Development of a Bayesian estimator for the therapeutic drug monitoring of mycophenolate mofetil in children with idiopathic nephrotic syndrome

Saint-Marcoux, Franck; Guigonis, Vincent; Decramer, Stéphane; Gandia, Peggy; Ranchin, Bruno; Parant, François; Bessenay, Lucie; Libert, Frédérick; Harambat, Jérôme; Bouchet, Stéphane; Broux, Françoise; Compagnon, Patricia; Marquet, Pierre

doi:10.1016/j.phrs.2011.01.009

Cited by 48 publications

(117 citation statements)

References 40 publications

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“…Dorresteijn et al, in children with SDNS, also reported low MPA AUC (27 mg*h/L) in one child who had three relapses within 6 months on MMF, whereas six children with AUC between 40 and 99 mg*h/L had no relapses [18]. Additional studies in pediatric patients with [31,32]. The frequency of adverse effects in our patients was similar to those reported in studies using the same MMF dosage.…”

Section: Discussionsupporting

confidence: 85%

Mycophenolate mofetil for steroid-dependent nephrotic syndrome: a phase II Bayesian trial

et al. 2011

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Mycophenolate mofetil (MMF) has emerged as a new therapeutic option in steroid-dependent nephrotic syndrome (SDNS). We conducted a phase II Bayesian trial of MMF in children with SDNS. Phase II trials, usually single-arm studies, investigate the effect of new treatments. Standard Fleming's procedure relies on observed results (relapse rate during the trial), whereas Bayesian approach combines observed results with prior information (expected relapse rate according to prior studies and clinical experience). All patients were required to have received prior alkylating-agent treatment. Sixty-seven percent of them had also received levamisole. Patients received MMF (1,200 mg/m(2)/day) and prednisone according to a defined schedule [reduction of alternate-day (e.o.d) dose to 50% of pre-MMF dose at 3 months, 25% at 6 months]. Twenty-four children (median age 6.0 years, 2.8-14.4) entered the study and 23 completed it. Bayesian analysis showed that adding four patients would not change significance of results, allowing stopping inclusions. Four patients relapsed during the first 6 months (estimated probability 17.6%, 95% credibility interval: 5.4-35.0%) and two at months 8 and 11.5. In the 19 patients free of relapse during the first 6 months, median (Q1-Q3) prednisone maintenance dose decreased from 25 (10-44) to 9 (7.5-11.2) mg/m(2) e.o.d (p < 0.001) and cumulative dose from 459 (382-689) to 264 (196-306) mg/m(2)/month (p < 0.001) before and on MMF respectively. Pre-MMF patient characteristics and MMF pharmacokinetics did not differ between patients with or without relapse. MMF reduces relapse rate and steroid dose in children with SDNS and should be proposed before cyclosporine and cyclophosphamide.

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Section: Discussionsupporting

confidence: 85%

Mycophenolate mofetil for steroid-dependent nephrotic syndrome: a phase II Bayesian trial

et al. 2011

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“…20 We also observed considerable intraindividual variability, as suggested by a significant decrease in achieved MPA-AUCs (with an unchanged MMF dose) after 3 and 6 months of treatment. This is in contrast to the increase in MPA-AUC observed after renal transplantation.…”

Section: Discussionmentioning

confidence: 53%

Mycophenolate Mofetil versus Cyclosporin A in Children with Frequently Relapsing Nephrotic Syndrome

Gellermann

Weber

Pape

et al. 2013

Journal of the American Society of Nephrology

143

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The severe side effects of long-term corticosteroid or cyclosporin A (CsA) therapy complicate the treatment of children with frequently relapsing steroid-sensitive nephrotic syndrome (FR-SSNS). We conducted a randomized, multicenter, open-label, crossover study comparing the efficacy and safety of a 1-year treatment with mycophenolate mofetil (MMF; target plasma mycophenolic acid trough level of 1.5-2.5 mg/ml) or CsA (target trough level of 80-100 ng/ml) in 60 pediatric patients with FR-SSNS. We assessed the frequency of relapse as the primary endpoint and evaluated pharmacokinetic profiles (area under the curve [AUC]) after 3 and 6 months of treatment. More relapses per patient per year occurred with MMF than with CsA during the first year (P=0.03), but not during the second year (P=0.14). No relapses occurred in 85% of patients during CsA therapy and in 64% of patients during MMF therapy (P=0.06). However, the time without relapse was significantly longer with CsA than with MMF during the first year (P,0.05), but not during the second year (P=0.36). In post hoc analysis, patients with low mycophenolic acid exposure (AUC ,50 mgzh/ml) experienced 1.4 relapses per year compared with 0.27 relapses per year in those with high exposure (AUC.50 mgzh/ml; P,0.05). There were no significant differences between groups with respect to BP, growth, lipid levels, or adverse events. However, cystatin clearance, estimated GFR, and hemoglobin levels increased significantly with MMF compared with CsA. These results indicate that MMF is inferior to CsA in preventing relapses in pediatric patients with FR-SSNS, but may be a less nephrotoxic treatment option.

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“…As previously published for the description of MPA pharmacokinetic profiles in adult patients with kidney [17] or bone marrow [18] transplantation, with systemic lupus erythematosus (SLE) [19] or nephrotic syndrome [20], we used a single-compartment model with first-order elimination and two parallel routes of absorption described by a sum of two gamma distributions. Two independent modeling approaches were used for parameter estimation: the iterative two stage method (ITS) [21,22] and a non-parametric approach implemented in Pmetrics [16].…”

Section: Population Pk Approachesmentioning

confidence: 99%

Mycophenolic mofetil optimized pharmacokinetic modelling, and exposure-effect associations in adult heart transplant recipients

Woillard

Saint-Marcoux

Monchaud

et al. 2015

Pharmacological Research

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Development of a Bayesian estimator for the therapeutic drug monitoring of mycophenolate mofetil in children with idiopathic nephrotic syndrome

Cited by 48 publications

References 40 publications

Mycophenolate mofetil for steroid-dependent nephrotic syndrome: a phase II Bayesian trial

Mycophenolate mofetil for steroid-dependent nephrotic syndrome: a phase II Bayesian trial

Mycophenolate Mofetil versus Cyclosporin A in Children with Frequently Relapsing Nephrotic Syndrome

Mycophenolic mofetil optimized pharmacokinetic modelling, and exposure-effect associations in adult heart transplant recipients

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