Pharmacokinetics of mycophenolate mofetil in children with lupus and clinical findings in favour of therapeutic drug monitoring

Abstract

AIMSThe use of mycophenolate mofetil (MMF) in children with systemic lupus erythematosus (SLE) is increasing. However, the clinical benefit of its monitoring has been scarcely studied, and little is known about its pharmacokinetics in this context. The objectives of the present study were: (i) to describe mycophenolic acid (MPA, the active moiety of MMF) pharmacokinetics, (ii) to develop a Bayesian estimator (BE) allowing the determination AUC (area under the curve) from a limited number of blood samples and (iii) to explore the relationships between exposure indices to MPA and the clinical status in children with SLE. METHODSThis was a retrospective study including 36 children with SLE, extracted from the expert system ISBA, for whom full-pharmacokinetic profiles of MPA were collected together with clinical data. A pharmacokinetic model and a BE were developed using an iterative two stage Bayesian approach. ROC curve analyses and logistic regressions were used to investigate the association of exposure and active disease. RESULTSA pharmacokinetic model and a BE were developed that allowed good AUC estimation performance (bias ± SD = −0.02 ± 0.15). ROC curve analyses showed that AUC/dose <0.06 and AUC <4 mg l −1 h were associated with a good sensitivity and specificity for active disease (78%/94% and 94%/56%, respectively). When introduced in a logistic regression model, AUC <44 mg l −1 h and AUC/dose <0.06 were associated with an increased risk of active disease (OR = 21.2, 95% CI 2.3, 196.1, P = 0.007 and OR = 59.5, 95% CI 5.9, 588.2, P = 0.0005 respectively]. CONCLUSIONSThe developed pharmacokinetic BE could be used to test prospectively the interest of MPA monitoring for limiting relapse of the disease or its progression. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Literature reports poor information about the therapeutic strategies to treat children with systemic lupus erythematosus (SLE).• Several studies in children with autoimmune diseases have shown that therapeutic drug monitoring of mycophenolic acid using AUC measurements could improve the therapeutic response of patients.• There is a need for a pharmacokinetic Bayesian estimator for MPA in a population of children with SLE.

Monitoring of mycophenolate mofetil metabolites in children with nephrotic syndrome and the proposed novel target values of pharmacokinetic parameters

“…These results should be interpreted with caution as the study group was small and at the same time MPA CL/F increased with treatment time although, according to the literature data, CL/F should decrease in children treated with MMF longer. MPA CL/F in our study was lower than in pediatric renal transplant recipients (Ghio et al, 2009;Woillard et al, 2014) and comparable to the results of only one study (Rother et al, 2012).…”

Mycophenolic Acid Pharmacokinetics and Relapse in Children with Steroid–Dependent Idiopathic Nephrotic Syndrome

“…), whereas too low doses may lead to reduced efficacy. The potential interest in therapeutic drug monitoring of MMF was first shown in inflammatory diseases, such as SLE, as well as solid organ transplantation (8)(9)(10)(11)(12)(13)(14). However, little is known about the role of therapeutic drug monitoring of MPA in INS.…”

Pharmacokinetics of Mycophenolate Mofetil in Omani Patients on Cyclosporine or Tacrolimus

“…Cyclosporine may interact negatively with MMF, whereas Tac may permit earlier achievement of MMF-AUC. Bayesian pharmacokinetics models show good sensitivity and specificity of the AUC and lupus flares [16]. Target AUC permits good control and reduced relapse rate of the disease [17].…”