Drug Monitoring Of Mycophenolic Acid Research Articles

Therapeutic Drug Monitoring of Mycophenolic Acid

Mycophenolic acid (MPA)-based therapies are widely used in combination with calcineurin inhibitors as maintenance immunosuppression for kidney transplant recipients (1). The two MPA therapies used in clinical transplantation are mycophenolate mofetil (MMF [brand name CellCept, Roche Pharmaceuticals, Nutley, NJ]) and mycophenolate sodium (MPS [brand name Myfortic, Norvartis Pharmaceuticals, Nutley, NJ]). MMF has been used for more than a decade and is a prodrug of MPA. The standard dosage of MMF in combination with cyclosporine (CsA) is 1 g given twice daily, although the dosage may be somewhat lower when co-administered with tacrolimus. MPS is an enteric coated form of MPA that was more recently introduced into the clinical arena. A dosage of 720 mg of MPS provides bioequivalence to a dosage of 1000 mg of MMF in kidney transplant patients (2). Immunosuppression afforded by MPA is achieved via reversible and uncompetitive inhibition of inosine monophosphate dehydrogenase (IMPDH), resulting in inhibition of guanine nucleotide biosynthesis (3,4). This consequently leads to suppression of both new DNA synthesis and other pathways that depend on a continuous supply of guanine nucleotide pool, such as T cell surface antigens and other glycosylated membrane proteins (4). Although there has been increased interest to incorporate MPA therapeutic drug monitoring into routine clinical practice (5–9), this has not yet become widespread in the United States for several possible reasons, including ( 1 ) lack of availability of US Food and Drug Administration–approved automated simple assays, ( 2 ) attainment of low rejection rates using empiric dosing of MMF in many maintenance immunosuppression regimens, ( 3 ) the complex pharmacokinetics (PK) of MPA, and ( 4 ) absence of overt organ toxicity. Here we discuss and review the pertinent information and study data regarding ( 1 ) our current understanding of MPA PK and major factors that can influence MPA clearance, ( 2 ) the performance …

Therapeutic drug monitoring of mycophenolic acid: does it improve patient outcome?

Treatment with the immunosuppressive agent mycophenolate mofetil (MMF) decreases the risk of rejection after renal transplantation and improves graft survival compared with azathioprine. The exposure to the active metabolite mycophenolic acid (MPA) is correlated to the risk of developing acute rejection. The interpatient variability in exposure of MPA is wide relative to the proposed therapeutic window of the MPA AUC0 – 12 (30 – 60 mg.h/l). The pharmacokinetics of MPA are influenced by patient characteristics such as gender, time after transplantation, serum albumin concentration, renal function, comedication and pharmacogenetic factors. Therapeutic drug monitoring is likely to reduce inter-patient variability. Limited sampling strategies are used to predict the full AUC0 – 12. Three prospective randomised studies compared concentration controlled MMF therapy to a fixed-dose regimen. Preliminary outcomes of these studies showed conflicting results and longer follow up is needed to further clarify the role of therapeutic drug monitoring in increasing the therapeutic potential of MMF.

Therapeutic Drug Monitoring of Mycophenolic Acid in Kidney Transplant Patients: A Abbreviated Sampling Strategy

Mycophenolic acid (MPA) levels have demonstrated a good correlation with clinical outcomes, but with great pharmacokinetic variability between patients. Therapeutic drug monitoring (TDM) is recommended to include a 12-hour area under the concentration–time curve (AUC). Since full AUC estimates are not practical for routine monitoring, limited sampling strategies have been suggested. We evaluated MPA pharmacokinetics in 18 stable renal transplant patients receiving mycophenolate mofetil (MMF) as part of their immunosuppressive therapy. The correlation between measured and estimated AUC was assessed using 4 different sparse sampling algorithms. The mean values for C 0 and AUC 0–6h were 1.8 ± 1.2 mg/L and 31.1 ± 14.8 mg*h/L, respectively. The dose-corrected AUC 0–6h was 35.4 ± 17.9 mg*h/L. Regarding the single time points, C 0 showed a low correlation with AUC 0–6h ( r 2 = .34); C 1.5, the best correlation ( r 2 = .72); and C 3, the worst ( r 2 = .07). Sparse sample algorithms used to estimate 12-hour AUC including C 0, C 1, C 2, C 3, C 4, and/or C 6 showed a good correlation with the calculated AUC 0–6 ( r 2 = .81–.96). The algorithm that used C 0, C 1, C 2, and C 4 showed the best correlation, but we also found a good correlation ( r 2 = .91) with C 0, C 1, and C 2. Based on these results, we have suggested using the 3-point algorithm (C 0, C 1, and C 2) for MPA TDM in stable renal transplant patients due to the good correlation with drug exposure and better functionality than an algorithm using a 4-hour postdose measurement.

