Pharmacokinetics of Mycophenolic Acid in Renal Transplant Patients with Delayed Graft Function

Shaw, Leslie M.; Mick, Rosemarie; Nowak, Irena; Korecka, Magdalena; Brayman, Kenneth L.

doi:10.1002/j.1552-4604.1998.tb04424.x

Cited by 127 publications

(106 citation statements)

References 12 publications

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“…Patients in the cyclosporin cohort were significantly older and had a significantly higher median plasma bilirubin concentration than those in the tacrolimus group (median [IQR] =13 [10][11][12][13][14][15][16][17][18] and 7 [5][6][7][8][9][10][11][12] mmol l -1 , respectively; P = 0.01). Otherwise there were no other significant differences between groups relating to race, sex, body weight, body mass index (BMI), diabetes, CAPD, transplant type, HLAM, PRA, ischaemic time, creatinine clearance, graft function or blood biochemistry.…”

Section: Baseline Characteristicsmentioning

confidence: 99%

Mycophenolic acid pharmacokinetics and related outcomes early after renal transplant

Atcheson¹,

Taylor

Mudge

et al. 2005

Brit J Clinical Pharma

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AimsThe pharmacokinetics of mycophenolic acid and its glucuronide are complex. This study investigated the pharmacokinetics, pharmacodynamics and protein binding of mycophenolic acid and its glucuronide metabolite, early post-transplant in renal allograft recipients. MethodsForty-two de novo renal transplant recipients receiving mycophenolate mofetil and concomitant cyclosporin ( n = 32) or tacrolimus ( n = 10) participated in the study. Blood samples were taken on day 5 post-transplant for measurement of free and total concentrations of mycophenolic acid, mycophenolic acid glucuronide and relevant biochemistry. Associations between free fraction and biochemistry were investigated. Free and total 6-h area under the concentration-time curve (AUC 0 -6 ) of mycophenolic acid was assessed relative to clinical outcomes in the first month post-transplant. ResultsKinetic variability of free and total mycophenolic acid and its glucuronide was g reater in patients on cyclosporin (12-to 18-fold variation) than on tacrolimus (four-to fivefold) cotherapy. Cyclosporin-treated patients also had significantly lower predose total mycophenolic acid concentrations than tacrolimus-treated patients (median 0.8 mg l -1 and 1.6 mg l -1 , respectively, P = 0.002). Mycophenolic acid glucuronide predose concentration correlated positively with mycophenolic acid glucuronide AUC 0 -6 ( r > 0.95). Mycophenolic acid free fraction varied 11-fold, from 1.6% to 18.3%, whilst the glucuronide free fraction varied threefold, from 17.4% to 54.1%. Urea and creatinine concentrations correlated positively ( r > 0.46), whilst albumin correlated negatively ( r = -0.54) with free fraction of mycophenolic acid. Similar relationships were found for the free fraction of mycophenolic acid glucuronide. Mycophenolic acid free fraction was on average 70% higher in patients with albumin concentrations below a specified albumin cut-off concentration of 31 g l -1 [free fraction = 7 ± 4% for lower albumin and 4 ± 3% for higher albumin, respectively; P = 0.001; 95% confidence interval (CI) for the difference 1.9, 4.2]. Neither free nor total mycophenolic acid AUC 0 -6 was related to rejection ( P > 0.07). Free AUC 0 -6 was significantly higher in those patients with thrombocytopenic, leukopenic and/or infectious outcomes than in those without (mean ± SD 1.9 ± 0.3 mg h -1 l -1 and 1.1 ± 0.1 mg h -1 l -1 , P = 0.0043; 95% CI for the difference 0.3, 1.4).

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Section: Baseline Characteristicsmentioning

confidence: 99%

Mycophenolic acid pharmacokinetics and related outcomes early after renal transplant

Atcheson¹,

Taylor

Mudge

et al. 2005

Brit J Clinical Pharma

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“…In patients with delayed graft function, AUC of MPG, the free fraction of MPA and the AUC of free-MPA are all increased. These perturbed pharmacokinetics improve with resumption of normal renal function (8).…”

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confidence: 99%

“…The desired exposure is 35 to 60 g ⅐ h/ml (6,7). Mycophenolic acid AUC is increased by renal dysfunction, which may be clinically relevant early after transplantation or during rejection episodes (8,9). When heart transplant patients who had rejection were compared with patients who did not reject, doses were the same but rejecters had low AUC and trough levels (10).…”

