Regression and Genomic Analyses on the Association Between Dose-Normalized Mycophenolic Acid Exposure and Absolute Neutrophil Count in Steroid-Free, De Novo Kidney Transplant Recipients

Kiang, Tony K. L.; Partovi, Nilufar; Shapiro, R. Jean; Berman, Jacob M.; Collier, Abby C.; Ensom, Mary H H

doi:10.1007/s40261-018-0694-5

Cited by 14 publications

(21 citation statements)

References 38 publications

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“…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%

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: 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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“…Kuypers et al [47] also reported this finding but only among patients treated with 2 g MMF, and van Schaik et al [39] reported that the association was dependent on tacrolimus treatment. On the contrary, in patients treated with cyclosporine or macrolides, no association with MPA or MPAG pharmacokinetics was found by others [14,40,48,49] .…”

Section: Ugt1a9mentioning

confidence: 80%

“…The effect of UGT2B7 polymorphisms on MPA exposure in kidney recipients also was investigated. UGT2B7 c.-900G>A and 802C>T variants had no effect on MPA pharmacokinetics in patients treated with or without corticosteroids, which may induce glucuronidation and result in low MPA exposure [36,39,49,53,55] . Baldelli et al [48] found that the UGT2B7 802TT genotype was associated with higher MPA peak concentration without differences in AUC 0-12 MPA.…”

Section: Ugt2b7mentioning

confidence: 89%

“…The variants UGT1A9 rs3832043 (-118delT), rs72551330 (c.98T>C) and rs2741049 (I399T>C or IVS1 + 399T>C) do not seem to influence MPA or MPAG pharmacokinetics in kidney transplant patien ts [14,33,35,38,40,47,49,50] . Nevertheless, higher MPA AUC 0-12 was associated with the presence of UGT1A9 c.98TC genotype in one study with 338 patients [39] .…”

Section: Ugt1a9mentioning

confidence: 94%

“…Regarding the clinical outcomes, many investigations showed that the UGT1A9 c.-2152C>T, -665C>T, c.-275T>A, c.-440C>T, and c.98T>C variants were not associated with AR and MPA-related adverse events [13,22,27,29,34,[47][48][49] .…”

Section: Ugt1a9mentioning

confidence: 99%

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Mycophenolic acid pharmacogenomics in kidney transplantation

Genvigir¹,

Cerda²,

Hirata³

et al. 2020

jtgg

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Mycophenolic acid (MPA) is a potent antiproliferative drug prescribed to prevent acute rejection in kidney transplantation. MPA reversibly inhibits the enzymes involved in the synthesis of guanosine nucleotides, thus preventing DNA replication of immune cells. Consequently, the repression of both cell and humoral immunity induces renal allograft tolerance. MPA is an effective and safe immunosuppressive drug, but some patients show variability in drug concentration, acute rejection, graft dysfunction, or MPA-related adverse events. Although the pharmacogenomics of immunosuppressive drugs has been widely investigated, MPA has been explored to a lesser extent. This review of MPA pharmacogenomic studies, included pharmacokinetics, adverse events, and main clinical outcomes of MPA treatment in kidney transplantation. Associations of variants in genes encoding MPA metabolizing enzymes, transporters, and targets with drug efficacy and safety are described. Most pharmacogenetic studies have focused on small sample sizes and few simultaneously analyzed genetic variants. Some studies reported significant associations of pharmacokinetics-and pharmacodynamics-related genes with MPA exposure, acute rejection, graft dysfunction, hematological events, and gastrointestinal complications. However, even large cohorts did not replicate the findings, possibly due to divergent study design, immunosuppressive scheme, follow-up time, and other factors. Finally, the heterogeneity of aspects between studies limit conclusions on pharmacogenetic biomarkers of MPA in kidney transplantation.

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Pharmacogenomics of Immunosuppressants

Qiu

et al. 2020

Pharmacogenomics in Precision Medicine

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Regression and Genomic Analyses on the Association Between Dose-Normalized Mycophenolic Acid Exposure and Absolute Neutrophil Count in Steroid-Free, De Novo Kidney Transplant Recipients

Abstract: These findings support the clinical strategy for conducting MPA therapeutic drug monitoring in adult kidney transplant patients on steroid-free immunosuppressant therapy. The novel population genomic analysis data warrant further epidemiological investigations in a larger study sample.

Cited by 14 publications

References 38 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

Mycophenolic acid pharmacogenomics in kidney transplantation

Pharmacogenomics of Immunosuppressants

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