Limited Sampling Strategy for the Estimation of Mycophenolic Acid Area Under the Plasma Concentration-Time Curve in Adult Patients Undergoing Liver Transplant

Mycophenolate mofetil (MMF), the oral prodrug of mycophenolic acid (MPA), is increasingly used in liver transplantation and plays a central role in the immunosuppressive regimen in liver transplantation. To study pharmacokinetic-pharmacodynamic relationships and therapeutic drug monitoring of MPA in the clinical setting, limited sampling strategies have been investigated for the estimation of MPA areas under the curves (AUCs). Thirty-eight adult patients undergoing liver transplant (31 males, seven females) receiving 1.0 g MMF twice daily and concomitant tacrolimus provided a total of 72 pharmacokinetic profiles. Multiple stepwise regression analysis was used to determine the algorithms for limited sampling strategies. Twenty-eight one-, two-, three-, and four-sampling estimation models were fitted (r = 0.288-0.964) to all the profiles using linear regression and were used to estimate MPA AUC0-12h comparing those estimates with the corresponding AUC0-12h values calculated with the linear trapezoidal rule, including all 10 timed MPA concentrations. The four-point estimates at C1h, C2h, C6h, and C8h resulted in the best correlation between estimated AUC and true AUC when using the formula AUC = 6.03 + 0.89C1h + 1.94C2h + 2.24C6h + 4.64 C8h (r = 0.911). Bland and Altman analysis revealed good agreement between estimated AUC and AUC from the full profile. This limited sampling strategy provides an effective approach for estimation of full MPA AUC0-12h in patients undergoing liver transplant receiving concomitant tacrolimus therapy.

Therapeutic Drug Monitoring of Mycophenolic Acid in Solid Organ Transplant Patients Treated With Mycophenolate Mofetil: Review of the Literature

Mycophenolate mofetil (MMF) has conventionally been administered at a fixed dose without routinely monitoring blood levels of mycophenolic acid (MPA), the active metabolite. The contribution of therapeutic drug monitoring (TDM) during MMF therapy remains controversial. A literature review was performed to explore the usefulness of TDM for MPA in solid organ transplantation. In addition, emphasis was placed on the potential clinical benefits and limitations of TDM for MPA. Available studies have limitations and report conflicting results. Although early after transplantation MPA area under the curve might have predictive value for the risk of acute rejection, predose levels appear less reliable. With regard to MPA toxicity, most studies showed no correlation between MPA pharmacokinetics and adverse effects. TDM is hampered by several factors such as the considerable intra-subject variability of MPA pharmacokinetics and the increasing number of different drug combinations. Proposed target ranges are restricted to the early posttransplant period when MMF is used in combination with cyclosporine. The current review of the literature indicates no clear support for a substantial clinical benefit of TDM and more data from prospective randomized trials are needed.

