Mycophenolic Acid Exposure Optimization Based on Vitamin D Status in Children with Systemic Lupus Erythematosus: A Single-Center Retrospective Study

Abstract

Introduction: Systemic lupus erythematosus (SLE) can affect bone metabolism and homeostasis of serum electrolytes that are associated with abnormal levels of vitamin D. Mycophenolate mofetil (MMF) is a commonly used immunosuppressant with the active metabolite mycophenolic acid (MPA). The area under the plasma concentration-time curve (AUC) of MPA is often monitored during the treatment to assess the exposure levels. This study aims to explore the association between exposure levels of MPA and 25-hydroxyvitamin D [25(OH)D] levels in children with SLE. Methods: Repeated measured data of children with SLE who were treated with MMF and under therapeutic drug monitoring (TDM) were retrospectively collected from the electronic medical records. MPA exposure levels were reflected by the area under the concentration-time curve over 24 h (AUC 0-24h ). Univariate and multivariate linear regression models were employed to analyze factors associated with 25(OH)D levels. Hierarchical linear models were developed to analyze the intra-and inter-individual effects of AUC 0-24h on the variance of 25(OH)D levels. Results: Data from 184 children with SLE (142 female and 42 male) with 518 follow-ups were collected. The median age was 14 years (range 3-18 years) at TDM. Children with normal 25(OH)D levels had significantly higher AUC 0-24h than children with low 25(OH)D levels (98.71 vs. 84.05 mgÁh/L, P = 0.004). Intraand inter-individual effects of AUC 0-24h on 25(OH)D levels were similar (c 10 = 0.034 vs. c 01 = 0.037) but only the intra-individual effect was significant (P = 0.001) in hierarchical models. Other associated factors include age, sex, season at measurement, glucocorticoid daily dose, and external vitamin D 3 supplements. Conclusion: 25(OH)D levels are associated with MPA exposure levels, and may serve as a potential indicator to optimize the exposure level of MPA during treatment. AUC 0-24h of 98.71 mgÁh/L or AUC 0-12h of 49.36 mgÁh/L could be the targeted exposure level for children with SLE.

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

“…Ye et al [96] observed increased levels of MPA exposure with decreased incidence odds of diabetes, acute kidney injury, or pneumonia and proposed even higher target exposure levels of MPA AUC for clinical practice (100.39 and 50.20 mg•h/L for AUC 0-24 and AUC 0-12 , respectively) in systemic lupus erythematosus children. In other study, Ye et al [94] suggested that target exposure levels might amount to 98.71 and 49.36 mg•h/L for AUC 0-24 and AUC 0-12 , respectively. Chen et al [92] evaluated target MPA pharmacokinetic parameters using different analysis and criteria and found that in studied children, 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 disease (ROC analysis), whereas an AUC 0-12 of <34 µg•h/mL or a C trough <1.2 µg/mL (logistic regression analysis) might be associated with active disease.…”

“…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][103][104][105]…”

“…Recently, Ye et al [94] postulated that 25-hydroxyvitamin D levels were associated with MPA exposure levels and may serve as a potential indicator to optimize the exposure level of MPA during treatment.…”

Clinical Research Progress of Small Molecule Compounds Targeting Nrf2 for Treating Inflammation-Related Diseases

“…Nrf2 inhibits Th17 differentiation and reduces STAT3 phosphorylation by upregulating Socs3 expression ( Figure 6 ) [ 141 ]. SLE can affect bone metabolism and serum electrolysis through renal impairment and by disturbing endocrine homeostasis [ 142 ]. In general, dysimmunity, oxidative stress, and inflammation are the key pathogenic features of SLE and LN [ 143 , 144 ].…”