Sequential Determination of Pharmacokinetics and Pharmacodynamics of Mycophenolic Acid in Liver Transplant Patients Treated with Mycophenolate Mofetil

Brunet, Mercè; Cirera, Isabel; Martorell, Jaume; Vidal, Elsie González; Millán, Olga; Jiménez, O.; Rojo, Isabel; Londoño, María-Carlota; Rimola, Antoni

doi:10.1097/01.tp.0000200307.79962.48

Cited by 55 publications

(35 citation statements)

References 26 publications

(29 reference statements)

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“…185,188 Hepatic UGT2B7 is the main enzyme involved in the formation of the quantitatively less important but pharmacologically active acyl-glucuronide of MPA (AcMPAG). 188 UGT1A7, UGT1A8, and UGT1A10 expressed in the gastrointestinal tract and the kidney play a minor role in both MPAG and AcMPAG 134 Shaw et al, 135 van Hest et al, 136 Gonzalez-Roncero et al, 137 Kaplan et al, 138 Johnson et al 139 136 Atcheson et al, 143 Atcheson et al, 144 Jain et al, 145 128 Weber et al, 131 Oellerich et al, 132 Kuypers et al, 133 Borrows et al, 142 Jain et al, 145 Cattaneo et al, 149 Brunet et al, 150 Cattaneo et al, 151 formation. 188 Importantly, both MPA and MPAG are extensively bound to serum albumin with a mean albumin binding of 97% and 82%, respectively.…”

Section: Mpa: Basic Principles Of Pharmacodynamics and Pharmacokineticsmentioning

confidence: 97%

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

138

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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Section: Mpa: Basic Principles Of Pharmacodynamics and Pharmacokineticsmentioning

confidence: 97%

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

138

108

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“…This resulted in death in two patients and required retransplantation in one patient [67]. In all studies using MPA monotherapy, there was no pharmacological monitoring of mycophenolic acid (the active form of MPA) blood levels, although significant inter-individual and intra-individual variability in the pharmacokinetics is well established [68].…”

Section: Cni Withdrawalmentioning

confidence: 99%

“…MPA monotherapy after CNI withdrawal is considered too risky due to a 12-15% risk of rejection, but safety could be improved by pharmacological monitoring of MPA [68], an approach which is currently under investigation [92].…”

Section: Cni Withdrawalmentioning

confidence: 99%

Immunosuppression in liver transplant recipients with renal impairment

Duvoux

Pageaux

2011

Journal of Hepatology

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“…A recent study reported that in liver transplant patients, the consistent pharmacologic activity of MPA was shown from patients' sera only when MPA AUC or predose concentration was within the recommended range listed previously (49). Also, in kidney transplant patients who were on CsA-based therapy, MPA AUC on day 3 was predictive of later incidence of acute rejection (P ϭ 0.007) (50), suggesting the importance of adequate MPA exposure, as early as posttrans- plantation day 3, for prevention of acute rejection.…”

Section: Therapeutic Drug Monitoringmentioning

confidence: 99%

Therapeutic Monitoring of Mycophenolate Mofetil

Jeong¹,

Kaplan²

2007

Clinical Journal of the American Society of Nephrology

100

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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.MMF is morpholinoethyl ester of MPA, a potent and reversible inhibitor of inosine monophosphate dehydrogenase (IM-PDH), isoform 2 (1). MPA originally was discovered from Penicillium brevicompactum and related fungi in the late 19th century, and its major activity on IMPDH first was reported in 1969 (2). MPA was developed as an immunosuppressant by Syntex in 1980s to complement existing immunosuppressive agents, including calcineurin inhibitor, azathioprine, and corticosteroids (3). IMPDH became a target for immunosuppression because lymphocytes depend on the de novo guanosine nucleotide synthesis pathway for DNA synthesis and cell division (3). Because other cell types, including neurons, depend primarily on the alternative salvage pathway for DNA synthesis, MPA selectively inhibits the proliferation of human T and B lymphocytes. Since the 1990s, when large, double-blind, randomized trials in kidney transplant recipients (4 -6) showed the efficacy of MMF in preventing early acute rejection, in combination with cyclosporine (CsA) and prednisone, MMF has been used widely as a part of various combination regimens of immunosuppressive agents. To appreciate fully the complexities and controversies involved in therapeutic monitoring, one must have a substantial understanding of the pharmacokinetics and pharmacodynamics of MPA. This review covers the basic pharmacology of MMF and then discusses the data that are available on the utility of monitoring of MPA concentrations. PharmacokineticsMMF, being a pro-drug of MPA, is absorbed rapidly and completely from the gastrointestinal tract and undergoes extensive presystemic de-esterification to become MPA, the active moiety. After an oral dose, MMF in the systemic circulation quickly disappears and the plasma concentration of MPA rises rapidly, reaching its maximum concentration within 1 h (7). Food intake can delay the rate of MMF absorption but does not affect the extent. Co-administration of antacids or cholestyramine decreases the extent of absorption by approximately 20 and 40%, respectively (7). Mean apparent half-life (t 1/2 ) of MPA in the systemic circulation is approximately 17 h (7).MPA undergoes enterohepatic circulation; its plasma concentration profile shows a secondary peak at 6 to 12 h after intravenous or oral dosing. The pathway of enterohepatic circulation is depicted in Figure 1, which is composed of processes of MPA metabolism, biliary excretion of its metabolites, de-glucuronidation of the...

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Sequential Determination of Pharmacokinetics and Pharmacodynamics of Mycophenolic Acid in Liver Transplant Patients Treated with Mycophenolate Mofetil

Abstract: During the first postoperative months, exposure to MPA is low in a considerable proportion of liver transplant patients receiving MMF at a fixed dose of 1 g bid. MPA monitoring appears necessary in these patients.

Cited by 55 publications

References 26 publications

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

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

Immunosuppression in liver transplant recipients with renal impairment

Therapeutic Monitoring of Mycophenolate Mofetil

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