Date: Sunday, November 8, 2015
Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Background/Purpose: Mycophenolate mofetil (MMF) is an immunosuppressive drug used off-label for the treatment of childhood-onset systemic lupus erythematosus (cSLE). Therapeutic drug monitoring (TDM) of MMF’s active metabolite, Mycophenolic acid (MPA), has been increasingly used in order to achieve a target area under the curve (AUC) and improve cSLE patient outcomes. However, multiple timed blood samples are required to estimate AUC. We applied a population pharmacokinetics (PK) approach to derive a prediction model of MMF AUC in cSLE patients, so that we could test validity of limited sampling strategies
Methods: Our retrospective analysis included cSLE patients (≥ 4/11 ACR classification criteria) followed at the Hospital for Sick Children, Toronto. Patients were on stable dose of MMF for at least 6 weeks with no concomitant calcineurin inhibitors. Blood samples at baseline (trough levels), 1 h, 2h and 6 h were used for AUC estimation. A population pharmacokinetics (popPK) model describing MPA plasma concentration was developed using nonlinear mixed effects modeling (NONMEM) software. A Bayesian estimator based on the population pharmacokinetic model was used to predict the MPA AUC0-12. The final model was examined using goodness of fit, bootstrap method and visual predictive check. The individual MPA AUC0-12 predicted by a Bayesian estimator was compared to the individual MPA AUC0-12calculated by a limited sampling strategy formula (1) to evaluate validity of the model.
Results: We included 648 samples from 90 cSLE patients to build the popPK model. 128 samples with time window +/- 10 minutes from 32 patients were included to compare the AUC predicted by popPK model with the AUC calculated by the formula. All patients had normal liver/kidney function. The median age was 16 years (range: 6-19). Mean MMF dose was 626 mg/m2 (SD: 19) and the mean formula-derived AUC was 67.2mg- h/L (SD:4.5). The MPA PK was best described by a 2-compartment model with lag time and first order absorption. The popPK model-derived MPA AUC0-12 was closely correlated to the observed AUC calculated by the formula (r2=0.93, P<0.01) (Fig. 1). However, correlation between Ctrough and the model-predicted AUC was poor (r2=0.47). Also, none of the other MPA concentrations at single time point (1h, 2h and 6h post-dose) showed significant correlation with the model-derived AUC. The covariate analysis identified body weight as individual factor influencing the apparent oral clearance and volume distribution. Different steroid dosage, concomitant use of proton-pump inhibitors or ethnicity did not influence in observed and predicted AUC.
Conclusion: MPA trough levels, or levels based on a single post-dose time point (such as 1h, 2h or 6h) are not a reliable predictor for MPA AUC0-12.
1. Filler G, Mai I. Limited sampling strategy for mycophenolic acid area under the curve. Ther Drug Monit. 2000;22(2):169-73.
To cite this abstract in AMA style:Borgia RE, Takeuchi M, Levy DM, Ito S, Silverman E. Predicting Area Under the Curve of Mycophenolate Mofetil in Childhood-Onset Systemic Lupus Erythematosus [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/predicting-area-under-the-curve-of-mycophenolate-mofetil-in-childhood-onset-systemic-lupus-erythematosus/. Accessed September 28, 2021.
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