Therapeutic Drug Monitoring of Mycophenolic Acid Can Be Used as Predictor of Clinical Events for Kidney Transplant Recipients Treated With Mycophenolate Mofetil

Objective This study was designed to investigate the relationship between clinical events and the pharmacokinetics of mycophenolic acid (MPA) in adult renal transplant patients. Methods Thirty-seven adult kidney transplant recipients received a cyclosporine, mycophenolate mofetil, and steroids. MPA-AUC 0–12 was obtained before and 12 days after grafting by RP-HPLC. Predose blood samples were measured for MPA-C 0 were gathered from all the recipients at 4, 12, and 21 days as well as 1, 1.5, 2, 2.5, 3, and 6 months after grafting. The clinical events at corresponding time points were recorded to correlate with each MPA-C 0 value. Results In addition to single-dose and multidose MPA-AUC 0–12, 357 MPA-C 0 values were obtained from 37 patients. The 357 units were divided into three subgroups: group A patients, including 239 units (66.9%), experienced uneventful outcomes; group B of 100 units (28.0%) showed MPA-related side effects, and group C, 18 units (5.0%) of acute rejection episodes. MPA-C 0 for groups A, B, and C were 0.8416 ± 0.1373 mg/L, 1.5903 ± 0.3741 mg/L and 0.6057 ± 0.2338 mg/L, respectively ( P < .001 between groups A and B, groups B and C, and P = .021 between groups A and C). The three groups were also divided into an initial phase (≤1 month, 251 units) and a stable phase (>1 month, 106 units). The relationship between MPA-C 0 and associated clinical events was also investigated. Conclusion Our results suggested a relationship between MPA pharmacokinetics and clinical events. The MPA-C 0 might be an appropriate pharmacokinetic monitoring parameter for kidney transplantation.

Pharmacokinetics of Mycophenolic Acid and Its Glucuronidated Metabolites in Stable Lung Transplant Recipients

Mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil, an immunosuppressive agent commonly used in solid organ transplantation. MPA is metabolized to the inactive metabolite 7-O-mycophenolic acid glucuronide (MPAG) and the active metabolite acyl glucuronide (AcMPAG). Pharmacokinetic profiling of MPA by determining AUC is a tool for determining drug exposure. Many studies, conducted primarily in kidney and some heart and liver transplant recipients, have shown wide interpatient variability in MPA's pharmacokinetic parameters. There have been few studies in the lung transplant group and, even though the lung is not involved in drug elimination, these patients may have different MPA pharmacokinetic characteristics. To characterize the pharmacokinetic parameters and metabolic ratios of MPA in stable adult lung transplant recipients. In an open-label manner, lung transplant recipients were recruited. Blood samples were obtained at 0, 0.3, 0.6, 1, 1.5, 2, 4, 6, 8, 10, and 12 hours postdose. Plasma was separated and acidified for drug concentration analysis (MPA, MPAG, AcMPAG) by an HPLC-ultraviolet detection method. Conventional pharmacokinetic parameters were determined via noncompartmental methods. There was large interpatient variability in all pharmacokinetic parameters of MPA, MPAG, and AcMPAG. Similar variability was observed after stratifying patients into concomitant medication groups: cyclosporine and tacrolimus. There was a trend for the tacrolimus group to have a higher dose-normalized AUC, higher AUC, lower apparent clearance, and lower AUC ratio of AcMPAG/MPA compared with the cyclosporine group. In addition, the cyclosporine group had a lower minimum concentration and higher AUC ratio of MPAG/MPA than did the tacrolimus group (p < 0.05). Because of the large interpatient variability in the pharmacokinetic parameters of MPA, MPAG, and AcMPAG, therapeutic drug monitoring of MPA and its metabolites in lung transplant recipients may be beneficial.

Molecularly imprinted solid-phase extraction for rapid screening of mycophenolic acid in human plasma

A molecularly imprinted solid-phase extraction coupled with high performance liquid chromatography (MISPE–HPLC) method was developed for rapid screening of mycophenolic acid (MPA) in human plasma. MPA imprinted polymers (MPA-MIP) were synthesized and then tested for their performance both in organic and in aqueous solution. MPA was selectively trapped and preconcentrated on the MPA-MIP sorbent using different loading and washing conditions. The good selectivity of MPA-MIP enabled further clean-up of the interfering components in human plasma. For the proposed MISPE–HPLC method, the linearity between responses (peak area) and concentration was found over the range of 1–100 μg/ml with a linear regression coefficient ( R 2) of 0.9989. The limit of detection (LOD) and theoretical limit of quantification (LOQ) for MPA in plasma were 0.10 and 0.32 μg/ml, respectively. The precisions were 7.3, 3.5 and 4.7% RSD for intra-day assay and 9.2, 4.1 and 5.5% RSD for inter-day reproducibility, respectively, at three concentration levels of MPA in spiked plasma (1, 10 and 100 μg/ml). Both recoveries for the extraction (more than 74%) and for the analytical method (more than 87%) were acceptable for screening MPA in plasma samples. Twelve-hour pharmacokinetic profile of MPA for a renal transplant recipient receiving chronic oral dosing of 500 mg mycophenolate mofetil (MMF) was investigated. Results indicated that this method could be applied for therapeutic drug monitoring of mycophenolic acid in patient plasma.

