Pharmacokinetic, pharmacodynamic, and outcome investigations as the basis for mycophenolic acid therapeutic drug monitoring in renal and heart transplant patients (original) (raw)
Related papers
Therapeutic drug measurement of mycophenolic acid derivatives in transplant patients
Clinical Biochemistry, 2007
Introduction: Mycophenolic acid, the active metabolite of the prodrug mycophenolate mofetil, is widely used as an immunosuppressive agent in transplant patients for the prophylaxis of acute rejection. Recent prospective trials suggested the need for therapeutic drug monitoring, which raises the necessity to acquire accurate methods to measure MPA and its metabolites.
Transplantation, 2005
The addition of mycophenolate mofetil (MMF) to calcineurin inhibitor-based regimens reduces the incidence of acute rejection after kidney transplantation. The interpatient variability, changes over time of pharmacokinetic parameters, and the potential for drug interactions make the systemic exposure of mycophenolic acid (MPA) unpredictable at a fixed-dose regimen. An increase in plasma concentration of MPA significantly correlates with a decreased likelihood of an acute rejection after kidney or heart transplantation; therefore, a strategy of therapeutic drug monitoring for MMF therapy could improve outcome. Two large randomized, multicenter, prospective trials investigating the added value of therapeutic drug monitoring for MPA, by comparing fixed-dose treatment with concentration-controlled MMF treatment in kidney transplant recipients, are currently ongoing. More data are needed to fully establish the meaning of the reported prognostic value of preoperative inosine monophosphate dehydrogenase (IMPDH) activity, and longitudinal studies monitoring IMPDH activity after transplantation are eagerly awaited.
Pharmaceutics
In the clinical practice management of heart transplant (HTx), the impact of calcineurin inhibitors co-administration on pharmacokinetics (PKs) of mycophenolic acid (MPA), mycophenolate mofetil (MMF) active drug, is not adequately considered. This retrospective study investigated full MPA-PK profiles by therapeutic drug monitoring (TDM) in 21 HTx recipients treated with MMF combined with cyclosporine (CsA) or tacrolimus (TAC) at a median time of 2.6 months post-transplant. The two treatment groups were compared. We described the main MPA-PK parameters in patients developing acute cellular rejection (ACR) and those who did not. Median dose-adjusted MPA-trough levels and MPA-AUC0–12h were higher in patients co-treated with TAC than with CsA (p = 0.0001 and p = 0.006, respectively). MPA-Cmax and Tmax were similar between the two groups, whereas the enterohepatic recirculation biomarker of MPA (MPA-AUC4–12h) was higher in the MMF and TAC group (p = 0.004). Consistently, MPA clearance wa...
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...
Journal of Clinical Pharmacy and Therapeutics, 2006
The aim of this study was to investigate the effect of time on pharmacokinetic (PK) parameters of mycophenolic acid (MPA) in the early post-transplant period in kidney recipients. MPA is the active metabolite of mycophenolate mofetil (MMF), which was introduced into clinical practice ten years ago. Method: Mycophenolate mofetil was co-administered with cyclosporin (CsA) in a subgroup of 23 patients and with tacrolimus (Tac) in a subgroup of 10 patients. MPA plasma concentration profiles were measured by a validated high performance liquid chromatography method 1 week, 2 and 3 months after transplantation. Results: Despite a comparable MMF dose, a large inter-patient variability in both MPA area under the curve (AUC) from 0 to 12 h (range 10AE03-135AE4 lg h/mL) and in predose concentrations (0AE31-6AE09 lg/mL) was observed. Patients with AUC > 35 lg h/mL showed better (P < 0AE1) renal function than patients with AUC < 20 lg h/mL (mean creatinine concentration 1AE48 ± 0AE12 vs. 3AE35 ± 0AE4 mg/dL respectively). The total MPA trough and AUC did not correlate with biochemical parameters: leucocyte cell count and haematocrit. A higher trough level of the metabolite MPA glucuronide (MPAG) in the 1 week after transplantation was found when compared with the 3-month level (mean 150AE1 ± 146AE7; range 17AE1 to 560 vs. 75AE8 ± 40AE0; range 27AE3 to 174AE2 lg/ mL). The concentration of MPA, and MPA AUC values were significantly lower in patients receiving MMF and CsA than those receiving MMF and Tac during all three periods studied (P < 0AE02). The influence of C 0 and MPA AUC values on the risk of graft rejection was investigated using receiver operating characteristic (ROC) curve analysis. The area under the ROC curve for AUC was 0AE847, whereas that of C 0 was 0AE632. Conclusions: The MPA AUC 0)12h appeared to be the more effective PK parameter for predicting acute rejection. We recommend that routine MPA and MPAG therapeutic drug level monitoring should be an important part of MMF therapy.
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.
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.
Transplant Immunology, 1997
Mycophenolate mofetil (MMF) a potent immunosuppressive agent, has recently been approved for clinical use (CellCept TM) in renal transplant patients in combination with cyclosporine (CsA). With the expanded use of tacrolimns (Prograf TM) as well in renal transplant patients, there is a lack of pharmacokinetic studies clarifying drug interactions between the three agents. A pharmacokinetic study was performed on 18 stable renal transplant patients receiving MMF and tacrolimus together, and four control groups, one receiving tacrolimus alone, two receiving CsA, in combination with MMF (1.0 or 1.5 g bid), and one receiving CsA microemulsion (NeoralTM). Area-under-the-curve values were calculated for each drug to assess if there was a reciprocal effect on the respective bioavailability of each. In vitro, the immunosuppressive effect of trough level plasma from each patient group was studied using mixed lymphocyte culture (MLC), as well as MLC reactions spiked with various combinations of each drug. There was a minimal effect of MMF on tacrolimus pharmacokinetics. However, patients receiving tacrolimns and MMF displayed significantly higher levels (Cmi~ and area under the curve) of mycophenolic acid (MPA) than those receiving CsA (Sandimmune TM or Neoral TM) and the same dose of MMF (50.2 _ 16.5 vs 32.1-+ 16.7 ttg h/mi AUC, p < 0,02). Equivalent MPA levels could be attained in patients receiving CsA if the MMF dose was increased by 50% (1.5 g bid). There were also significantly lower levels of the glueuronide metabolite of MPA (MPAG) (755-+ 280 vs 1230-250 ~tg h/ml AUC, p = 0.02), suggesting a specific inhibition (either direct or indirect) of the conversion of MPA to MPAG in tacrolimus patients, as opposed to those receiving CsA. For each drug combination, there was a positive correlation between the plasma immunosuppressive effect seen in MLC assays and the MMF dose. In addition, trough plasma from patients receiving tacrolimus and MMF was significantly more MLC inhibitory than from those receiving CsA or CsA microemulsion and equivalent-dose MME Culture media containing MPA and tacrolimus equal to clinical therapeutic trough concentratlons (10 ng/ml) were significantly more MLC inhibitory than CsA at equivalent clinical therapeutic trough concentrations (200 ng/ml) with equivalent MPA levels. These studies in renal transplant patients suggest that tacrolimus in combination with MMF may result in a greater degree of immunosuppression than may be anticipated.