Drug-drug interaction of potassium competitive acid blocker with tacrolimus and mycophenolate in kidney transplant recipients: a randomized controlled trial using smart clinical trial platform
Seong Wook LeeYoung-Hwan LeeYou Hyun JeonJeong‐Hoon LimHee‐Yeon JungSun-Hee ParkChan‐Duck KimYong-Lim KimJang‐Hee Cho
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Seong Wook Lee, Young-Hwan Lee, You Hyun Jeon, Jeong-Hoon Lim, Hee-Yeon Jung, Sun-Hee Park, Chan-Duck Kim, Yong-Lim Kim, Jang-Hee Cho. Korean J Transplant 2023;37:110. https://doi.org/10.4285/ATW2023.F-6899Keywords:
Mycophenolate
The immunosuppressive agent mycophenolate mofetil has been successfully used over the past 10 years to prevent acute allograft rejection after renal transplantation. It has mainly been administered as a fixed dose of mycophenolate mofetil 1000 mg b.i.d. The pharmacokinetics of mycophenolic acid, the active moiety of the prodrug mycophenolate mofetil, show large between-patient variability, and exposure to mycophenolic acid correlates with the risk for acute rejection. This suggests that already excellent clinical results can be further improved by mycophenolate mofetil dose individualization. This review discusses different arguments in favour of individualization of mycophenolate mofetil dose, as well as strategies for managing mycophenolate mofetil therapy individualization, including pharmacokinetic and pharmacodynamic monitoring and dose individualization based on pharmacogenetic information. It is expected that pharmacokinetic monitoring of mycophenolic acid will offer the most effective and feasible tool for mycophenolate mofetil dose individualization.
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Pharmacodynamics
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Active metabolite
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Stability of mycophenolic acid in plasma samples from patients during mycophenolate mofetil therapy.
The aim of this study was to investigate the stability of mycophenolic acid (MPA) in human plasma from patients receiving mycophenolate mofetil (MMF) therapy. MPA was measured using a validated HPLC method. MPA concentrations were determined immediately after receiving the samples in the laboratory, and after 24 h, 72 h, 96 h, 7, 14, 21 days of storage at two different temperatures at -20 degrees C and 4 degrees C. The number of samples used in different conditions of temperature was limited by plasma volume in patients specimens. Monitoring human plasma samples stored at -20 degrees C showed that MPA was stable at this temperature for at least 3 weeks. MPA concentrations were found to be stable also up to 96 hours when stored at 4 degrees C.
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Chemical Stability
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The introduction of mycophenolate mofetil has improved graft survival after organ transplantation; however, its use may be limited by important adverse effects. For overcoming these problems, an enteric-coated formulation of mycophenolate sodium has been developed, but pharmacokinetic data of mycophenolic acid release from this formulation are scanty.Pharmacokinetic studies in 32 kidney transplant recipients who were given the enteric-coated formulation of mycophenolate sodium (n = 12) or mycophenolate mofetil (n = 20) were performed. The profiles of mycophenolic acid from the two formulations at months 6, 12, 18, and 24 after transplantation were compared. Subsequently, all patients who were receiving the enteric-coated formulation were shifted to mycophenolate mofetil, and the pharmacokinetic evaluations were repeated.At month 6 after surgery, aberrant and variable pharmacokinetic curves were found in patients who were given the enteric-coated formulation, whereas those who were taking mycophenolate mofetil had regular mycophenolic acid kinetic profiles. Patients who were taking the enteric-coated formulation had mycophenolic acid time of occurrence for maximum drug concentration that ranged from 0 to 480 min and higher dosage-adjusted mycophenolic acid trough levels compared with patients who were given mycophenolate mofetil. Conversion from the enteric-coated formulation of mycophenolate sodium to mycophenolate mofetil resulted in an improvement of the mycophenolic acid kinetics profiles.Given the emerging clinical benefit of mycophenolic acid monitoring in the transplant setting, therapeutic drug monitoring problems with the enteric-coated formulation of mycophenolate sodium should be taken into account.
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Enteric coated
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Mycophenolate mofetil (MMF) is considered to be less effective than calcineurin inhibitors in the treatment of minimal change disease (MCD), but some studies have shown its comparable efficacy in patient not responding to corticosteroids with better tolerance than calcineurin inhibitors.The aim of this study is to describe the characteristics and outcomes of patients with MCD treated with MMF.
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Objectives To study the pharmacologic activity of mycophenolate mofetil in stable kidney transplant recipients receiving mycophenolate mofetil therapy for different periods from 2 months to 3 years. Methods Seventeen patients were enrolled during a 9-month period. Blood samples were collected before administration and ½, 1, 2, 4, and 6 hours after administration. Mycophenolic acid, the active metabolite of mycophenolate mofetil, was measured in plasma with use of the enzyme multiplication immunoassay technique (EMIT) assay and the activity of inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo biosynthesis of purines inhibited by mycophenolate mofetil, was determined in whole blood by the estimation of the 3H-release from [2,8-3H]-hypoxanthine. Results As the length of mycophenolate mofetil therapy increased, the inhibitory effect of mycophenolate mofetil on IMPDH activity was reduced (0.13 ± 0.03 for long-term treatment versus 0.46 ± 0.06 for short-term treatment; P = .0006) and a stimulatory effect of mycophenolate mofetil on IMPDH activity was observed (1.16 ± 0.56 for long-term treatment, versus 0.03 ± 0.01 for short-term treatment; P < .0001). These modifications of IMPDH activity were associated with fluctuations in the pharmacokinetics of mycophenolic acid. Conclusion Long-term treatment with mycophenolate mofetil was associated with an induction of IMPDH activity. Such induction could be deleterious if it is followed by a restoration or a stimulation of the proliferative capacity of lymphocytes. These results strongly suggest that the place of mycophenolate mofetil in long-term treatment of kidney transplant patients needs to be carefully assessed. Clinical Pharmacology & Therapeutics (1999) 65, 640–648; doi: 10.1016/S0009-9236(99)90085-1
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IMP Dehydrogenase
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Inosine
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Brunet, Merce1; Vilardell, Jordi2; Martorell, Jaume3; Millan, Olga3; Rojo, Isabel3; Corbella, Jaume1; Oppenheimer, Federico2 Author Information
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Free fraction
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The mycophenolate mofetil, a prodrug of mycophenolic acid, is a new immunosuppressive drug with a specific mechanism of action consisting in the inhibition of T- and B-lymphocytes proliferation. A series of animal experiments showed efficiency of the mycophenolate mofetil administered in monotherapy or in combination with other immunosuppressants to prolong the survival of different allo- and xenotransplanted grafts. In clinical trials, the mycophenolate mofetil, cyclosporine, and steroids demonstrated high efficacy in the prevention of acute rejection in the solid allotransplanted organs. The mycophenolate mofetil seems to be a suitable candidate for the treatment of many other, e.g., autoimmune and inflammatory diseases.
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Immunosuppressive drug
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