Higher exposure to mycophenolic acid with sirolimus than with cyclosporine cotreatment

Büchler, Matthias; Lebranchu, Yvon; Benéton, M. N. C.; Lemeur, Yannick; Heng, Anne-Élisabeth; Westeel, Pierre-François; LEGUELLEC, C; Libert, Frédérick; Hary, L.; Marquet, Pierre

doi:10.1016/j.clpt.2005.03.005

Cited by 32 publications

(18 citation statements)

References 24 publications

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“…As a result of the gradual increase in MPA exposure, a subset of patients will be above the target window with standard MMF doses of 1000 mg twice daily after 6 to 12 mo after transplantation. This is most likely in patients who are no longer treated with cyclosporine and who have good renal function, albumin level, and hemoglobin (41). The increased MPA exposure may be very welcome in regimens in which cyclosporine is tapered or stopped, and in patients who tolerate such levels without toxicity, dose reductions may not be necessary.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…Numerous studies showed that dose-corrected MPA exposure is significantly lower in patients treated with a combination of MMF and cyclosporine than in patients receiving MMF alone or in combination with tacrolimus or sirolimus. 151,[154][155][156][157][158][159][160][161][162] This is due to a reduced enterohepatic recirculation of MPA/MPAG in cyclosporine-treated patients, secondary to an inhibition of the MRP2-mediated biliary secretion of MPAG. 154,[215][216][217] Importantly, recent data show that there is an inverse correlation between cyclosporine dose and/or exposure and MPA exposure, 136,147,218 suggesting that MRP2 inhibition by cyclosporine is dose/exposure related.…”

Section: Drug-drug Interactions With Concomitant Immunosuppressive Mementioning

confidence: 95%

New Insights Into the Pharmacokinetics and Pharmacodynamics of the Calcineurin Inhibitors and Mycophenolic Acid: Possible Consequences for Therapeutic Drug Monitoring in Solid Organ Transplantation

Jonge

Naesens²,

Kuypers³

2009

Therapeutic Drug Monitoring

140

108

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Although therapeutic drug monitoring (TDM) of immunosuppressive drugs has been an integral part of routine clinical practice in solid organ transplantation for many years, ongoing research in the field of immunosuppressive drug metabolism, pharmacokinetics, pharmacogenetics, pharmacodynamics, and clinical TDM keeps yielding new insights that might have future clinical implications. In this review, the authors will highlight some of these new insights for the calcineurin inhibitors (CNIs) cyclosporine and tacrolimus and the antimetabolite mycophenolic acid (MPA) and will discuss the possible consequences. For CNIs, important relevant lessons for TDM can be learned from the results of 2 recently published large CNI minimization trials. Furthermore, because acute rejection and drug-related adverse events do occur despite routine application of CNI TDM, alternative approaches to better predict the dose-concentration-response relationship in the individual patient are being explored. Monitoring of CNI concentrations in lymphocytes and other tissues, determination of CNI metabolites, and CNI pharmacogenetics and pharmacodynamics are in their infancy but have the potential to become useful additions to conventional CNI TDM. Although MPA is usually administered at a fixed dose, there is a rationale for MPA TDM, and this is substantiated by the increasing knowledge of the many nongenetic and genetic factors contributing to the interindividual and intraindividual variability in MPA pharmacokinetics. However, recent, large, randomized clinical trials investigating the clinical utility of MPA TDM have reported conflicting data. Therefore, alternative pharmacokinetic (ie, MPA free fraction and metabolites) and pharmacodynamic approaches to better predict drug efficacy and toxicity are being explored. Finally, for MPA and tacrolimus, novel formulations have become available. For MPA, the differences in pharmacokinetic behavior between the old and the novel formulation will have implications for TDM, whereas for tacrolimus, this probably will not to be the case.

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“…Coadministration of MMF with cyclosporine decreases exposure to MPA and increases plasma levels of MPAG compared to patients treated with MMF plus tacrolimus or sirolimus or corticosteroids in adults and children (5,6,30,(42)(43)(44)(45)(46)(47).…”

Section: Mmf Metabolism and Pharmacokineticsmentioning

confidence: 99%

Therapeutic Drug Monitoring of Mycophenolic Acid in Solid Organ Transplant Patients Treated With Mycophenolate Mofetil: Review of the Literature

Arns

Cibrik²,

Walker

et al. 2006

Transplantation

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Mycophenolate mofetil (MMF) has conventionally been administered at a fixed dose without routinely monitoring blood levels of mycophenolic acid (MPA), the active metabolite. The contribution of therapeutic drug monitoring (TDM) during MMF therapy remains controversial. A literature review was performed to explore the usefulness of TDM for MPA in solid organ transplantation. In addition, emphasis was placed on the potential clinical benefits and limitations of TDM for MPA. Available studies have limitations and report conflicting results. Although early after transplantation MPA area under the curve might have predictive value for the risk of acute rejection, predose levels appear less reliable. With regard to MPA toxicity, most studies showed no correlation between MPA pharmacokinetics and adverse effects. TDM is hampered by several factors such as the considerable intra-subject variability of MPA pharmacokinetics and the increasing number of different drug combinations. Proposed target ranges are restricted to the early posttransplant period when MMF is used in combination with cyclosporine. The current review of the literature indicates no clear support for a substantial clinical benefit of TDM and more data from prospective randomized trials are needed.

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Higher exposure to mycophenolic acid with sirolimus than with cyclosporine cotreatment

Abstract: These data show that exposure to mycophenolic acid is higher in patients cotreated with sirolimus than in those cotreated with cyclosporine.

Cited by 32 publications

References 24 publications

Explaining Variability in Mycophenolic Acid Exposure to Optimize Mycophenolate Mofetil Dosing

Explaining Variability in Mycophenolic Acid Exposure to Optimize Mycophenolate Mofetil Dosing

New Insights Into the Pharmacokinetics and Pharmacodynamics of the Calcineurin Inhibitors and Mycophenolic Acid: Possible Consequences for Therapeutic Drug Monitoring in Solid Organ Transplantation

Therapeutic Drug Monitoring of Mycophenolic Acid in Solid Organ Transplant Patients Treated With Mycophenolate Mofetil: Review of the Literature

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