Pharmacokinetics of tacrolimus and mycophenolate mofetil in renal transplant recipients on a corticosteroid-free regimen

Greanya, Erica D.; Poulin, Éric C.; Partovi, Nilufar; Shapiro, R. Jean; Al-Khatib, Mai; Ensom, Mary H H

doi:10.2146/ajhp110287

Cited by 9 publications

(4 citation statements)

References 39 publications

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“…Our first discovery was that the concentrations of MPAG generated in this in vitro system (i.e. up to 1.05 μg/mL per million cells) were comparable with those observed in human plasma (Greanya et al, ), indicating the physiological relevance and the suitability for in vitro – in vivo extrapolation of our model. Because MPA is known to be primarily metabolized by UGT1A9 in the formation of MPAG (Staatz & Tett, ), another discovery was the confirmation of functional expression of UGT1A9 in HepaRG cell line.…”

Section: Resultssupporting

confidence: 61%

“…0.4 μg/mL, in 0.4% v/v methanol). This MPA concentration corresponded to the average free maximum concentration that can be attained in human subjects administered therapeutic doses of MMF (Greanya et al, ; Kiang et al, ). In order to determine MPAG and AcMPAG formation in relation to incubation time, cell supernatant was collected at (a) 0, 3, 6, 12, 18, 20 and 24 h and (b) 36, 48, 60 and 72 h following MPA (1.25 μ m ) treatment.…”

Section: Methodsmentioning

confidence: 93%

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Development and validation of a sensitive liquid‐chromatography tandem mass spectrometry assay for mycophenolic acid and metabolites in HepaRG cell culture: Characterization of metabolism interactions between p‐cresol and mycophenolic acid

Rong

Kiang

2019

Biomedical Chromatography

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Mycophenolic acid (MPA), a frequently used immunosuppressant, exhibits large interpatient pharmacokinetic variability. This study (a) developed and validated a sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for MPA and metabolites [MPA glucuronide (MPAG) and acyl-glucuronide (AcMPAG)] in the culture medium of HepaRG cells; and (b) characterized the metabolism interaction between MPA and p-cresol (a common uremic toxin) in this in vitro model as a potential mechanism of pharmacokinetic variability. Chromatographic separation was achieved with a C 18 column (4.6 × 250 mm,5 μm) using a gradient elution with water and methanol (with 0.1% formic acid and 2 mM ammonium acetate). A dual ion source ionization mode with positive multiple reaction monitoring was utilized. Multiple reaction monitoring mass transitions (m/z) were: MPA (320.95 → 207.05), MPAG (514.10 → 303.20) and AcMPAG (514.10 → 207.05). MPA-d 3 (323.95 → 210.15) and MPAG-d 3 (517.00 → 306.10) were utilized as internal standards. The calibration curves were linear from 0.00467 to 3.2 μg/mL for MPA/MPAG and from 0.00467 to 0.1 μg/mL for AcMPAG. The assay was validated based on industry standards. p-Cresol inhibited MPA glucuronidation (IC 50 ≈ 55 μM) and increased MPA concentration (up to >2-fold) at physiologically relevant substrate-inhibitor concentrations (n = 3). Our findings suggested that fluctuations in p-cresol concentrations might be in part responsible for the large pharmacokinetic variability observed for MPA in the clinic.

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Section: Resultssupporting

confidence: 61%

Section: Methodsmentioning

confidence: 93%

Development and validation of a sensitive liquid‐chromatography tandem mass spectrometry assay for mycophenolic acid and metabolites in HepaRG cell culture: Characterization of metabolism interactions between p‐cresol and mycophenolic acid

Rong

Kiang

2019

Biomedical Chromatography

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“…MPA pharmacokinetics has been studied mainly in transplanted patients and has exhibited high inter- and intra-individual variability, 9,10 but large variability was also observed in patients with SLE and LN. 1,11,12 Different factors contribute to variability, such as renal function, genetic polymorphisms in drug metabolizing enzymes and transporters, albumin concentrations and co-medication.…”

Section: Introductionmentioning

confidence: 99%

Population pharmacokinetics of mycophenolic acid in Mexican patients with lupus nephritis

