Mycophenolate mofetil in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis: a prospective pharmacokinetics and clinical study

Chaigne, Benjamin; Darrouzain, François; Barbet, Christelle; Degenne, Danielle; François, Maud; Szymanski, Patryk; Rabot, Nolwenn; Golea, George Ionut; Diot, Élisabeth; Maillot, F.; Lebranchu, Yvon; Nivet, Hubert; Paintaud, Gilles; Jm, Halimi; Guillevin, Loı̈c; Büchler, Matthias

doi:10.1111/cei.12246

Cited by 14 publications

(16 citation statements)

References 51 publications

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“…21 In antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), it was shown that MPA AUC 0-12 correlates with disease activity even if MMF was not recommended as a standard treatment in AAV. 14 Finally, a large inter-individual variability in MPA plasma exposure was documented in these three conditions. 14,29,30 In the present study, SSc patients exhibited a median MPA AUC 0-12 of 44 mg/L.h (interquartile range (IQR) 32–58), close to the targeted range in renal transplant recipients and to the median MPA AUC 0-12 previously reported in SLE and vasculitis cohort.…”

Section: Discussionmentioning

confidence: 85%

“…20,21 Overall, practitioners generally consider that the target MPA AUC 0–12 range (30–60 mg/L.h) should be the same in autoimmune diseases as in renal transplant recipients. 14 However, to our knowledge, no data are available in SSc patients.…”

Section: Introductionmentioning

confidence: 97%

“…MMF was first introduced in solid organ transplantation (SOT) in 1996 6,7 and more recently prescribed in systemic autoimmune diseases. 8–14 Initially, the recommended dose of MMF for solid organ recipients was 1000 mg MMF twice daily, regardless of weight. 6 After oral intake, MMF is quickly and almost entirely absorbed and hydrolyzed by carboxyesterases to mycophenolic acid (MPA), the active component.…”

Section: Introductionmentioning

confidence: 99%

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Mycophenolic acid drug monitoring in patients with systemic sclerosis associated with diffuse skin and/or pulmonary involvement: A monocentric and retrospective French study

Legendre

Blanchet

Porcher

et al. 2020

Journal of Scleroderma and Related Disorders

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Objective: To explore pharmacokinetic/pharmacodynamic relationship between mycophenolic acid area under the curve and clinical response at 1 year on skin involvement or interstitial lung disease in patients with systemic sclerosis. Method: Retrospective, monocentric study based on French Scleroderma Database in patients receiving mycophenolate mofetil who experienced a limited sampling strategy to estimate individual mycophenolic acid area under the curve plus two pulmonary function tests and skin evaluation after 1 month and 1 year. Efficacy criterions were variations of modified Rodnan skin score, forced vital capacity, and diffusing lung capacity for carbon monoxide at 1 year. Results: We included 52 patients; mean age was 49 years (range 17–79), and 36 (69%) were females. Fifty patients (96%) had skin sclerosis, 39 (75%) had diffuse skin involvement with a median modified Rodnan skin score of 14 (0–38). Thirty-eight (76%) had interstitial lung disease, with median forced vital capacity and diffusing lung capacity for carbon monoxide of 81% (37–127) and 56% (28–103) from predicted values, respectively. Twenty-five (51%) patients had pulmonary fibrosis. Mycophenolate mofetil was given for 10 months (0–173) at a median dose of 2000 mg/day (500–3000). In the entire population, no relationship was found between area under the curve and modified Rodnan skin score (p = 0.085), forced vital capacity (p = 0.80), or diffusing lung capacity for carbon monoxide (p = 0.72) variations at 1 year. Conclusion: In this retrospective study, we failed to document any relationship between mycophenolic acid area under the curve and skin involvement or interstitial lung disease evolution. Routine monitoring of mycophenolic acid in systemic sclerosis patients treated with mycophenolate mofetil cannot be recommended based on our results.

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Section: Discussionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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Mycophenolic acid drug monitoring in patients with systemic sclerosis associated with diffuse skin and/or pulmonary involvement: A monocentric and retrospective French study

Legendre

Blanchet

Porcher

et al. 2020

Journal of Scleroderma and Related Disorders

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“…We did not perform therapeutic drug monitoring of MMF, and the therapeutic doses are, therefore, not known. Previous studies have shown that patients with ANCAassociated vasculitis as well as healthy individuals exhibit a high interindividual variability with respect to the plasma concentrations of MPA, the active metabolite of MMF (15). It was demonstrated that MPA concentrations were associated with outcome in ANCA-associated vasculitis, and possibly, higher dosages of MMF might have resulted in better outcome (16).…”

Section: Discussionmentioning

confidence: 99%

Mycophenolate Mofetil Versus Cyclophosphamide for the Induction of Remission in Nonlife-Threatening Relapses of Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

