The utility of trough mycophenolic acid levels for the management of lupus nephritis

Pourafshar, Negiin; Karimi, Ashkan; Wen, Xuerong; Sobel, Eric S.; Pourafshar, Shirin; Agrawal, Nikhil; Segal, Emma; Mohandas, Rajesh; Segal, Mark S.

doi:10.1093/ndt/gfy026

Cited by 22 publications

(18 citation statements)

References 46 publications

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“…Nevertheless, contrary to the renal transplant recipients due to better kidney function observed in autoimmune diseases [21,22], in a number of PK studies conducted in non-transplant patients a significant correlation between total MPA C 0 and MPA AUC 0-12 was reported (r = 0.545 [23], r = 0.561 [20], r = 0.578 [21], r = 0.643 [2], r = 0.79 [24], r = 0.90 [6], r = 0.94 [22]). The recent retrospective study that evaluated the relationship between total MPA C 0 and AUC 0-4 has also reported significant correlation (r = 0.55) [25]. These findings are consistent with our study since weak but still statistically significant correlation between absolute as well as dose-normalized total C 0 and AUC 0-2 was observed (r = 0.5508 and r = 0.5699, respectively).…”

Section: Discussionsupporting

confidence: 92%

Pharmacokinetics of free and total mycophenolic acid in adult lupus nephritis patients—implications for therapeutic drug monitoring

Łuszczyńska

Pawiński

Kunicki

et al. 2018

Eur J Clin Pharmacol

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Purpose To evaluate the relationship between total and free MPA pharmacokinetic (PK) parameters and renal outcome markers, and to verify whether conducting therapeutic drug monitoring (TDM) in lupus nephritis (LN) patients would be of value in routine clinical practice. Methods Eighty-four samples were collected from sixteen LN patients. Total and free MPA concentrations were measured at predose, 0.5 and 2 h after mycophenolate mofetil (MMF) intake. Area under the concentration time curve from 0 to 2 h (AUC 0-2) and free fraction were calculated. Results High between-patient variability was observed (CV% of 53.5% for dose-normalized total MPA AUC 0-2). A significant but weak correlation between dose-normalized total C 0 and AUC 0-2 was noted (r = 0.5699). Dose-normalized total C 0 above 2.76 μg/mL•g may indicate patients with eGFR < 81 mL/min with sensitivity of 83.3% and specificity of 75.0%. Hypoalbuminemic LN patients demonstrated significantly elevated MPA free fraction when compared with patients with serum albumin concentration ≥ 3.5 g/dL (1.49 ± 0.64% vs 1.08 ± 0.75%). Conclusion This study examined relationship between free and total pharmacokinetic MPA parameters as well as the effect of hypoalbuminemia on MPA plasma protein binding in adult LN patients. The study results suggest that TDM of MPA in LN seems to be a more reasonable approach than the fixed-dose protocol. Moreover, predose total MPA concentration may be a possible estimation of MPA exposure, while monitoring free rather than total MPA may be more beneficial in hypoalbuminemic patients.

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Section: Discussionsupporting

confidence: 92%

Pharmacokinetics of free and total mycophenolic acid in adult lupus nephritis patients—implications for therapeutic drug monitoring

Łuszczyńska

Pawiński

Kunicki

et al. 2018

Eur J Clin Pharmacol

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“…Clinical pharmacokinetics show that the mean clinical trough plasma MPA concentration of lupus nephritis female patients who were administered 1500 mg twice a day of oral MMF is 10.6 μM (3.4 mg/L) [ 23 ]. Another clinical study reported that the plasma concentration of MPA at trough in patients with severe lupus nephritis is 7.7 μM (2.47 mg/L) [ 24 ].…”

Section: Resultsmentioning

confidence: 99%

Mycophenolic acid, the active form of mycophenolate mofetil, interferes with IRF7 nuclear translocation and type I IFN production by plasmacytoid dendritic cells

