Pharmacokinetics and Pharmacodynamics of Mycophenolic Acid and Their Relation to Response to Therapy of Childhood-Onset Systemic Lupus Erythematosus

Sagcal‐Gironella, Anna Carmela P.; Fukuda, Tsuyoshi; Wiers, Kristina; Cox, Shareen; Nelson, Shannen; Dina, Blair; Sherwin, Catherine M.T.; Klein‐Gitelman, Marisa S.; Vinks, Alexander A.; Brunner, Hermine I.

doi:10.1016/j.semarthrit.2010.05.007

Cited by 51 publications

(50 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Based on our data, targeting higher exposures (total MPA AUC(0,12 h) >30 mg l -1 h) may be beneficial to improve clinical outcomes. This is in line with previous studies in which lower limit cut-off values for total MPA AUC(0,12 h) of 30, 35 and 45 mg l -1 h have been proposed for childhood-onset SLE [6], adult SLE [7] and lupus nephritis [8], respectively. It should be noted, however, that there are many factors that can influence target recommendations (e.g.…”

Section: Discussionsupporting

confidence: 92%

Exposure–effect relationship of mycophenolic acid and prednisolone in adult patients with lupus nephritis

Rahman

Tett

Gafor

et al. 2015

Brit J Clinical Pharma

View full text Add to dashboard Cite

AIMSThe aim was to examine relationships between total and unbound mycophenolic acid (MPA) and prednisolone exposure and clinical outcomes in patients with lupus nephritis. METHODSSix blood samples were drawn pre-and at 1, 2, 4, 6 and 8 h post-dose and total and unbound MPA and prednisolone pre-dose (C 0 ), maximum concentration (C max ) and area under the concentration-time curve (AUC) were determined using non-compartmental analysis in 25 patients. The analyses evaluated drug exposures in relation to treatment response since starting MPA and drugrelated adverse events. [7][8][9][10][11][12][13][14][15][16][17][18][19] was observed in patients with lowest tertile exposure to both total MPA and prednisolone as compared with patients with middle and higher tertile exposure (17% vs. 74%, P = 0.023). RESULTS Dose CONCLUSIONSThis study suggests a potential role for therapeutic drug monitoring in individualizing immunosuppressant therapy in patients with lupus nephritis.

show abstract

Section: Discussionsupporting

confidence: 92%

Exposure–effect relationship of mycophenolic acid and prednisolone in adult patients with lupus nephritis

Rahman

Tett

Gafor

et al. 2015

Brit J Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…The wide MPA area under the concentration-time curve for 0-12 hours (AUC 0-12 h ) variability in SLE patients (of which 86% suffered from LN) has been indicated by Zahr et al 9 11 The racial and ethnic factors may also have a significant influence on diversifying pharmacokinetic profiles and thus the effectiveness of the treatment. In a multicenter, randomized, open-label controlled trial, where the black patients constituted majority of overall number of participants, MMF was more effective than intravenous CYC in inducing remission of LN and had a more favorable safety profile.…”

Section: Therapeutic Drug Monitoring Of Mycophenolic Acid In Lupus Nementioning

confidence: 98%

“…It is worth mentioning that the main limitation of the majority of the studies, 10,11,[27][28][29][30][31] with exception of the study conducted by Zahr et al, 9 is the small sample size that ranges from 5 to 34 patients. Moreover, although free MPA fraction is pharmacologically active, none of the studies conducted so far has determined the free fraction of MPA.…”

