Therapeutic monitoring of mycophenolic acid in renal transplanted patients by a validated HPLC method

Introduction: Mycophenolate mofetil and its active metabolite mycophenolic acid are routinely used as immunosuppressant drugs in solid organ transplantation in a fixed daily dose regimen in association with cyclosporine, tacrolimus and steroids. Therapeutic drug monitoring for mycophenolic acid concentration has been suggested to optimize outcomes by reducing rejection and drug related toxicities in clinical renal transplantation. Aim: To determine the predose concentration of mycophenolic acid in renal transplanted patients by a validated proposed high-performance liquid chromatography (HPLC) method and to estimate the interindividual variability based on the therapeutic target. Materials and methods: An HPLC method combined with protein precipitation has been validated for mycophenolic acid determination in the human plasma obtained from 21 renal transplant recipients. HPLC analysis was carried out using the chromatographic system Agilent Technologies 1200 DAD. Samples were injected manually, and the compounds were separated on a LiChrosphere® select B C18 analytical column. The mobile phase was 45:55 (v/v) acetonitrile-buffer phosphate, pH 2.5, flow rate of 1.0 mL/min and column temperature of 30°C. Detection was performed at 215 nm. Whole blood samples were collected into vacutainers containing EDTA and separated at 6000 g for 10 minutes. A 200-μL aliquot of patient plasma was transferred to a tube, followed by addition of 10 μL of naproxen as internal standard and 400 μL of acetonitrile (v/v) as a protein precipitating agent. Each tube was vortex-mixed for 30 sec and then centrifuged for 10 min at 10000 rpm. 20 μL of the supernatant was injected into the HPLC system for analysis. Results: The method showed appropriate linearity for MPA with correlation coefficient greater than 0.999. High inter-patient variability is observed with 18% of patients within the target trough concentration range, 27% of patients below the target trough concentration range and 54% over the range with risk of toxicity. Conclusions: Therapeutic monitoring of MPA might contribute to a better management of renal transplant recipient with the goal of optimizing therapeutic regimens in order to reduce the risk of rejection and MPA‐related toxicity.

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Effects of Corticosteroid Treatment on Mycophenolic Acid Exposure in Renal Transplant Patients—Results From the SAILOR Study

Frontiers in Pharmacology ◽

10.3389/fphar.2021.742444 ◽

2021 ◽

Vol 12 ◽

Author(s):

Nima Nourbakhsh ◽

Jana Ekberg ◽

Karin Skov ◽

Christian Daugaard Peters ◽

Aygen Øzbay ◽

...

Keyword(s):

Body Weight ◽

Renal Transplant ◽

Mycophenolic Acid ◽

Interindividual Variation ◽

Fixed Dose ◽

Therapeutic Drug ◽

Solid Organ ◽

Renal Transplant Recipients ◽

Post Transplant

Background: Mycophenolic acid (MPA) is a potent immunosuppressive agent used in solid organ transplantation. MPA exhibits large interindividual variation in dose-normalized plasma concentrations but is nevertheless usually prescribed as a fixed dose without use of therapeutic drug monitoring (TDM). Data on the effect of corticosteroid (CS) treatment on MPA concentrations during concomitant tacrolimus treatment remains sparse.Methods: Data is based on TDM of MPA area under the concentration curve (AUC) in 210 renal transplant recipients participating in the prospective, randomized, controlled, multi-center trial (SAILOR) where a steroid-free immunosuppressive regimen with mycophenolate mofetil (MMF) and low-dose tacrolimus was compared with a conventional prednisolone-based treatment regimen. Multilevel mixed-effects linear regression post-hoc analyses of MPA AUC was performed.Results: Median MPA AUC at baseline (within the first 2 weeks post-transplant) in patients taking 2 g MMF daily was 53 mg*h/L (interquartile range: 43–69 mg*h/L, min: 24—max: 117 mg*h/L). Between-patient variation in MPA AUC was up to 5-fold on the same MMF dose. Patients in the steroid-free group had 12.5% lower (95% CI; 3.2–20.9%, p = 0.01) MPA AUC levels at baseline compared to the steroid treated group. During follow-up (14 days–2 years post-transplant) there were no significant differences in MPA AUC between the groups with MPA AUC being 4.2% lower (95% CI: −4.8%−12,5%, p = 0.35) in the steroid-free vs standard treatment group in restricted analysis after multivariate adjustment for tacrolimus trough level, body weight, time after transplantation and MMF dose. MMF dose was positively correlated with MPA AUC (p < 0.001) whereas body weight was negatively correlated with MPA AUC (p < 0.001). MPA AUC was 0.4% (95% CI: 0.2–0.6%, p < 0.001) lower per 1 kg increase in weight. Tacrolimus trough levels had no significant effect on MPA AUC.Conclusion: Immunosuppression with CS during concomitant tacrolimus treatment was shortly after transplantation associated with a significantly higher MPA exposure but the effect was small and not maintained during follow-up. Low body weight was associated with higher MPA exposure, which suggests a potential for weight adjusted MMF dosing.

