Dataset Information

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

ABSTRACT: 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 AUC_0-12 or C_trough, respectively. Results: The MPA AUC_0-12 in patients with active SLE was significantly lower than that in patients with inactive SLE. ROC analysis revealed that an AUC_0-12 threshold of 39 μg h/ml or a C_trough of 1.01 μg/ml was associated with the lowest risk of active SLE. Logistic regression analysis revealed that an AUC_0-12 of less than 34 μg h/ml or a C_trough of less than 1.2 μg/ml probably is associated with active SLE. The results of the exposure-response modeling also indicated that an AUC_0-12 less than 32 μg h/ml or a C_trough less than 1.1 μg/ml was associated with suboptimal clinical outcome. An AUC_0-12 above 50 μg h/ml or a C_trough above 1.7 ug/ml was associated with disease control. Conclusion: Both AUC_0-12 and C_trough of MPA are predictive of the likelihood of active SLE in pediatric patients receiving MMF. An individualized dosing regimen of MMF, with a target AUC_0-12 or C_trough, should be considered for SLE patients.

SUBMITTER: Chen Y

PROVIDER: S-EPMC7819284 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Chen Yewei Y Sun Li L Xu Hong H Dong Min M Mizuno Tomoyuki T Vinks Alexander A AA Brunner Hermine I HI Li Yifan Y Li Zhiping Z

Frontiers in pharmacology 20201221

<b>Objectives:</b> 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). <b>Methods:</b> 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 I ...[more]

PMID: 33488386

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Project description:ImportanceAnti-double-stranded DNA (dsDNA) antibody has been reported to have a close relationship with systemic lupus erythematosus (SLE) flares and participates in the pathogenesis of lupus nephritis (LN) as well as causing damage to other organs. However, whether early use of mycophenolate mofetil (MMF) could prevent SLE flares is not clear.ObjectiveTo assess the efficacy and safety of MMF plus prednisone and hydroxychloroquine sulfate compared with prednisone and hydroxychloroquine sulfate alone in patients with SLE.Design, setting, and participantsThis investigator-initiated, multicenter, observer-blinded randomized clinical trial enrolled 130 participants aged 18 to 65 years and was conducted in 3 hospitals across China. Treatment-naive patients with newly diagnosed SLE, a high titer of anti-dsDNA antibody, and no major organ involvement were included. The study was started September 1, 2018, and the follow-up was completed September 30, 2021. Data were analyzed from December 1, 2021, to March 31, 2022.InterventionsPatients were randomized 1:1 to receive oral prednisone (0.5 mg/kg/d) and hydroxychloroquine sulfate (5 mg/kg/d) (control group) or prednisone (0.5 mg/kg/d) and hydroxychloroquine sulfate (5 mg/kg/d) plus MMF (500 mg twice daily) (MMF group) for 96 weeks.Main outcomes and measuresThe primary outcome was the proportion of patients presenting with flares according to the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) Flare Index. The secondary outcomes included the proportion with lupus low disease activity state at week 96, 36-Item Short Form Health Survey scores before and after treatment, proportion of adverse events (AEs), and changes in SLEDAI-2000 scores and prednisone doses.ResultsAmong 130 randomized patients (mean [SD] age, 34.5 [12.5] years; 112 [86.2%] women), 119 (91.5%) completed the follow-up. The risk of severe flare was significantly lower in the MMF group (7 of 65 [10.8%]) vs the control group (18 of 65 [27.7%]) (relative risk [RR], 0.39 [95% CI, 0.17-0.87]; P = .01). Additionally, 1 of 65 patients in the MMF group (1.5%) and 9 of 65 in the control group (13.8%) manifested LN (RR, 0.11 [95% CI, 0.01-0.85]; P = .008). Most common serious study drug-related AEs were infections (20 of 65 [30.8%] in the control group and 22 of 65 [33.8%] in the MMF group).Conclusions and relevanceThe findings of this randomized clinical trial suggest that MMF may reduce the rate of severe flare and lower the incidence of LN in patients with new-onset SLE and a high titer of anti-dsDNA antibody without major organ involvement.Trial registrationChinese Clinical Trial Registry: ChiCTR1800017540.

