Mycophenolic acid area under the concentration-time curve is associated with therapeutic response in childhood-onset lupus nephritis

Godron-Dubrasquet, Astrid; Woillard, Jean‐Baptiste; Decramer, Stéphane; Fila, Marc; Guigonis, Vincent; Tellier, Stéphanie; Morin, Denis; Sordet, Maud; Saint-Marcoux, F.; Harambat, Jérôme

doi:10.1007/s00467-020-04733-x

Cited by 21 publications

(15 citation statements)

References 39 publications

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“…The authors observed that the risk of active disease was 21 times greater in patients with an AUC <44 mg•h/L and 59 times greater for patients with a value of AUC/dose <0.06. Similar observation was found by Godron-Dubrasquet et al [73], who found the highest response rates of 89% in patients with MPA AUC >45 mg•h/L and concluded that this value may be considered as a target value in pediatric lupus nephritits. In their opinion, MPA TDM leading to individualized dosing may improve efficacy of MMF.…”

Section: Tdm Based On Pharmacokineticssupporting

confidence: 86%

“…MPA was firstly registered in prevention of acute rejection after renal transplantation; however, its activity is used not only after solid organ, intestinal, and HSCT but in other diseases, mainly of autoimmune background (lupus nephritis, nephrotic syndrome) as well. MPA TDM is recommended in pediatric patients, but it is still not a routine practice although numerous studies proved the advantage of dose adjustment based on TDM [66][67][68][69][70][71][72][73]. Our review includes studies on the MPA TDM in children after renal transplantation [67,[74][75][76][77][78][79][80][81], other organ transplantation such as heart [82,83], liver [72], or intestine [65], children after hematopoietic stem cell transplantation [84][85][86][87][88][89] or cord blood transplantation [90], and children with lupus [71,73,[91][92][93][94][95][96], nephrotic syndrome [69,70,[97][98][99][100][101][102]…”

Section: Mpa Characteristicsmentioning

confidence: 99%

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Recent Advances in Therapeutic Drug Monitoring of Voriconazole, Mycophenolic Acid, and Vancomycin: A Literature Review of Pediatric Studies

2021

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The review includes studies dated 2011–2021 presenting the newest information on voriconazole (VCZ), mycophenolic acid (MPA), and vancomycin (VAN) therapeutic drug monitoring (TDM) in children. The need of TDM in pediatric patients has been emphasized by providing the information on the differences in the drugs pharmacokinetics. TDM of VCZ should be mandatory for all pediatric patients with invasive fungal infections (IFIs). Wide inter- and intrapatient variability in VCZ pharmacokinetics cause achieving and maintaining therapeutic concentration during therapy challenging in this population. Demonstrated studies showed, in most cases, VCZ plasma concentrations to be subtherapeutic, despite the updated dosages recommendations. Only repeated TDM can predict drug exposure and individualizing dosing in antifungal therapy in children. In children treated with mycophenolate mofetil (MMF), similarly as in adult patients, the role of TDM for MMF active form, MPA, has not been well established and is undergoing continued debate. Studies on the MPA TDM have been carried out in children after renal transplantation, other organ transplantation such as heart, liver, or intestine, in children after hematopoietic stem cell transplantation or cord blood transplantation, and in children with lupus, nephrotic syndrome, Henoch-Schönlein purpura, and other autoimmune diseases. MPA TDM is based on the area under the concentration–time curve; however, the proposed values differ according to the treatment indication, and other approaches such as pharmacodynamic and pharmacogenetic biomarkers have been proposed. VAN is a bactericidal agent that requires TDM to prevent an acute kidney disease. The particular group of patients is the pediatric one. For this group, the general recommendations of the dosing may not be valid due to the change of the elimination rate and volume of distribution between the subjects. The other factor is the variability among patients that concerns the free fraction of the drug. It may be caused by both the patients’ population and sample preconditioning. Although VCZ, MMF, and VAN have been applied in pediatric patients for many years, there are still few issues to be solve regarding TDM of these drugs to ensure safe and effective treatment. Except for pharmacokinetic approach, pharmacodynamics and pharmacogenetics have been more often proposed for TDM.

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Section: Tdm Based On Pharmacokineticssupporting

confidence: 86%

Section: Mpa Characteristicsmentioning

confidence: 99%

Recent Advances in Therapeutic Drug Monitoring of Voriconazole, Mycophenolic Acid, and Vancomycin: A Literature Review of Pediatric Studies