Therapeutic drug monitoring of mycophenolic acid in cardiac transplant recipients: does it make sense?

Therapeutic drug monitoring of mycophenolic acid in cardiac transplant recipients: does it make sense?

Mycophenolic acid clinical pharmacokinetics influenced by a cyclosporine C2 based immunosuppressive regimen in renal allograft recipients

Therapeutic drug monitoring of mycophenolic acid (MPA) in combination with cyclosporine 2-h concentration (CsA C2, n = 68) or tacrolimus trough concentration (n = 10) was investigated by repeated measurements of MPA and MPA-glucuronide (MPAG) trough concentrations in renal allograft recipients during the first 3 months post-transplant. The acute rejection rate was lower (19% vs. 43%; P < 0.05) in patients achieving CsA C2 target range during the first week (1600-2000 microg/l), n = 26, compared with those who did not, n = 42. Median MPA concentration was 0.9 and 1.2 microg/ml in patients within or below C2 range, respectively (P = 0.19). CsA C2 correlated with MPAG-to-MPA ratio (P < 0.01, r = 0.91) and gamma-glutamyl-transpeptidase (GGT, P < 0.01, r = 0.86). Total MPA concentration increased during the 3 months, but not in patients on tacrolimus. High CsA C2 lowered the acute rejection rate and plasma MPA. High CsA C2 is associated with elevated GGT, probably because of cholestatic effects, which explain the increased MPAG-to-MPA ratio. Increasing MPA concentration is ascribed to per-protocol CsA C2 reductions. In conclusion, CsA may confound the relationship between MPA and the incidence of rejection, and contribute to the difficulty of obtaining a therapeutic range for MPA in clinical practice.

Predicting the Usefulness of Therapeutic Drug Monitoring of Mycophenolic Acid

The usefulness of therapeutic drug monitoring (TDM) of mycophenolate mofetil (MMF) was investigated with a computer simulation model. For a fixed-dose (FD) and a concentration-controlled (CC) MMF dosing regimen exposure to mycophenolic acid (MPA) was compared. A nonlinear mixed-effects model (NONMEM) for MPA based on extensive pharmacokinetic data from 140 renal transplant recipients who all used cyclosporine and corticosteroids as maintenance immunosuppressive therapy provided Bayesian estimates for MPA oral clearance on 9 occasions during the first 24 weeks after transplantation. In 45 of these patients, the estimates for MPA oral clearance were used to calculate values for the area under the curve (AUC) of MPA. In the CC group, MMF doses were adjusted based on the calculated AUC, targeting at an AUC level of 45 mg.h/L. In the FD group, MMF doses were fixed at 1000 mg. On day 7 after transplantation, significantly more AUC values were on target (AUC range 30-60 mg.h/L) in the CC group than in the FD group: 76% versus 13%, respectively, P < 0.001. To accomplish this, a doubling of MMF dose was necessary in more than half of the patients after the AUC assessment on day 3 after transplantation. Between-patient variability (BPV) in AUC (average CV% for all occasions) was reduced in the CC regimen: 23% versus 44% in the FD group. By using TDM, adequate MPA exposure appears to be obtained more rapidly, and BPV in exposure is reduced. To reach target AUC levels as soon as possible in this cyclosporine-treated population, it appears that larger MMF doses as currently recommended are necessary in the first month after transplantation.

