Pharmacokinetics and pharmacodynamics of mycophenolate sodium (EC-MPS) co-administered with cyclosporine in the early-phase post-kidney transplantation (original) (raw)
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British Journal of Clinical Pharmacology, 2014
The use of mycophenolate mofetil (MMF) in children with systemic lupus erythematosus (SLE) is increasing. However, the clinical benefit of its monitoring has been scarcely studied, and little is known about its pharmacokinetics in this context. The objectives of the present study were: (i) to describe mycophenolic acid (MPA, the active moiety of MMF) pharmacokinetics, (ii) to develop a Bayesian estimator (BE) allowing the determination AUC (area under the curve) from a limited number of blood samples and (iii) to explore the relationships between exposure indices to MPA and the clinical status in children with SLE.
Pharmacokinetics of mycophenolate mofetil are influenced by concomitant immunosuppression
Pediatric Nephrology, 2000
The recommended dosage for mycophenolate mofetil (MMF) in combination with cyclosporin (CyA) for pediatric kidney transplant recipients is 600 mg/m 2 twice daily (b.i.d.). We recently published pharmacokinetic (PK) profiles of MMF in combination with tacrolimus (FK506): in order to keep the mycophenolic acid (MPA) pre-dose trough concentration between 2 and 5 µg/ml and to avoid side effects, mean MMF doses were reduced to 300 mg/m 2 b.i.d.. In order to investigate whether this striking difference was due to alterations of MPA clearance by CyA or FK506, we analyzed PK profiles from 13 patients who received MMF without CyA or FK506, and compared these data with 14 patients who received a combination of MMF and FK506 and 15 patients who received MMF and CyA. Mean area under the curve (AUC) in all PK profiles was 61.9±23.8 µg×h/ml. Although the AUCs did not differ between the groups, the dose per square meter was significantly lower in patients receiving concomitant FK506 compared with CyA, and the dose-normalized AUC was significantly higher. The MMF doses were 1,158±301 mg/m 2 per day in the CyA group, 555±289 mg/m 2 per day in the tacrolimus group, and 866±401 mg/m 2 per day in the group without concomitant calcineurin inhibitor treatment. The apparent clearance of MPA is reduced in combination with tacrolimus. The reason for this remains unknown. There was a trend towards lower dose-normalized AUCs in the CyA group compared with the group without calcineurin inhibitor treatment. We conclude that concomitant medication alters the clearance of MPA. It is noteworthy that there was substantial interindividual variation, despite the rather marked differences between the groups, and therefore we recommend starting MMF in combination with CyA at a dose of 600 mg/m 2 b.i.d., in combination with tacrolimus at a dose of 300 mg/m 2 b.i.d., and without a calcineurin inhibitor at a dose of 500 mg/m 2 b.i.d., and adjusting doses using therapeutic drug monitoring of MPA.
Indian Journal of Nephrology, 2016
In spite of the availability of various treatment options, the optimal therapy still remains to be defined. Mycophenolate mofetil (MMF) is one of the drugs used in the treatment of SLE. [2,3] MMF is immediately converted to mycophenolic acid (MPA) which is then metabolized to the inactive MPA glucuronide (MPAG) in the liver. [4] MMF, having a lower incidence of toxicity, is commonly prescribed by clinicians for the treatment of SLE due to a favorable comparison with cyclophosphamide and corticosteroids. Kazyra et al. reported that MMF when used in induction and remission therapy for children with SLE (with and without confirmed lupus nephritis)
2000
has been shown in patients receiving Tc-MMF combination therapy compared with CsA-MMF combination therapy at the same dose of MMF. The aim of this prospective study was to assess the pharmacokinetic/ pharmacodynamic (PK/PD) relationship for MPA in kidney transplant patients receiving low-dose MMF (500 mg twice a day) in combination with Tc. Methods: Adult kidney transplant recipients (n ؍ 51) were included. MPA-PK profiles (blood sampling at 0, 0.5, 1, 2, 4, 6, and 12 h after MMF oral dose) were obtained within the first 2 weeks after transplantation, 3 months after grafting, and at every adverse clinical event [side effect or acute rejection (AR)]. All patients received Tc, MMF (500 mg twice a day), and steroids. Results: Thirty patients (59%) had uneventful outcomes, and 21 patients had 33 episodes of MPA-related side effects; only 3 patients had AR. A total of 78 MPA-PK profiles were obtained. The following PK parameters were increased in the side-effects group compared with the non-side effects group: mean MPA c min , 2.63 ؎ 1.58 vs 1.75 ؎ 0.82 mg/L (P ؍ 0.016); mean c 30 , 10.47 ؎ 6.27 vs 7.66 ؎ 8.95 mg/L (P ؍ 0.009); mean c 60 , 9.67 ؎ 5.42 vs 5.83 ؎ 2.6 mg/L (P ؍ 0.0002); mean area under the MPA time-concentration curve from 0 to 12 h [MPA-AUC (0 -12) ], 48.38 ؎ 18.5 vs 36.04 ؎ 10.82 mg ⅐ h/L (P ؍ 0.0006); mean dose-normalized MPA-AUC, 0.16 ؎ 0.05 vs 0.12 ؎ 0.04 (mg ⅐ h/L)/(mg/m 2 ) (P ؍ 0.0015). For the three AR patients, MPA concentrations obtained at the time of AR revealed MPA c min values of 1.86, 1.76, and 3.83 mg/L, respectively, and MPA-AUC (0 -12) values of 37.7, 24.9, and 104.9 mg ⅐ h/L. The threshold of toxicity was 3 mg/L (sensitivity, 38.7%; specificity, 91.5%) for c min , 8.09 mg/L for maximum MPA concentration during the first hour (sensitivity, 77.8%; specificity, 67.4%), and 37.6 mg ⅐ h/L for MPA-AUC (0 -12) (sensitivity, 83.3%; specificity, 59.6%). Conclusions: These results demonstrate the relationship between plasma MPA concentrations and toxicity. High c min, c 30 , and c 60 values as well as AUC (0 -12) are associated with increased risk for side effects. These values may have an importance in a routine monitoring program.