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confidence: 99%

Immunosuppression with Mycophenolic Acid

Bennett¹

2003

Journal of the American Society of Nephrology

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Over the past decade, immunosuppression for renal transplantation has shifted from predominantly azathioprine-based regimens to those containing mycophenolic acid (MMF, CellCept) (1). In most centers, MMF is combined with cyclosporine or tacrolimus (calcineurin inhibitors) plus corticosteroid therapy. These combinations have led to unprecedented patient and graft survivals over the near term (1 to 3 yr) and low rates of acute rejection. The recommended MMF dose is standard for all patients at 1 g twice daily.Long-term survivals of patients and grafts are also improving but are suboptimal. Donor factors such as age, prolonged cold ischemia, and delayed graft function are associated with shortened graft half-life. The occurrence of acute rejection episodes remains a strong predictor of shortened allograft half-life and chronic allograft nephropathy. In this issue of JASN, Knoll et al. (2) present a retrospective study showing the rather obvious fact that there is a decreased time to first acute rejection if the recommended dose of MMF is reduced because of side effects. Furthermore, there is a quantitative relationship between the time the patient spends at less than the recommended dose and the risk for acute rejection.Although the study is flawed in design by its retrospective nature and its failure to examine important variables such as cytomegalovirus (CMV) status and the length of time the patient was on dialysis, this study does illustrate the difficulty clinicians have in using drugs that have no biologic end points for dose adjustment. The situation with MMF dosing is analogous to prescribing warfarin anticoagulation with no knowledge of INR but instead having to wait for bleeding or thrombosis before making dose adjustments. The consequences of long-term corticosteroid use and the nephrotoxic/metabolic side effects of calcineurin inhibitors are related to total drug exposure. For calcineurin inhibitors, we use pharmacokinetic parameters to allow individualization of therapy. With MMF, the current practice is that one size fits all. The data of Knoll et al. suggest that this is inadequate. It is difficult to ascribe cause and effect to the reduced MMF dose and acute rejection for several reasons. Cyclosporine and tacrolimus each have different pharmacokinetic interactions with mycophenolate mofetil, and they were used sequentially in the study. There is no adjustment for length of renal failure, which could influence bone marrow tolerance of MMF, particularly with second transplants. CMV infections, which can be associated with dose-limiting leukopenia, thrombocytopenia, and acute rejection, were not examined in this analysis, nor were renal function, liver function, and decreased drug-protein binding,

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“…Similar observations have been reported in renal transplant recipients. 10 The mild impairment in liver function observed in 2 patients during the study (determined by serum bilirubin level Ͼ2 mg/dL) is not likely to have …”

Section: Discussionmentioning

confidence: 95%

Effect of T-tube clamping on the pharmacokinetics of mycophenolic acid in liver transplant patients on oral therapy of mycophenolate mofetil

et al. 1999

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The aim of the study was to evaluate the effect of t-tube clamping on the pharmacokinetics of mycophenolic acid (MPA) after oral administration of mycophenolate mofetil (MMF) in primary liver transplant recipients treated with tacrolimus as the primary immunosuppressive drug. We evaluated the pharmacokinetics of MPA and its primary metabolite, mycophenolic acid glucuronide (MPAG), before and after clamping the t-tube in 8 primary liver transplant recipients treated with oral MMF and tacrolimus. The concentration of MPA and MPAG in plasma, bile, and urine samples obtained over one dosing interval was measured by high-pressure liquid chromatography. Pharmacokinetic parameters of MPA estimated before and after clamping the t-tube were compared to evaluate any significant differences at a P of .05 or less. There were no significant differences in the time to reach peak plasma concentration (1.8 ؎ 1.7 v 1.0 ؎ 0.5 hours), trough plasma concentration of MPA (1.1 ؎ 1.4 v 1.4 ؎ 1.1 g/mL), peak plasma concentration of MPA (10.6 ؎ 7.5 v 11.1 ؎ 4.6 g/ mL), area under the plasma concentration-versustime curve (AUC) (40.1 ؎ 31.9 v 43.2 ؎ 21.1 g/ mL/h) of MPA, or the percentage of MPA that is free or unbound in the plasma (3.9% ؎ 1.6% v 4.1% ؎ 3.0%). There was also no significant difference in the ratio of the AUC of MPAG to MPA. These observations suggest that t-tube clamping does not affect the kinetics of MPA or MPAG and that no dosing alterations of MMF are required when the t-tube is clamped in liver transplant recipients.

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Pharmacokinetics of Mycophenolic Acid in Renal Transplant Patients with Delayed Graft Function

Cited by 127 publications

References 12 publications

Mycophenolic acid pharmacokinetics and related outcomes early after renal transplant

Mycophenolic acid pharmacokinetics and related outcomes early after renal transplant

Immunosuppression with Mycophenolic Acid

Effect of T-tube clamping on the pharmacokinetics of mycophenolic acid in liver transplant patients on oral therapy of mycophenolate mofetil

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