Therapeutic Drug Monitoring of Mycophenolic Acid in Renal Transplant Recipients

Immunosuppressive regimens including mycophenolate mofetil (MMF, Cellcept) were used in a renal transplant transplant program since May 2000 including 67 patients in whom it was the primary drug. Acute rejection (AR) occurred in 9 cases (13%) with 1-year graft survival rate of 96.8%. Pharmacokinetic (PK) studies of mycophenolic acid (MPA) were performed in 46 recent patients (total, 127 times). There was no correlation between dose (mg/kg) and blood concentration (AUC 0–9: r 2 = 0.27). AUC 0–9 was well correlated with AUC 0–4 ( r 2 = 0.91), but not with a single timepoint concentration. MPA AUC 0–9 level was significantly higher among the AR-negative group (n = 33; 34.2 ± 16.8 ng · hr/mL) compared with AR-positive group (n = 3; 28.2 ± 1.9 ng · hr/mL; P = .04085) over the 2 weeks after transplantation. MPA AUC 0–9 level was higher among the adverse event (AE-positive) group (n = 15; 39.2 ± 22.8 ng · hr/mL) compared with the negative group (n = 21; 30.1 ± 8.0 ng · hr/mL; P = .08772) within 2 weeks after transplantation. These results suggest the necessity of measuring AUC for therapeutic drug monitoring (TDM) of MMF-containing immunosuppressive therapy. The possible target level of MPA AUC 0–9 would be approximately 30 ng · hr/mL using the present immunosuppressive regimen.

Mycophenolic Acid in Diabetic Renal Transplant Recipients

Limited sampling strategies may be useful in optimizing therapeutic drug monitoring of mycophenolic acid (MPA). Their use, however, may be limited by several patient factors, including comorbidity. In this study the pharmacokinetics of MPA in diabetic and nondiabetic renal transplant recipients were compared, and it was evaluated whether a limited sampling strategy developed and validated for nondiabetic patients can also be used in diabetic patients. The pharmacokinetics of MPA were analyzed on days 7 and 11 after transplantation in 136 renal transplant patients, among whom 7 patients had diabetes. All patients received cyclosporine and corticosteroids as maintenance immunosuppressive therapy. A limited sampling strategy [AUC (mg x h/L) = 7.182 + 4.607 C0 + 0.998 C0.67 + 2.149 C2] was developed and validated for nondiabetic patients and was subsequently tested for its usefulness in diabetic patients. Diabetic renal transplant patients did not have significantly different dose-normalized MPA area under concentration-time curve (AUC), MPA clearance, or MPA maximum concentration (Cmax). However, in diabetic patients Tmax (time of Cmax, 1.59 hours) was higher than for nondiabetic patients (0.67 hours) on day 11 (P = 0.04). The developed and validated limited sampling strategy performed acceptably, estimating MPA AUC in nondiabetic patients with a mean bias of 0.2 mg x h/L (95% confidence interval from -1.3 to 1.6 mg x h/L). Applying the limited sampling strategy in diabetic patients revealed a mean bias of -1.5 (-5.7, 2.7 mg x h/L). In conclusion, although diabetic renal transplant patients exhibit increased Tmax, this does not affect the accuracy of the limited sampling strategy.

Twelve-month evaluation of the clinical pharmacokinetics of total and free mycophenolic acid and its glucuronide metabolites in renal allograft recipients on low dose tacrolimus in combination with mycophenolate mofetil.

The establishment of a rationale for therapeutic drug monitoring for mycophenolic acid (MPA) and outlining a therapeutic window remains a challenging task in renal transplantation. Furthermore, the pharmacokinetic characteristics of free and total MPA and its glucuronides depend directly or indirectly on graft function and the type of co-administered calcineurin-inhibitor. The authors conducted a prospective 12-month multicenter pharmacokinetic study on MPA (MPA, free MPA, free fraction MPA) and its metabolites (MPAG, Acyl-MPAG). The aim of this study was to examine the long-term pharmacokinetic characteristics of MMF when combined with tacrolimus in renal allograft recipients and to identify a possible relationship between these pharmacokinetic parameters and clinical outcome parameters. They have demonstrated that in renal transplant recipients MPA, free MPA, Acyl-MPAG and MPAG have a particular pharmacokinetic profile when combined with tacrolimus which differs from the combination with CsA. They could not establish a relationship between pre-dose trough concentration of MPA and its metabolites and clinical efficacy endpoints and drug-related adverse events, except for anemia. These findings suggest that trough plasma concentration monitoring of MPA and its metabolites might not provide a useful clinical tool for guiding MMF dose adjustments to avoid drug-related toxicity. More extensive pharmacokinetic measurements like area under the concentration curves might be necessary for routine therapeutic drug monitoring of MMF.

