Exposure levels of mycophenolic acid are associated with comorbidities in children with systemic lupus erythematosus

Abstract

Introduction Little is known about the relationship between exposure levels of mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), and comorbidities of systemic lupus erythematosus (SLE) in children. This study aims to explore this association. Methods Longitudinal data from SLE children, who were taking MMF for immunosuppression and under therapeutic drug monitoring (TDM), were retrospectively collected. Area under the concentration-time curve of mycophenolic acid (MPA) over 24 hours (AUC0–24h) was estimated with Bayesian methods. Logistic regression and random forest models were used to explore the association between comorbidities and MPA exposure levels. Results This study included 107 children with 358 times of follow-up (median age 169.02 months). The incidence of diabetes, acute kidney injury (AKI), or pneumonia was significantly associated with AUC0–24h (odds ratio [OR] 0.991, 95% confidence interval [CI] 0.982–0.999), SLE duration (OR 1.012, 95% CI 1.002–1.022), lymphocyte percentage (OR 0.959, 95% CI 0.925–0.991), plasma albumin levels (OR 0.891, 95% CI 0.843–0.940), use of aspirin (OR 0.292, 95% CI 0.126–0.633) and hydroxychloroquine (OR 0.407, 95% CI 0.184–0.906). The random forest model showed that albumin and AUC0–24h were two important predictors. The case group (with the three comorbidities) had a mean AUC0–24h of 73.63 mg · h/L, while the control group had a mean AUC0–24h of 100.39 mg · h/L. Conclusions Increased levels of MPA exposure are associated with decreased incidence odds of diabetes, AKI or pneumonia in SLE children. An AUC0–24h of 100.39 mg · h/L or an AUC0-12h of 50.20 mg · h/L could be used as the targeted exposure level for clinical practice.

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

“…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]…”

“…In their opinion, MPA TDM leading to individualized dosing may improve efficacy of MMF. 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.…”

Utility of salivary mycophenolic acid concentration monitoring: Modeling and Monte Carlo validation approach

“…This decrease in protein binding seems to be caused both by the uremic state itself and by competition with the retained metabolite mycophenolic acid glucuronide (MPAG). 9 , 10 Mycophenolic acid pharmacokinetics demonstrated significant intra‐ and interindividual variability. Interindividual and intraindividual variability in the pharmacokinetics of several drugs has been reported in organ transplant patients.…”

“… 11 It has been shown that plasma MPA exposure, reflected by the area under the concentration‐time curve (AUC), varies widely in patients following the same dosage. 10 , 12 Previous studies reported that the MPA AUC 0‐12 is closely related to the risk for acute rejection. 13 , 14 , 15 Also, results of the previous studies demonstrated association between MPA exposure, ALB and adverse effects.…”

“…Previous studies noticed change in MPA‐albumin binding in patients with unstable kidney function, hypoalbuminemia and uremia, which may expose patients to adverse effects. This decrease in protein binding seems to be caused both by the uremic state itself and by competition with the retained metabolite mycophenolic acid glucuronide (MPAG) 9,10 . Mycophenolic acid pharmacokinetics demonstrated significant intra‐ and interindividual variability.…”