Unexpected augmentation of mycophenolic acid pharmacokinetics in renal transplant patients receiving tacrolimus and mycophenolate mofetil in combination therapy, and analogous in vitro findings

Zucker, Keith; Rosén, Anne; Tsaroucha, Alexandra; Faria, Ludmilla de; Roth, David; Ciancio, Gaetano; Esquenazi, Violet; Burke, George W.; Tzakis, Andreas G.; Miller, Joshua

doi:10.1016/s0966-3274(97)80042-1

Cited by 214 publications

(122 citation statements)

References 11 publications

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“…In our study, calcineurin antagonists such as comedications seem to affect the MPA pharmacokinetics. For equivalent doses of MMF, combination therapy with FK506 had been reported to result in higher MPA AUC than does a CsA-based regimen (Zucker et al, 1997). Furthermore, our study confirmed previous observations (Kuriata-kordek et al, 2003) of significantly higher MPA C 0 in the FK506-treated group than that in patients receiving CsA.…”

Section: Discussionsupporting

confidence: 90%

Pharmacokinetics of mycophenolic acid in Chinese kidney transplant patients

Huang

Sheng-Tu

et al. 2005

J. Zhejiang Univ. Sci.

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Abstract:To assess the influence of cyclosporin A (CsA) and tacrolimus (FK506) on mycophenolic acid (MPA) and correlation analysis of the pharmacokinetic parameters and patient characteristics, clinical outcome in Chinese kidney transplant recipients, the pharmacokinetics of 1000 mg mycophenolate mofetil (MMF) twice daily was measured by high-performance liquid chromatography (HPLC). PKS (Pharmaceutical Kinetics Software) 1.0.2 software package was used for the calculation of pharmacokinetic parameters. The mean C max , t max , and AUC (0−12) were (21.88±10.52) µg/ml, (1.20±0.95) h, and (52.546±13.215) µg·h/ml, respectively. The level of AUC (0−12) in the FK506 group was significantly higher than that in the CsA group. MPA appeared not to be affected by renal function. MPA AUC (0−12) showed statistically significant difference according to the patient's gender.

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Section: Discussionsupporting

confidence: 90%

Pharmacokinetics of mycophenolic acid in Chinese kidney transplant patients

Huang

Sheng-Tu

et al. 2005

J. Zhejiang Univ. Sci.

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“…[18][19][20][21][22] This effect is proportional to the concentration of cyclosporine in the blood 23 and does not occur with tacrolimus 21 or sirolimus. 24 The MPA AUC after a 750-mg dose of MMF in the absence of cyclosporine approximates the MPA AUC after a 1000-mg dose of MMF in the presence of cyclosporine at therapeutic concentrations in the blood.…”

Section: Treatment Planmentioning

confidence: 99%

Evaluation of mycophenolate mofetil for initial treatment of chronic graft-versus-host disease

Martin

Storer

Rowley

et al. 2009

Blood

141

118

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We conducted a double-blind, randomized multicenter trial to determine whether the addition of mycophenolate mofetil (MMF) improves the efficacy of initial systemic treatment of chronic graft-versushost disease (GVHD). The primary endpoint was resolution of chronic GVHD and withdrawal of all systemic treatment within 2 years, without secondary treatment. Enrollment of 230 patients was planned, providing 90% power to observe a 20% difference in success rates between the 2 arms. The study was closed after 4 years because the interim estimated cumulative incidence of success for the primary endpoint was 23% among 74 patients in the MMF arm and 18% among 77 patients in the control arm, indicating a low probability of positive results for the primary endpoint after completing the study as originally planned. Analysis of secondary endpoints showed no evidence of benefit from adding MMF to the systemic regimen first used for treatment of chronic GVHD. The estimated hazard ratio of death was 1.99 (95% confidence interval, 0.9-4.3) among patients in the MMF arm compared with the control arm. MMF should not be added to the initial systemic treatment regimen for chronic GVHD. This trial was registered at www.clinicaltrials.gov

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“…For example, some studies found that impaired renal function and low albumin levels result in high total MPA clearance and thus low total MPA exposure (5,9,11,13,14), although this could not be confirmed in all stud-ies (15)(16)(17)(18)(19)(20). Also with regard to the effect of the use of comedication (3,10,18,21,22), diabetes (23,24), body weight (11,13,17,20), age (5,11,18 -20), gender (11,20,23), and race (9,23,25), contrasting results have been obtained. Most of these studies were underpowered, based on MPA predose levels only, and some studies did not control adequately for confounding factors.…”

mentioning

confidence: 96%

Explaining Variability in Mycophenolic Acid Exposure to Optimize Mycophenolate Mofetil Dosing

Hest¹,

Mathôt²,

Pescovitz

et al. 2006

Journal of the American Society of Nephrology

177

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Large between-and within-patient variability has been observed in the pharmacokinetics of mycophenolic acid (MPA). However, conflicting results exist about the influence of patient characteristics that explain the variability in MPA exposure. This population pharmacokinetic meta-analysis of MPA in renal transplant recipients was performed to explore whether race, renal function, albumin level, delayed graft function, diabetes, and co-medication are determinants of total MPA exposure. A total of 13,346 MPA concentration-time data points from 468 renal transplant patients who participated in six clinical studies were combined and analyzed retrospectively. Sampling occasions ranged from day 1 after transplantation to 10 yr after transplantation. Concentration-time data were analyzed with nonlinear mixed-effect modeling. Exposure to total MPA, as determined by MPA clearance, significantly increased with increasing renal function, albumin level, and hemoglobin as well as decreasing cyclosporine predose level (P < 0.001). These variables could explain 18% of the between-patient and 38% of the within-patient variability in MPA exposure. Differences in MPA exposure between patients with or without delayed graft function or between patients of different races are likely to be caused by the effect of renal function on MPA exposure. Diabetes did not have an effect on MPA exposure. The clinical implication is that a change in renal function or albumin level provides an indication for therapeutic drug monitoring as MPA exposure may be altered. Patients in whom cyclosporine and mycophenolate mofetil are combined may need higher mycophenolate mofetil doses, especially during the early phase after transplantation than currently recommended for optimal MPA exposure.

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Unexpected augmentation of mycophenolic acid pharmacokinetics in renal transplant patients receiving tacrolimus and mycophenolate mofetil in combination therapy, and analogous in vitro findings

Cited by 214 publications

References 11 publications

Pharmacokinetics of mycophenolic acid in Chinese kidney transplant patients

Pharmacokinetics of mycophenolic acid in Chinese kidney transplant patients

Evaluation of mycophenolate mofetil for initial treatment of chronic graft-versus-host disease

Explaining Variability in Mycophenolic Acid Exposure to Optimize Mycophenolate Mofetil Dosing

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