Comparison of the Emit Immunoassay with HPLC for Therapeutic Drug Monitoring of Mycophenolic Acid in Pediatric Renal-Transplant Recipients on Mycophenolate Mofetil Therapy

HPLC is currently the preferred method for accurate measurement of mycophenolic acid (MPA). This study was designed to validate the Emit compared with HPLC in relation to clinical outcome measurements. Pediatric renal-transplant recipients (n = 50) on an immunosuppressive triple regimen consisting of cyclosporin A, prednisone, and mycophenolate mofetil (600 mg/m(2) twice per day) were investigated in an open-label prospective study. Pharmacokinetic profiles over 12 h were obtained at 1 week, 3 weeks, 3 months, and 6 months posttransplant. Plasma MPA was measured by both reversed-phase HPLC and the Emit immunoassay. There was an association between the risk of acute rejection episodes and low area under the curve values from t(0) to t(12h) (AUC(0-12)) for MPA (MPA-AUC(0-12)) or predose concentrations of MPA derived from both HPLC and Emit measurements. According to ROC analysis, an AUC value of 33.8 mg x h/L for MPA from t(0) to t(12h) (MPA-AUC(0-12)) determined by HPLC had a diagnostic sensitivity of 80% and a diagnostic specificity of 57%. The corresponding value of the Emit was 36.1 mg x h/L. For the predose concentration (MPA-c(12)), a concentration of 1.2 mg/L determined by HPLC and 1.4 mg/L determined by Emit gave a sensitivity of 80% and a specificity of 60%, respectively. There was no association of any pharmacokinetic variables derived from total MPA measurements with an increased risk of side effects related to mycophenolate mofetil. The Emit assay appears to have a comparable diagnostic efficacy to HPLC for assessing the risk of acute rejection in pediatric renal-transplant recipients. However, because of the cross-reactivity of the antibody used in the Emit assay with the active MPA acyl glucuronide metabolite, the decision thresholds for the Emit were higher than those calculated from HPLC measurements.

Current issues in therapeutic drug monitoring of mycophenolic acid: report of a roundtable discussion.

Current issues in therapeutic drug monitoring of mycophenolic acid: report of a roundtable discussion.

Pharmacokinetics and concentration-control investigations of mycophenolic acid in adults after transplantation.

Data have emerged that provide the scientific basis for therapeutic drug monitoring of mycophenolic acid (MPA) in transplant patients receiving mycophenolate mofetil (MMF), the parent drug, in combination with other immunosuppressive agents. There is a significant relationship between the dose-interval MPA AUC and risk for acute rejection based on retrospective investigations in renal and heart transplant patients and on prospective investigations in renal transplant patients. The MPA dose-interval AUC varies naturally by more than 10-fold in renal and heart transplant patients. Other significant sources of pharmacokinetic variability for MPA include the effects of concomitant medications, and the effects of disease states such as renal dysfunction and liver disease on the steady state MPA AUC. Individualized MMF dose evaluation, guided by MPA plasma concentrations, is becoming the standard of practice at a growing number of transplant centers worldwide because of these factors and because of the need to closely evaluate the immunosuppression afforded by MPA when a change in the immunosuppression regimen in stable transplant patients is planned. Investigations of therapeutic drug monitoring strategies with an emphasis on identifying an optimal abbreviated sampling strategy for MPA AUC estimation are ongoing. Based on the concentration-outcome studies and experience at the authors' institutions and other centers, the authors propose a set of therapeutic drug monitoring guidelines for MPA in stable renal and heart transplant patients for the immediate (first 3 months posttransplant) and maintenance (>3 months) periods. When MPA binding to human serum albumin is altered, as occurs in patients with significant renal dysfunction, liver disease, or a substantial reduction in human serum albumin concentration, the possibility of increased MPA free fraction and free concentration will need to be taken into account in the interpretation of MPA total concentrations.

