Therapeutic drug measurement of mycophenolic acid derivatives in transplant patients (original) (raw)
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Clinical Biochemistry, 2001
Mycophenolate mofetil is widely used in combination with either cyclosporine or tacrolimus for rejection prophylaxis in renal and heart transplant patients. Although not monitored routinely nearly to the degree that other agents such as cyclosporine or tacrolimus, there is an expanding body of experimental evidence for the utility of monitoring mycophenolic acid, the primary active metabolite of mycophenolate mofetil, plasma concentration as an index of risk for the development of acute rejection. The following are important experimentally-based reasons for recommending the incorporation of target therapeutic concentration monitoring of mycophenolic acid: (1) the MPA dose-interval area-under-the-concentration-time curve, and less precisely, MPA predose concentrations predict the risk for development of acute rejection;
Therapeutic Monitoring of Mycophenolate Mofetil in Organ Transplant Recipients
Clinical Pharmacokinetics, 2002
M ycophenolate mofetil (MMF) has become the single most used immunosuppressant in solid-organ transplantation. Despite a well-documented relationship and efficacy (in terms of acute rejection prophylaxis) and exposure to mycophenolic acids (MPA) as measured by area under the curve (AUC), excellent results have been achieved using a fixed-dosage regimen. In the past several years, there has been an increased interest in the utility of monitoring MPA concentrations to both increase efficacy and decrease toxicity, particularly in many current drug minimization protocols.
Therapeutic Drug Monitoring of Mycophenolic Acid
Clinical Journal of the American Society of Nephrology, 2007
M ycophenolic 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 characteristics of MPA analysis methods and prospects for more widespread availability of simple automated methods, (3) results and limitations of clinical outcome studies in renal transplant patients, (4) the status of ongoing prospective trials to evaluate various concentration-control approaches for dosing MMF in renal transplant patients under a variety of contemporary maintenance immunosuppression protocols, and (5) suggested rationale and guidelines for monitoring MPA. Renal and Liver Dysfunction Kidney or liver disease can influence clearance by increasing the free fraction of MPA. Thus in kidney recipients who receive concomitant CsA and have poor renal function in the first days after transplant surgery, there can be a two-to threefold increase in the free fraction (12). It is important to appreciate that
Journal of Chromatography B-analytical Technologies in The Biomedical and Life Sciences, 2007
Background and objective: Difference in the hydrophilic properties of mycophenolic acid metabolites makes it technically difficult to simultaneously determine their plasma levels in one analytical run. Therapeutic drug monitoring (TDM) for MPA ensures adequate MPA exposure levels to both prevent rejection and avoid related toxicity. One measure limitation for TDM for MPA is the availability of simple, rapid and reproducible method for determination of MPA derivatives. Method: Herein we report a single method to measure MPA and its metabolites using a gradient elution system in less than 10 min. We further tested applicability of our method in both stable and unstable renal transplant recipients with a wide range of levels. Results: Intra-and inter-day imprecision were less than 8% and 10%, respectively. Accuracy of the estimated concentrations ranges from 90% to 108%. Conclusion: Collectively these data show that the new method is reasonably accurate and precise for the simultaneous determination of MPA and its metabolites in human plasma.
Transplantation Proceedings, 2004
Background: Mycophenolate mofetil (MMF) is widely used in organ transplantation to prevent acute rejection. Because MMF can produce hematologic and/or gastrointestinal toxicity, therapeutic monitoring is becoming mandatory. This study was designed to investigate the relationship between the clinical events and the pharmacokinetics of mycophenolic acid (MPA) in adult renal transplantation. Methods: Thirty-one adult kidney recipients were prospectively included in the study. MPA pharmacokinetic profiles (blood sampling at 0, 0.5, 1, 2, 4, 6, and 12 h after MMF oral dose) were obtained after transplantation (desired creatinine clearance, 40 mL/min), at 3 months after grafting, and at every clinical event (e.g., side effect or rejection). All patients received a 10-day course of anti-thymocyte globulin, cyclosporine, MMF (1 g twice daily), and steroids. Results: We divided the 31 patients into two groups (groups 1 and 2). Ten patients (32%; group 1) had uneventful outcomes, and 21 patients (68%; group 2) presented with MPA-related side effects. For groups 1 and 2, the MPA trough concentrations (C min) were 1.63 ؎ 1.07 and 2.29 ؎ 1.16 mg/L, respectively (P ؍ 0.06), and the areas under the curve (AUCs) for MPA from t 0 to t 12 h (MPA-AUC 0-12h) were 39.80 ؎ 15.29 and 62.10 ؎ 21.07 mg ⅐ h/L, respectively (P ؍ 0.0005, two-sample t-test). Three patients experienced acute graft rejection after the oral MMF dose was reduced because of side effects. In this group, the MPA-C min and MPA-AUC were significantly lower by the time acute rejection occurred (1.00 ؎ 0.45 mg/L and 25.00 ؎ 6.20 mg ⅐ h/L, respectively). At a fixed dose (1 g twice per day), we compared the pharmacokinetic parameters of MPA [C min , the MPA concentration 30 min after the oral dose of MMF (C 30), and AUC] according to the presence or absence of side effects in the two groups. C min and AUC did not differ between the two groups [C min ؍ 2.22 ؎ 1.13 vs 2.17 ؎ 1.13 mg/L (P ؍ 0.9); AUC ؍ 66.82 ؎ 29.87 vs 55.70 ؎ 11.74 mg ⅐ h/L (P ؍ 0.11)]; and C 30 was significantly higher in group 2 than in group 1 (C 30 ؍ 32.99 ؎ 12.59 vs 7.45 ؎ 5.40 mg/L; P <0.0001). Conclusions: Our results demonstrate a pharmacokinetic/pharmacodynamic relationship between MPA and clinical events. At a fixed dose of 2 g/day, a high C 30 is associated with increased risk for side effects. This study suggests that dividing the MMF daily oral dose into more than two divided doses might prevent early MPA toxicity.
Clinical chemistry, 2001
Mycophenolate mofetil (MMF) is widely used in organ transplantation to prevent acute rejection. Because MMF can produce hematologic and/or gastrointestinal toxicity, therapeutic monitoring is becoming mandatory. This study was designed to investigate the relationship between the clinical events and the pharmacokinetics of mycophenolic acid (MPA) in adult renal transplantation. Thirty-one adult kidney recipients were prospectively included in the study. MPA pharmacokinetic profiles (blood sampling at 0, 0.5, 1, 2, 4, 6, and 12 h after MMF oral dose) were obtained after transplantation (desired creatinine clearance, 40 mL/min), at 3 months after grafting, and at every clinical event (e.g., side effect or rejection). All patients received a 10-day course of anti-thymocyte globulin, cyclosporine, MMF (1 g twice daily), and steroids. We divided the 31 patients into two groups (groups 1 and 2). Ten patients (32%; group 1) had uneventful outcomes, and 21 patients (68%; group 2) presented w...