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Therapeutic drug monitoring of tacrolimus and mycophenolic acid in outpatient renal transplant recipients using a volumetric dried blood spot sampling device

British Journal of Clinical Pharmacology ◽

10.1111/bcp.13755 ◽

2018 ◽

Vol 84 (12) ◽

pp. 2889-2902 ◽

Cited By ~ 21

Author(s):

Tom C. Zwart ◽

Sumit R.M. Gokoel ◽

Paul J.M. van der Boog ◽

Johan W. de Fijter ◽

Dina M. Kweekel ◽

...

Keyword(s):

Renal Transplant ◽

Therapeutic Drug Monitoring ◽

Mycophenolic Acid ◽

Drug Monitoring ◽

Dried Blood Spot ◽

Therapeutic Drug ◽

Renal Transplant Recipients ◽

Transplant Recipients ◽

Sampling Device ◽

Blood Spot

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Consensus Report on Therapeutic Drug Monitoring of Mycophenolic Acid in Solid Organ Transplantation

Clinical Journal of the American Society of Nephrology ◽

10.2215/cjn.07111009 ◽

2010 ◽

Vol 5 (2) ◽

pp. 341-358 ◽

Cited By ~ 203

Author(s):

Dirk R.J. Kuypers ◽

Yannick Le Meur ◽

Marcelo Cantarovich ◽

Michael J. Tredger ◽

Susan E. Tett ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Organ Transplantation ◽

Mycophenolic Acid ◽

Drug Monitoring ◽

Solid Organ Transplantation ◽

Therapeutic Drug ◽

Solid Organ ◽

Consensus Report

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Therapeutic Drug Monitoring of Mycophenolic Acid in Renal Transplant Recipients

Transplantation Proceedings ◽

10.1016/j.transproceed.2004.12.238 ◽

2005 ◽

Vol 37 (2) ◽

pp. 859-860 ◽

Cited By ~ 17

Author(s):

M. Okamoto ◽

Y. Wakabayashi ◽

A. Higuchi ◽

Y. Kadotani ◽

S. Ogino ◽

...

Keyword(s):

Renal Transplant ◽

Therapeutic Drug Monitoring ◽

Mycophenolic Acid ◽

Drug Monitoring ◽

Therapeutic Drug ◽

Renal Transplant Recipients ◽

Transplant Recipients

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Comparison of the Emit Immunoassay with HPLC for Therapeutic Drug Monitoring of Mycophenolic Acid in Pediatric Renal-Transplant Recipients on Mycophenolate Mofetil Therapy

Clinical Chemistry ◽

10.1093/clinchem/48.3.517 ◽

2002 ◽

Vol 48 (3) ◽

pp. 517-525 ◽

Cited By ~ 90

Author(s):

Lutz T Weber ◽

Maria Shipkova ◽

Victor W Armstrong ◽

Natalie Wagner ◽

Ekkehard Schütz ◽

...

Keyword(s):

Mycophenolate Mofetil ◽

Renal Transplant ◽

Acute Rejection ◽

Mycophenolic Acid ◽

Therapeutic Drug ◽

Renal Transplant Recipients ◽

Transplant Recipients ◽

Increased Risk ◽

Pediatric Renal Transplant ◽

Pediatric Renal Transplant Recipients

Abstract Background: HPLC is currently the preferred method for accurate measurement of mycophenolic acid (MPA). This study was designed to validate the Emit compared with HPLC in relation to clinical outcome measurements. Methods: Pediatric renal-transplant recipients (n = 50) on an immunosuppressive triple regimen consisting of cyclosporin A, prednisone, and mycophenolate mofetil (600 mg/m2 twice per day) were investigated in an open-label prospective study. Pharmacokinetic profiles over 12 h were obtained at 1 week, 3 weeks, 3 months, and 6 months posttransplant. Plasma MPA was measured by both reversed-phase HPLC and the Emit immunoassay. Results: There was an association between the risk of acute rejection episodes and low area under the curve values from t0 to t12h (AUC0–12) for MPA (MPA-AUC0–12) or predose concentrations of MPA derived from both HPLC and Emit measurements. According to ROC analysis, an AUC value of 33.8 mg · h/L for MPA from t0 to t12h (MPA-AUC0–12) determined by HPLC had a diagnostic sensitivity of 80% and a diagnostic specificity of 57%. The corresponding value of the Emit was 36.1 mg · h/L. For the predose concentration (MPA-c12), a concentration of 1.2 mg/L determined by HPLC and 1.4 mg/L determined by Emit gave a sensitivity of 80% and a specificity of 60%, respectively. There was no association of any pharmacokinetic variables derived from total MPA measurements with an increased risk of side effects related to mycophenolate mofetil. Conclusions: The Emit assay appears to have a comparable diagnostic efficacy to HPLC for assessing the risk of acute rejection in pediatric renal-transplant recipients. However, because of the cross-reactivity of the antibody used in the Emit assay with the active MPA acyl glucuronide metabolite, the decision thresholds for the Emit were higher than those calculated from HPLC measurements.