Current opinions on therapeutic drug monitoring of immunosuppressive drugs

The pharmacokinetics of the immunosuppressive drugs cyclosporine, tacrolimus, mycophenolate mofetil (MMF), and sirolimus are complex and unpredictable. A narrow therapeutic index unique to each patient, as well as variable absorption, distribution, and elimination, are characteristics of these drugs. Therapeutic drug monitoring plays a key role in helping clinicians maintain blood and plasma levels of immunosuppressive drugs within their respective therapeutic ranges. Variation in concentrations outside the narrow therapeutic ranges can result in adverse clinical outcomes. Therapeutic drug monitoring ensures that concentrations are not too high or too low, thereby reducing the risks of toxicity or rejection, respectively. Therapeutic monitoring of immunosuppressive drugs has been based on several choices of assay and biologic fluid (ie, whole blood, plasma) appropriate for a particular drug. High-performance liquid chromatography (HPLC) remains the gold standard among assay methods used to monitor immunosuppressive drugs. Although HPLC is the assay of choice for cyclosporine, newer monoclonal assays are suitable as well for routine monitoring. HPLC is also widely used for therapeutic drug monitoring of mycophenolic acid, the active metabolite of MMF, and an immunoassay (used in European centers) has been developed. Therapeutic drug monitoring of tacrolimus has been improved with the recent development of assays with greater sensitivity and specificity for tacrolimus than those previously available. No commercial assays are currently available for the therapeutic monitoring of sirolimus. It is also important to identify a specific pharmacokinetic parameter for each individual drug, whether it is trough or area under the concentration-time curve, that may be most useful as a tool for optimal therapeutic drug monitoring in clinical practice. With an increased understanding of the pharmacokinetics of immunosuppressive drugs, therapeutic drug monitoring guidelines will be more clearly defined to ensure the safe and effective management of transplant recipients.

Stability of Mycophenolic Acid and Mycophenolic Acid Glucuronide in Human Plasma

Mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), is being used increasingly in immunosuppressant therapy after solid organ transplantation (1)(2)(3). Its immunosuppressive activity is thought to reside in the inhibition of inosine monophosphate dehydrogenase (IMPDH), leading to a suppression of purine nucleotide synthesis in lymphocytes, thereby suppressing cell mitosis (3)(4). MPA is converted in the liver mainly to the 7- O -glucuronide metabolite, mycophenolic acid glucuronide (MPAG), which does not have immunosuppressant activity (3)(5). During MMF therapy, MPAG peak concentrations observed in plasma of patients (5–600 mg/L) can be up to 300-fold higher than those of MPA (0.1–50 mg/L). Whether drug monitoring of MPA or MPAG is required to improve the therapeutic efficacy or to minimize adverse side effects is still under investigation (3)(6). For monitoring of MPA concentrations in human plasma, several HPLC procedures as well as one immunoassay (Emit; Behring-Syva) are available (3)(6). In the present investigation we addressed the question as to whether MPA and MPAG are stable in human plasma because it is possible that deglucuronidation of MPAG might take place in vitro during shipping and sample storage, thus leading to false high MPA concentrations. For this purpose, we added three different MPA and MPAG concentrations to three different pools of human plasma and followed both MPA and MPAG plasma concentrations for 7 days at three different storage temperatures. MPA and MPAG concentrations were measured using an HPLC method developed recently in our laboratory (7). For this study, MPA, MPAG, and the carboxy butoxy ether of MPA (MPAC) were a gift of Hoffmann-La Roche (Grenzach-Wyhlen, Germany). Sodium tungstate dihydrate, potassium dihydrogen phosphate, sodium hydroxide, phosphoric acid, and perchloric acid were from Merck. Acetonitrile (HPLC grade) was obtained from S.T. Baker …

Drug monitoring of mycophenolic acid in the early period after renal transplantation

Drug monitoring of mycophenolic acid in the early period after renal transplantation