et al. 2020

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Background Both humoral and cellular immune mechanisms are involved in the onset and progression of autoimmune responses in systemic lupus erythematosus (SLE). Plasmacytoid dendritic cells (pDCs) play a central role in the pathogenesis of SLE via the dysregulation of type I interferon (IFN) production; these cells act together with activated myeloid DCs (mDCs) to amplify the vicious pathogenic spiral of autoimmune disorders. Therefore, control of aberrant DC activation in SLE may provide an alternative treatment strategy against this disease. Mycophenolate mofetil (MMF), which has been used to treat lupus nephritis, specifically blocks the proliferation of B and T lymphocytes via inhibition of inosine-5-monophosphate dehydrogenase. Here, we focus on the effects of MMF in targeting DC functions, especially the IFN response of pDCs. Methods We isolated human blood pDCs and mDCs by flow cytometry and examined the effect of mycophenolic acid (MPA), which is a metabolic product of MMF, on the toll-like receptor (TLR) ligand response of DC subsets. Additionally, we cultured pDCs with serum from SLE patients in the presence or absence of MPA and then examined the inhibitory function of MPA on SLE serum-induced IFN-α production. Results We found that treatment with 1−10 μM of MPA (covering the clinical trough plasma concentration range) dose-dependently downregulated the expression of CD80 and CD86 on mDCs (but not pDCs) without inducing apoptosis, in response to R848 or CpG-ODN, respectively. Notably, in pDCs, MPA significantly suppressed IFN-α production with IRF7 nuclear translocation and repressed the AKT activity. In addition, MPA inhibited IL-12 production with STAT4 expression in mDCs. We further identified that MPA had an inhibitory effect on SLE serum-induced IFN-α production by pDCs. Conclusions Our data suggest that MPA can interrupt the vicious pathogenic spiral of autoimmune disorders by regulating the function of DC subsets. This work unveiled a novel mechanism for the therapeutic ability of MMF against SLE.

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“…Clinical concentrations of MPA do not affect the survival of human DC subsets Clinical pharmacokinetics show that the mean clinical trough plasma MPA concentration of lupus nephritis female patients who were administered 1,500 mg twice a day of oral MMF is 10.6 mM (3.4 mg/L) (22). Another clinical study reported that the plasma concentration of MPA at trough in patients with severe lupus nephritis is 7.7 mM (2.47 mg/L) (23).…”

Section: Resultsmentioning

confidence: 99%

Mycophenolic acid, the active form of mycophenolate mofetil, interferes with IRF7 nuclear translocation and type I IFN production by plasmacytoid dendritic cells

Shigesaka

Ito

Inaba

et al. 2020

Preprint

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Background Both humoral and cellular immune mechanisms are involved in the onset and progression of autoimmune responses in systemic lupus erythematosus (SLE). Plasmacytoid dendritic cells (pDCs) play a central role in the pathogenesis of SLE via the dysregulation of type I interferon (IFN) production; these cells act together with activated myeloid DCs (mDCs) to amplify the vicious pathogenic spiral of autoimmune disorders. Therefore, control of aberrant DC activation in SLE may provide an alternative treatment strategy against this disease. Mycophenolate mofetil (MMF), which has been used to treat lupus nephritis, specifically blocks the proliferation of B and T lymphocytes via inhibition of inosine-5-monophosphate dehydrogenase. Here, we focus on the effects of MMF in targeting DC functions, especially the IFN response of pDCs. Methods We isolated human blood pDCs and mDCs by flow cytometry and examined the effect of mycophenolic acid (MPA), which is a metabolic product of MMF, on the toll-like receptor (TLR) ligand response of DC subsets. Additionally, we cultured pDCs with serum from SLE patients in the presence or absence of MPA and then examined the inhibitory function of MPA on SLE serum-induced IFN-a production.Results We found that treatment with 1-10 mM of MPA (covering the clinical trough plasma concentration range) dose-dependently downregulated the expression of CD80 and CD86 on mDCs (but not pDCs) without inducing apoptosis, in response to R848 or CpG-ODN, respectively. Notably, in pDCs, MPA significantly suppressed IFN-α production with IRF7 nuclear translocation and repressed the AKT activity. In addition, MPA inhibited IL-12 production with STAT4 expression in mDCs. We further identified that MPA had an inhibitory effect on SLE serum-induced IFN-α production by pDCs. Conclusions Our data suggest that MPA can interrupt the vicious pathogenic spiral of autoimmune disorders by regulating the function of DC subsets. This work unveiled a novel mechanism for the therapeutic ability of MMF against SLE.

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The utility of trough mycophenolic acid levels for the management of lupus nephritis

Abstract: Trough levels of MPA do not show a strong correlation with AUC. In clinical situations where MPA levels are essential to guide therapy, an AUC0-4 would be a better indicator of the adequacy of treatment.

Cited by 22 publications

References 46 publications

Pharmacokinetics of free and total mycophenolic acid in adult lupus nephritis patients—implications for therapeutic drug monitoring

Pharmacokinetics of free and total mycophenolic acid in adult lupus nephritis patients—implications for therapeutic drug monitoring

Mycophenolic acid, the active form of mycophenolate mofetil, interferes with IRF7 nuclear translocation and type I IFN production by plasmacytoid dendritic cells

Mycophenolic acid, the active form of mycophenolate mofetil, interferes with IRF7 nuclear translocation and type I IFN production by plasmacytoid dendritic cells

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