Mycophenolate Mofetil Pharmacokinetic Monitoring in Pediatric Kidney Transplant Recipients
Transplantation Proceedings, 2005
This open-label, longitudinal, long-term study of de novo pediatric renal transplant recipients was designed to investigate the pharmacokinetics (PK) of mycophenolic acid (MPA) and its possible interaction with cyclosporine (CsA). Thirty-four children on an immunosuppressive regimen of CsA, prednisone, and mycophenolate mofetil (MMF, 300 -400 mg/m 2 twice daily) were investigated at 6, 30, 180, and 360 days after transplantation. Considerable interindividual variability in the areas under the concentration curve (AUC (0 -12) ) of MPA was observed during the follow-up, although the dose of MMF remained the same over the same time. Predose levels (C0) increased significantly during the first 6 months after transplantation: C0 at 6 and 180 days after transplantation was 0.8 Ϯ 0.6 and 1.9 Ϯ 1.1 g/mL (P Ͻ .0001). A significant time-dependent increase in the AUC of MPA was also observed during the first 6 posttransplant months: AUC (0 -12) at 6 and 180 days after transplantation was 23.3 Ϯ 10.8 and 40 Ϯ 11.6 mg*h/L (P ϭ .003). MPA concentrations 3 and 4 hours after MMF intake were the individual time points that best correlated with the full MPA AUC (r ϭ 0.8 and 0.79; P Ͻ .001). The abbreviated MPA AUC (0 -4 hours) correlated reasonably with the full AUC (r ϭ 0.87; P Ͻ .001). Finally, a significant reduction in CsA dose during the first 6 posttransplant months (P Ͻ .001) matched the significant increases in both MPA C0 and full MPA AUC, thus demonstrating the interaction of the 2 immunosuppressive drugs. These observations suggest the need for therapeutic drug monitoring when adjusting the dose of MMF in children.
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.
Transplantation Journal, 2004
This open-label, longitudinal, long-term study of de novo pediatric renal transplant recipients was designed to investigate the pharmacokinetics (PK) of mycophenolic acid (MPA) and its possible interaction with cyclosporine (CsA). Thirty-four children on an immunosuppressive regimen of CsA, prednisone, and mycophenolate mofetil (MMF, 300 -400 mg/m 2 twice daily) were investigated at 6, 30, 180, and 360 days after transplantation. Considerable interindividual variability in the areas under the concentration curve (AUC (0 -12) ) of MPA was observed during the follow-up, although the dose of MMF remained the same over the same time. Predose levels (C0) increased significantly during the first 6 months after transplantation: C0 at 6 and 180 days after transplantation was 0.8 Ϯ 0.6 and 1.9 Ϯ 1.1 g/mL (P Ͻ .0001). A significant time-dependent increase in the AUC of MPA was also observed during the first 6 posttransplant months: AUC (0 -12) at 6 and 180 days after transplantation was 23.3 Ϯ 10.8 and 40 Ϯ 11.6 mg*h/L (P ϭ .003). MPA concentrations 3 and 4 hours after MMF intake were the individual time points that best correlated with the full MPA AUC (r ϭ 0.8 and 0.79; P Ͻ .001). The abbreviated MPA AUC (0 -4 hours) correlated reasonably with the full AUC (r ϭ 0.87; P Ͻ .001). Finally, a significant reduction in CsA dose during the first 6 posttransplant months (P Ͻ .001) matched the significant increases in both MPA C0 and full MPA AUC, thus demonstrating the interaction of the 2 immunosuppressive drugs. These observations suggest the need for therapeutic drug monitoring when adjusting the dose of MMF in children.