration strategies matched our criteria. However, the best overall limited sampling strategies (and their predictive performance) were the following: log AUC = 0.241 log C0 + 0.406 log C2 + 1.140 (bias -5.82%, precision 5.97%, r2= 0.828) and log AUC = 0.202 log C0 + 0.411 log C1.5 + 1.09 (bias -5.71%, precision 6.94%, r2= 0.791), where Cx is mycophenolic acid concentration at time x hours. CONCLUSION: Two-concentration limited sampling strategies provided minimally biased and highly precise estimation of mycophenolic acid AUC in lung transplant recipients. These optimal and most clinically feasible limited sampling strategies are based collectively on the number of blood samples required, r2 value, bias, and precision.     

Pharmacokinetics of mycophenolic acid in live donor liver transplant patients vs deceased donor liver transplant patients

The exposure of mycophenolic acid in live donor liver transplant patients (those receiving a partial hepatic volume) in comparison to deceased donor liver transplant patients (those receiving the whole hepatic volume) after administration of mycophenolate mofetil has not been reported earlier. The aim of the present study is to compare the pharmacokinetics parameters of mycophenolic acid and mycophenolic acid glucuronide in live donor liver transplant patients versus deceased donor liver transplant patients. Twelve live donor liver transplant and 12 deceased donor liver transplant recipients were studied over a dosing interval after intravenous administration of mycophenolate mofetil. The maximum concentration (Cmax) and the area under the plasma concentration versus time curve (AUC) for mycophenolic acid in live donor liver transplant patients were significantly higher than in deceased donor liver transplant patients (Cmax/AUC: live donor liver transplant patients: 16.1 +/- 6.6 microg/mL/43.9 +/- 12.6 microg/mL.h vs deceased donor liver transplant patients: 10.7 +/- 2.0 microg/mL/28.9 +/- 7.1 microg/mL.h; P = .046/.002). The volume of distribution was higher in the deceased donor liver transplant patients compared with live donor liver transplant patients. However, the mean plasma concentration at 12 hours (Clast), drug disposition rate constant, half-life (t 1/2), and mean residence time were similar in both groups. The mean plasma concentration of mycophenolic acid glucuronide was 1.4 to 2.0 times higher in deceased donor liver transplant patients compared with live donor liver transplant patients. These observations point to the need to use a lower dosage (approximately 30%) of mycophenolate mofetil in live donor liver transplant patients compared with deceased donor liver transplant patients.