2021

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“…In 19 pediatric patients with lupus nephritis or discoid lupus, Sagcal-Gironella et al reported that an MPA AUC 0-12 of 30 μg h/ml or higher was associated with improved disease control, whereas MPA AUC 0-12 lower than that were not ( Sagcal-Gironella et al, 2011 ). An MPA AUC 0-12 > 45 μg h/ml was proposed to significantly associated with therapeutic response in childhood-onset lupus nephritis in the study by Godron-Dubrasquet et al ( Godron-Dubrasquet et al, 2020 ). In the present study, an MPA AUC 0-12 of 39 μg h/ml or a C trough of 1.01 μg/ml was found as the target threshold for SLE in pediatric patients by ROC analysis, which is higher than the target MPA AUC 0-12 thresholds proposed by Zahr et al ( Zahr et al, 2010 ) and Sagcal-Gironella et al ( Sagcal-Gironella et al, 2011 ), but lower than the AUC 0-12 threshold reported by Godron-Dubrasquet et al ( Godron-Dubrasquet et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…An MPA AUC 0-12 > 45 μg h/ml was proposed to significantly associated with therapeutic response in childhood-onset lupus nephritis in the study by Godron-Dubrasquet et al ( Godron-Dubrasquet et al, 2020 ). In the present study, an MPA AUC 0-12 of 39 μg h/ml or a C trough of 1.01 μg/ml was found as the target threshold for SLE in pediatric patients by ROC analysis, which is higher than the target MPA AUC 0-12 thresholds proposed by Zahr et al ( Zahr et al, 2010 ) and Sagcal-Gironella et al ( Sagcal-Gironella et al, 2011 ), but lower than the AUC 0-12 threshold reported by Godron-Dubrasquet et al ( Godron-Dubrasquet et al, 2020 ). In general, the target MPA AUC 0-12 threshold for SLE patients proposed by our team is consistent with that reports by other previous studies.…”

Section: Discussionmentioning

confidence: 99%

PK/PD Study of Mycophenolate Mofetil in Children With Systemic Lupus Erythematosus to Inform Model-Based Precision Dosing

Chen

Sun

et al. 2020

Front. Pharmacol.

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Objectives: To evaluate the mycophenolic acid [MPA, the active form of mycophenolate mofetil (MMF)] pharmacokinetic parameters in relation to clinical response to identify target exposure ranges in pediatric patients with systemic lupus erythematosus (SLE).Methods: This was a retrospective study using pharmacokinetic data collected in 67 pediatric patients aged 4–18 years with SLE. Target MPA exposures for effective inhibition of SLE activity (as measured by SLE disease Activity Index (SLEDAI), active SLE was defined as a SLEDAI score of ≥6, and a controlled disease was defined as a SLEDAI score of ≤4) were assessed by receiver operating characteristic (ROC) curve and logistic regression. Exposure-response models were developed to quantitatively describe the relationship between SLEDAI score and AUC0–12 or Ctrough, respectively.Results: The MPA AUC0-12 in patients with active SLE was significantly lower than that in patients with inactive SLE. ROC analysis revealed that an AUC0–12 threshold of 39 μg h/ml or a Ctrough of 1.01 μg/ml was associated with the lowest risk of active SLE. Logistic regression analysis revealed that an AUC0–12 of less than 34 μg h/ml or a Ctrough of less than 1.2 μg/ml probably is associated with active SLE. The results of the exposure-response modeling also indicated that an AUC0-12 less than 32 μg h/ml or a Ctrough less than 1.1 μg/ml was associated with suboptimal clinical outcome. An AUC0-12 above 50 μg h/ml or a Ctrough above 1.7 ug/ml was associated with disease control.Conclusion: Both AUC0–12 and Ctrough of MPA are predictive of the likelihood of active SLE in pediatric patients receiving MMF. An individualized dosing regimen of MMF, with a target AUC0–12 or Ctrough, should be considered for SLE patients.

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“…158,244 Finally, a retrospective study analyzing 62 MPA AUC in 27 patients using a logistic regression adjusted for age, sex, LN classification, and time since MMF initiation showed that an MPA AUC .45 mg$h/L was significantly associated with a therapeutic response [odds ratio (OR) 3.6, 95% CI 2.4-9.5, P = 0.03]. 245…”

Section: Lupus Nephritismentioning

confidence: 99%

Personalized Therapy for Mycophenolate: Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology

Bergan¹,

Brunet²,

Hesselink³

et al. 2021

Therapeutic Drug Monitoring

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119

254

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When mycophenolic acid (MPA) was originally marketed for immunosuppressive therapy, fixed doses were recommended by the manufacturer. Awareness of the potential for a more personalized dosing has led to development of methods to estimate MPA area under the curve based on the measurement of drug concentrations in only a few samples. This approach is feasible in the clinical routine and has proven successful in terms of correlation with outcome. However, the search for superior correlates has continued, and numerous studies in search of biomarkers that could better predict the perfect dosage for the individual patient have been published. As it was considered timely for an updated and

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Mycophenolic acid area under the concentration-time curve is associated with therapeutic response in childhood-onset lupus nephritis

Cited by 21 publications

References 39 publications

Recent Advances in Therapeutic Drug Monitoring of Voriconazole, Mycophenolic Acid, and Vancomycin: A Literature Review of Pediatric Studies

Recent Advances in Therapeutic Drug Monitoring of Voriconazole, Mycophenolic Acid, and Vancomycin: A Literature Review of Pediatric Studies

PK/PD Study of Mycophenolate Mofetil in Children With Systemic Lupus Erythematosus to Inform Model-Based Precision Dosing

Personalized Therapy for Mycophenolate: Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology

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