Romano‐Aguilar

Reséndiz-Galván

Medellín‐Garibay

et al. 2020

Lupus

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Background Mycophenolic acid (MPA) is an effective oral immunosuppressive drug used to treat lupus nephritis (LN), which exhibits large pharmacokinetic variability. This study aimed to characterize MPA pharmacokinetic behaviour in Mexican LN patients and to develop a population pharmacokinetic model which identified factors that influence MPA pharmacokinetic variability. Methods Blood samples from LN patients treated with mycophenolate mofetil (MMF) were collected pre dose and up to six hours post dose. MPA concentrations were determined by a validated ultra-performance liquid chromatography tandem mass spectrometry technique. Patients were genotyped for polymorphisms in enzymes (UGT1A8, 1A9 and 2B7) and transporters (ABCC2 and SLCO1B3). The anthropometric, clinical, genetic and co-medication characteristics of each patient were considered as potential covariates to explain the variability. Results A total of 294 MPA concentrations from 40 LN patients were included in the development of the model. The data were analysed using NONMEM software and were best described by a two-compartment linear model. MPA CL, Vc, Vp, Ka and Q were 15.4 L/h, 22.86 L, 768 L, 1.28 h−1 and 20.3 L/h, respectively. Creatinine clearance and prednisone co-administration proved to have influence on clearance, while body weight influenced Vc. The model was internally validated, proving to be stable. MMF dosing guidelines were obtained through stochastic simulations performed with the final model. Conclusions This is the first MPA population pharmacokinetic model to have found that co-administration of prednisone results in a considerable increase on clearance. Therefore, this and the other covariates should be taken into account when prescribing MMF in order to optimize the immunosuppressant therapy in patients with LN.

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“…The data were arranged in four different groups, depending on the type of CNI with which the patient was co‐treated (CsA or Tac) and depending on time after transplantation (<6 or >6 months post‐transplant). A detailed overview of MPA exposure data from the papers included in this review can be found in Tables a , b , a , and b . Overall, the dose‐normalized MPA‐AUC 0–12 was higher in Asian than in Caucasian/AA patients and similar for Caucasian and AA patients.…”

Section: Resultsmentioning

confidence: 96%

Do Asian renal transplant patients need another mycophenolate mofetil dose compared with Caucasian or African American patients?

Shuker

Hesselink

et al. 2014

Transpl Int

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Summary Mycophenolate mofetil (MMF) is used to prevent acute rejection following solid organ transplantation in transplant centers all over the world. Patients from different ethnic backgrounds are treated with this drug, for which therapeutic drug monitoring (TDM) has not become the standard of practice in most centers. Whether or not some ethnic groups require a different MMF dose has been a topic of debate in recent years. In this review, it is shown that Asian patients, compared with Caucasian patients, with a comparable MMF dose reach higher mycophenolic acid (MPA) exposure. Also clinical experience points toward more adverse events in case of treatment with 1 g MMF bid in Asian patients, and therefore, for this ethnic group, a lower maintenance dose seems justified. In contrast, African American patients reach similar drug concentrations as Caucasians patients receiving the same MMF dose, but due to immunological reasons, they require a higher MMF dose to reach comparable acute rejection incidences. When TDM is performed, clinicians can correct the dose and compensate for interethnic differences in drug exposure. Otherwise, it is important to choose the right dose. This optimal dose is 20–46% lower in Asian transplant recipients than in Caucasian or African American patients.

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Pharmacokinetics of tacrolimus and mycophenolate mofetil in renal transplant recipients on a corticosteroid-free regimen

Cited by 9 publications

References 39 publications

Development and validation of a sensitive liquid‐chromatography tandem mass spectrometry assay for mycophenolic acid and metabolites in HepaRG cell culture: Characterization of metabolism interactions between p‐cresol and mycophenolic acid

Development and validation of a sensitive liquid‐chromatography tandem mass spectrometry assay for mycophenolic acid and metabolites in HepaRG cell culture: Characterization of metabolism interactions between p‐cresol and mycophenolic acid

Population pharmacokinetics of mycophenolic acid in Mexican patients with lupus nephritis

Do Asian renal transplant patients need another mycophenolate mofetil dose compared with Caucasian or African American patients?

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