Section: Correlation Between Mpa Pharmacokinetics and Renal Response mentioning

confidence: 99%

Therapeutic Drug Monitoring of Mycophenolic Acid in Lupus Nephritis

Łuszczyńska

Pawiński

2015

Therapeutic Drug Monitoring

View full text Add to dashboard Cite

In recent years, mycophenolate mofetil (MMF)-based immunosuppressive regimen was recommended in induction and in maintenance therapy in lupus nephritis (LN), one of the most severe and common manifestations of systemic lupus erythematosus. However, no recommendations were made so far regarding monitoring of mycophenolic acid (MPA) plasma concentrations. Therapeutic drug monitoring (TDM) constitutes a practical tool to ensure optimal posology. In renal transplantation, it was proved that acute allograft rejection incidences decreased when the recommended MPA target exposure has been maintained (30-60 mg·h·L). The results obtained in the field of transplant medicine indicate the potential benefit of carrying out TDM in LN. To date, the correlation of MPA exposure and clinical outcomes in the population of LN patients was the objective of just a few studies. The aim of this review was therefore to present TDM studies in LN patients on MMF therapy and to compare their results. Based on the conclusions drawn from TDM studies in LN, it can be suggested that the area under the concentration-time curve threshold values of 30-45 mg·h·L can potentially be associated with favorable treatment outcome. Moreover, the majority of the analyzed studies indicate relatively good correlation between trough concentration and the area under the concentration-time curve in patients treated with MMF that constitutes an important implication for TDM approach in routine setting. The threshold of 3 mg/L can potentially be recommended as a target trough value.

show abstract

“…Pharmacokinetic and demographic data were obtained from a cohort of 19 patients with cSLE on MMF therapy as recently described [3]. The study was approved by the institutional review boards of the Cincinnati Children’s Hospital Medical Center and Children’s Memorial Hospital, Chicago, IL.…”

Section: Methodsmentioning

confidence: 99%

“…Mycophenolate mofetil (MMF) is an immunosuppressive pro-drug commonly used in solid organ transplantation[1, 2] which is increasingly used off-label in the treatment of childhood-onset systemic lupus erythematosus (cSLE) [3]. After oral administration, MMF undergoes rapid conversion to its active form, mycophenolic acid (MPA)[1].…”

Section: Introductionmentioning

confidence: 99%

Nonsteroidal Anti-Inflammatory Drugs May Reduce Enterohepatic Recirculation of Mycophenolic Acid in Patients With Childhood-Onset Systemic Lupus Erythematosus

Fukuda

Brunner²,

Sagcal‐Gironella³

et al. 2011

Therapeutic Drug Monitoring

Self Cite

View full text Add to dashboard Cite

Background The large inter-individual differences observed in mycophenolic acid (MPA) pharmacokinetics (MPA-PK) are in part attributed to large variability in enterohepatic recirculation (EHC) of the drug. MPA’s main metabolite, MPA-glucuronide is actively secreted into the bile via the multidrug resistance-associated protein 2 (MRP2) transporter. Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to inhibit the MRP2 transporter which can alter EHC and drug exposure. Here, we evaluated the effects of this potential drug-transporter interaction on MPA-PK in a cohort for patients with childhood-onset systemic lupus erythematosus (cSLE) on mycophenolate mofetil (MMF) therapy. Methods and Materials Full MPA concentration-time profiles and demographics including co-medications were available for 19 patients with cSLE. Concentrations at pre-dose (Ctrough), 9 hour (C9) and nadir (Cnadir; defined as the lowest concentration between Cmax and C9), and Area under the curve (AUC0–12 and AUC6–12) were assessed using standard methods (WinNonlin5.1). AUC6–12/AUC0–12 and C9/Cnadir ratios were used to evaluate the effect of NSAIDs treatment on MPA-PK. Results Eleven out of 19 patients were on NSAID treatment, and did not show visual evidence of EHC in their PK profile. In contrast, patients not on NSAID therapy showed evidence of EHC-related MPA concentration increase in the later part of their PK profiles, typically after 6h. This phenomenon could be well characterized by the C9/Cnadir ratio, which was significantly lower in the NSAID-treated cohort (P<0.01). Conclusion These preliminary data suggest that concomitant intake of NSAID may lower EHC of MPA possibly through inhibition of MRP2 transport of MPA-G. Further mechanism-based studies are needed to further elucidate this potential transporter interaction.

show abstract

Pharmacokinetics and Pharmacodynamics of Mycophenolic Acid and Their Relation to Response to Therapy of Childhood-Onset Systemic Lupus Erythematosus

Cited by 51 publications

References 41 publications

Exposure–effect relationship of mycophenolic acid and prednisolone in adult patients with lupus nephritis

Exposure–effect relationship of mycophenolic acid and prednisolone in adult patients with lupus nephritis

Therapeutic Drug Monitoring of Mycophenolic Acid in Lupus Nephritis

Nonsteroidal Anti-Inflammatory Drugs May Reduce Enterohepatic Recirculation of Mycophenolic Acid in Patients With Childhood-Onset Systemic Lupus Erythematosus

Contact Info

Product

Resources

About