Project description:BackgroundMycophenolate mofetil is an immunosuppressant commonly used to treat systemic lupus erythematosus (SLE) and lupus nephritis. It is a known teratogen associated with significant toxicities, including an increased risk of infections and malignancies. Mycophenolate mofetil withdrawal is desirable once disease quiescence is reached, but the timing of when to do so and whether it provides a benefit has not been well-studied. We aimed to determine the effects of mycophenolate mofetil withdrawal on the risk of clinically significant disease reactivation in patients with quiescent SLE on long-term mycophenolate mofetil therapy.MethodsThis multicenter, open-label, randomised trial was conducted in 19 centres in the USA. Eligible patients were aged between 18 and 70 years old, met the American College of Rheumatology (ACR) 1997 SLE criteria, and had a clinical SLEDAI score of less than 4 at screening. Mycophenolate mofetil therapy was required to be stable or decreasing for 2 years or more if initiated for renal indications, or for 1 year or more for non-renal indications. Participants were randomly allocated in a 1:1 ratio to a withdrawal group, who tapered off mycophenolate mofetil over 12 weeks, or a maintenance group who maintained their baseline dose (1-3g per day) for 60 weeks. Adaptive random allocation ensured groups were balanced for study site, renal versus non-renal disease, and baseline mycophenolate mofetil dose (≥2 g per day vs <2 g per day). Clinically significant disease reactivation by week 60 following random allocation, requiring increased doses or new immunosuppressive therapy was the primary endpoint, in the modified intention-to-treat population (all randomly allocated participants who began study-provided mycophenolate mofetil). Non-inferiority was evaluated using an estimation-based approach. The trial was registered at ClinicalTrials.gov (NCT01946880) and is completed.FindingsBetween Nov 6, 2013, and April 27, 2018, 123 participants were screened, of whom 102 were randomly allocated to the maintenance group (n=50) or the withdrawal group (n=52). Of the 100 participants included in the modified intention-to-treat analysis (49 maintenance, 51 withdrawal), 84 (84%) were women, 16 (16%) were men, 40 (40%) were White, 41 (41%) were Black, and 76 (76%) had a history of lupus nephritis. The average age was 42 (SD 12·7). By week 60, nine (18%) of 51 participants in the withdrawal group had clinically significant disease reactivation, compared to five (10%) of 49 participants in the maintenance group. The risk of clinically significant disease reactivation was 11% (95% CI 5-24) in the maintenance group and 18% (10-32) in the withdrawal group. The estimated increase in the risk of clinically significant disease reactivation with mycophenolate mofetil withdrawal was 7% (one-sided upper 85% confidence limit 15%). Similar rates of adverse events were observed in the maintenance group (45 [90%] of 50 participants) and the withdrawal group (46 [88%] of 52 participants). Infections were more frequent in the mycophenolate mofetil maintenance group (32 [64%]) compared with the withdrawal group (24 [46%]).InterpretationsMycophenolate mofetil withdrawal is not significantly inferior to mycophenolate mofetil maintenance. Estimates for the rates of disease reactivation and increases in risk with withdrawal can assist clinicians in making informed decisions on withdrawing mycophenolate mofetil in patients with stable SLE.FundingThe National Institute of Allergy and Infectious Diseases and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Project description:BackgroundSystemic lupus erythematosus (SLE) is a clinically and biologically heterogeneous autoimmune disease. We explored whether the deconvolution of whole blood transcriptomic data could identify differences in predicted immune cell frequency between active SLE patients, and whether these differences are associated with clinical features and/or medication use.MethodsPatients with active SLE (BILAG-2004 Index) enrolled in the BILAG-Biologics Registry (BILAG-BR), prior to change in therapy, were studied as part of the MASTERPLANS Stratified Medicine consortium. Whole blood RNA-sequencing (RNA-seq) was conducted at enrolment into the registry. Data were deconvoluted using CIBERSORTx. Predicted immune cell frequencies were compared between active and inactive disease in the nine BILAG-2004 domains and according to immunosuppressant use (current and past).ResultsPredicted cell frequency varied between 109 patients. Patients currently, or previously, exposed to mycophenolate mofetil (MMF) had fewer inactivated macrophages (0.435% vs 1.391%, p = 0.001), naïve CD4 T cells (0.961% vs 2.251%, p = 0.002), and regulatory T cells (1.858% vs 3.574%, p = 0.007), as well as a higher proportion of memory activated CD4 T cells (1.826% vs 1.113%, p = 0.015), compared to patients never exposed to MMF. These differences remained statistically significant after adjusting for age, gender, ethnicity, disease duration, renal disease, and corticosteroid use. There were 2607 differentially expressed genes (DEGs) in patients exposed to MMF with over-representation of pathways relating to eosinophil function and erythrocyte development and function. Within CD4 + T cells, there were fewer predicted DEGs related to MMF exposure. No significant differences were observed for the other conventional immunosuppressants nor between patients according disease activity in any of the nine organ domains.ConclusionMMF has a significant and persisting effect on the whole blood transcriptomic signature in patients with SLE. This highlights the need to adequately adjust for background medication use in future studies using whole blood transcriptomics.

Dataset Information

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

Publications

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

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