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Enteric-Coated Mycophenolate Sodium

Annals of Pharmacotherapy ◽

10.1345/aph.1d063 ◽

2003 ◽

Vol 37 (11) ◽

pp. 1685-1693 ◽

Cited By ~ 34

Author(s):

Steven Gabardi ◽

Jennifer L Tran ◽

Michael R Clarkson

Keyword(s):

Mycophenolate Mofetil ◽

Adverse Events ◽

Acute Rejection ◽

Mycophenolic Acid ◽

Solid Organ Transplantation ◽

Solid Organ ◽

Renal Transplant Recipients ◽

Efficacy And Safety ◽

Mycophenolate Sodium ◽

Enteric Coated

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of mycophenolate sodium. DATA SOURCES: Primary literature was obtained via a MEDLINE search (1966–June 2003). Abstracts were obtained from the manufacturer and included in the analysis. STUDY SELECTION AND DATA EXTRACTION: All studies and abstracts evaluating mycophenolate sodium in solid organ transplantation were considered for inclusion. English-language studies and abstracts were selected for inclusion, but were limited to those consisting of human subjects. DATA SYNTHESIS: Mycophenolate sodium, a mycophenolic acid prodrug, is an inhibitor of T-lymphocyte proliferation. Mycophenolic acid reduces the incidence of acute rejection in renal transplantation. Mycophenolate sodium is enteric coated and has been suggested as a potential method to reduce the gastrointestinal adverse events seen with mycophenolate mofetil. Both mycophenolate mofetil and mycophenolate sodium have been shown to be therapeutically equivalent at decreasing the incidence of allograft rejection and loss. The frequency of adverse events is similar between both compounds, with the most common events being diarrhea and leukopenia. CONCLUSIONS: Mycophenolate sodium is effective in preventing acute rejection in renal transplant recipients. At doses of 720 mg twice daily, the efficacy and safety profiles are similar to those of mycophenolate mofetil 1000 mg twice daily. Mycophenolate sodium has been approved in Switzerland; approval in the US is pending.

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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 ◽

10.1097/ftd.0b013e3181aa36cd ◽

2009 ◽

Vol 31 (4) ◽

pp. 416-435 ◽

Cited By ~ 109

Author(s):

Hylke de Jonge ◽

Maarten Naesens ◽

Dirk R J Kuypers

Keyword(s):

Therapeutic Drug Monitoring ◽

Organ Transplantation ◽

Mycophenolic Acid ◽

Drug Monitoring ◽

Solid Organ Transplantation ◽

Calcineurin Inhibitors ◽

Therapeutic Drug ◽

Solid Organ ◽

Pharmacokinetics And Pharmacodynamics

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Lung Cancer in Renal Transplant Recipients

BANTAO Journal ◽

10.1515/bj-2016-0004 ◽

2016 ◽

Vol 14 (1) ◽

pp. 17-19

Author(s):

Mirela Jozicic ◽

Alen Imsirovic ◽

Lea Katalinic ◽

Branimir Krtalic ◽

Nikolina Basic Jukic

Keyword(s):

Lung Cancer ◽

Renal Transplant ◽

Graft Function ◽

Solid Organ Transplantation ◽

Significant Risk ◽

Sarcomatoid Carcinoma ◽

Smoking History ◽

Solid Organ ◽

Renal Transplant Recipients ◽

Transplant Recipients

AbstractIntroduction. Although the incidence of malignancy has increased after solid organ transplantation, data on lung cancer in this group of patients is scarce. The aim of this study was to determine clinical characteristics and outcome of patients who developed lung cancer after renal transplantation. Methods. Among a cohort of 1658 patients who received a transplant at our institution and were followedup between 1973 and 2014, five patients developed lung cancer. We analyzed risk factors, transplantation characteristics, treatment options and survival. Results. Lung cancer was diagnosed in 5 patients (0.3%). Time to diagnosis after the transplant procedure ranged from 26 to 156 months (mean 115 months). All of them had a smoking history. Tumors were classified as IIB (20%), IIIA (40%), and IV (40%). Histological types included adenocarcinoma (80%) and there was one case of sarcomatoid carcinoma (20%). One patient had concomitant thyroid papillary carcinoma. Radiotherapy was applied in 2 patients, 2 underwent chemotherapy (erlotinib and combination of carboplatinum and etopozide in one patient each), and 2 died within one month after the diagnosis from disseminated malignant disease. Patients with stage IIIA survived 14 and 24 months after the diagnosis. The patient with sarcomatoid cancer underwent thoracotomy with a complete resection, lost his graft function and died 7 months after the diagnosis. Conclusion. Lung cancer is relatively rare malignancy in renal transplant recipients, but associated with high mortality. Smoking is a significant risk factor, thus smoking cessation should be promoted among renal transplant recipients, as well as regular screening for lung cancer.

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