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


METHODS
This 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.


RESULTS
A 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].


CONCLUSIONS
The developed pharmacokinetic BE could be used to test prospectively the interest of MPA monitoring for limiting relapse of the disease or its progression.
INSERM, UMR-850, F-87025, Limoges, France; University Limoges, Laboratoire de Pharmacologie Médicale, F-87025, Limoges, France; CHU Limoges, Service de Pharmacologie, Toxicologie et Pharmacovigilance, F-87042, Limoges, France.
Jean-Baptiste
JB
Woillard
Brigitte
B
Bader-Meunier
Rémi
R
Salomon
Bruno
B
Ranchin
Stéphane
S
Decramer
Michel
M
Fischbach
Etienne
E
Berard
Vincent
V
Guigonis
Jérôme
J
Harambat
Olivier
O
Dunand
Julie
J
Tenenbaum
Pierre
P
Marquet
Franck
F
Saint-Marcoux
D000293:Adolescent; D019540:Area Under Curve; D001499:Bayes Theorem; D002648:Child; D002675:Child, Preschool; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D016015:Logistic Models; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D012189:Retrospective Studies
D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid
PK/PD; mycophenolic acid; pharmacokinetics; systemic lupus erythematosus