Tuin

Stassen²,

Bogdan

et al. 2019

CJASN

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Background and objectivesCyclophosphamide has been the mainstay of treatment of ANCA-associated vasculitis. However, cyclophosphamide has unfavorable side effects and alternatives are needed. Evidence suggests that mycophenolate mofetil can induce sustained remission in nonlife-threatening disease. The purpose of this study was to compare the efficacy and safety of mycophenolate mofetil versus cyclophosphamide for the induction treatment of nonlife-threatening relapses of proteinase 3-ANCA– and myeloperoxidase-ANCA–associated vasculitis.Design, setting, participants, & measurementsWe conducted a multicenter randomized, controlled trial. Participants with a first or second relapse of ANCA-associated vasculitis were randomized to induction treatment with cyclophosphamide or mycophenolate mofetil both in combination with glucocorticoids. Maintenance therapy consisted of azathioprine in both arms. Primary outcome was remission at 6 months, and secondary outcomes included disease-free survival at 2 and 4 years.ResultsEighty-four participants were enrolled, of whom 41 received mycophenolate mofetil and 43 received cyclophosphamide. Eighty-nine percent of participants were proteinase 3-ANCA positive. At 6 months, 27 (66%) mycophenolate mofetil–treated participants versus 35 (81%) cyclophosphamide-treated participants were in remission (P=0.11). Disease-free survival rates at 2 and 4 years were 61% and 39% for cyclophosphamide, respectively, and 43% and 32% for mycophenolate mofetil, respectively (at 4 years, log rank test, P=0.17).ConclusionsWe did not demonstrate mycophenolate mofetil to be similarly effective as cyclophosphamide in inducing remission of relapsed ANCA-associated vasculitis. However, mycophenolate mofetil might be an alternative to cyclophosphamide for the treatment of selected patients with nonlife-threatening relapses.

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“…In order to compare the relative drug exposure in patients prescribed different doses of MMF, we constructed the variable MPA_AUC 3g corresponding to a daily intake of 3 g MMF. This estimate was made by multiplying MPA_AUC 0–12 by 3 or 1.5, respectively, in patients using MMF at a dose of 1 or 2 g daily [ 26 , 27 ]. Descriptive data were presented using mean ± (SD) or median (IQR or range), and comparative analyses were done using non-parametric statistics including Spearman’s rank correlation ( r s ) coefficient, Kruskal-Wallis test and the Mann-Whitney U test.…”

Section: Methodsmentioning

confidence: 99%

Mycophenolate mofetil for systemic sclerosis: drug exposure exhibits considerable inter-individual variation—a prospective, observational study

et al. 2020

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Objective Mycophenolate mofetil (MMF) is an established therapy for systemic sclerosis (SSc), but its pharmacokinetics in this disease remains unexplored. We have investigated drug exposure in MMF-treated patients with SSc in relation to clinical features of the disease and common concomitant drugs. Methods This study was predefined to include 35 MMF-treated SSc patients who were using MMF at a fixed dose of 0.5, 1.0 or 1.5 g twice daily since at least 3 months. The 12-h drug exposure of the active MMF metabolite mycophenolic acid (MPA) was estimated by repeated analysis of plasma MPA over a 6-h period. This 12-h drug exposure was dose normalised to a daily intake of 3 g MMF (MPA_AUC3g) in order to compare subjects using MMF at different doses. Drug exposure was analysed in reference to the clinical characteristics including body weight, renal function, autoantibodies, intestinal dysbiosis, intestinal inflammation assessed by faecal (F)-calprotectin, intestinal symptoms assessed by the University of California Los Angeles Scleroderma Trial Consortium Gastrointestinal Tract Instrument 2.0 and concomitant drug usage including proton-pump inhibitors (PPI). Results Thirty-four out of 35 study participants completed the study. The mean daily MMF dose was 2.1 g. Drug exposure expressed as MPA_AUC3g varied up to 8-fold between patients (median 115, range 27–226 mg h/L). MPA_AUC3g was inversely related to body weight (rs = − 0.58, p < 0.001) and renal function (rs = − 0.34, p = 0.054). Anti-topoisomerase-1 antibodies and male sex were associated with lower MPA_AUC3g (87 vs 123 and 71 vs 141; p = 0.008 and p = 0.015, respectively). MPA_AUC3g was inversely related to the intestinal abundance of lactobacilli and to F-calprotectin (rs = − 0.54, p = 0.004; rs = − 0.36, p = 0.034), but not to gastrointestinal symptoms. MPA_AUC3g was inversely related to PPI usage (rs = − 0.45, p = 0.007). We found no association between MPA_AUC3g and disease subtype, disease duration or disease activity. Conclusion MMF-treated SSc patients exhibit considerable inter-individual variation in drug exposure, and lower MPA levels were primarily found in PPI users with poor prognostic factors. Body weight, renal function, sex, serology, gastrointestinal manifestations and/or measuring individual MPA exposure should be considered when using MMF for SSc.

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Mycophenolate mofetil in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis: a prospective pharmacokinetics and clinical study

Cited by 14 publications

References 51 publications

Mycophenolic acid drug monitoring in patients with systemic sclerosis associated with diffuse skin and/or pulmonary involvement: A monocentric and retrospective French study

Mycophenolic acid drug monitoring in patients with systemic sclerosis associated with diffuse skin and/or pulmonary involvement: A monocentric and retrospective French study

Mycophenolate Mofetil Versus Cyclophosphamide for the Induction of Remission in Nonlife-Threatening Relapses of Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

Mycophenolate mofetil for systemic sclerosis: drug exposure exhibits considerable inter-individual variation—a prospective, observational study

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