Abstract
PurposeTo evaluate the relationship between total and free MPA pharmacokinetic (PK) parameters and renal outcome markers, and to verify whether conducting therapeutic drug monitoring (TDM) in lupus nephritis (LN) patients would be of value in routine clinical practice.MethodsEighty-four samples were collected from sixteen LN patients. Total and free MPA concentrations were measured at predose, 0.5 and 2 h after mycophenolate mofetil (MMF) intake. Area under the concentration time curve from 0 to 2 h (AUC0–2) and free fraction were calculated.ResultsHigh between-patient variability was observed (CV% of 53.5% for dose-normalized total MPA AUC0–2). A significant but weak correlation between dose-normalized total C0 and AUC0–2 was noted (r = 0.5699). Dose-normalized total C0 above 2.76 μg/mL·g may indicate patients with eGFR < 81 mL/min with sensitivity of 83.3% and specificity of 75.0%. Hypoalbuminemic LN patients demonstrated significantly elevated MPA free fraction when compared with patients with serum albumin concentration ≥ 3.5 g/dL (1.49 ± 0.64% vs 1.08 ± 0.75%).ConclusionThis study examined relationship between free and total pharmacokinetic MPA parameters as well as the effect of hypoalbuminemia on MPA plasma protein binding in adult LN patients. The study results suggest that TDM of MPA in LN seems to be a more reasonable approach than the fixed-dose protocol. Moreover, predose total MPA concentration may be a possible estimation of MPA exposure, while monitoring free rather than total MPA may be more beneficial in hypoalbuminemic patients.
Highlights
Mycophenolate mofetil (MMF), a prodrug of an immunosuppressive agent mycophenolic acid (MPA), is recommended by the Joint European League Against Rheumatism (EULAR) and European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) for the management of class III and IV lupus nephritis (LN) in induction as well as the maintenance therapy [1]
Results of free MPA concentrations measured in the samples in which plasma volume was insufficient to determine total MPA concentrations are presented in Supplementary Table 1
Dose-normalized total MPA C0 amounted to 4.59 ± 2.32 μg/mL·g vs 1.41 ± 1.15 μg/mL·g, while dosenormalized free MPA C0 amounted to 43.50 ± 31.40 ng/mL· g vs 17.34 ± 10.83 ng/mL·g
Summary
Mycophenolate mofetil (MMF), a prodrug of an immunosuppressive agent mycophenolic acid (MPA), is recommended by the Joint European League Against Rheumatism (EULAR) and European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) for the management of class III and IV lupus nephritis (LN) in induction as well as the maintenance therapy [1]. MPA pharmacokinetics is characterized by the considerable inter- and intrapatient variability fixed dose approach in the LN population may not be beneficial for the renal outcome improvement in every patient [2]. Monitoring of MPA plasma concentrations in transplant patients resulted in the reduction of the acute graft rejection episodes occurrence [3, 4]. There are no recommendations regarding therapeutic drug monitoring (TDM) in LN [1, 5] it was demonstrated that MPA exposure correlates with the treatment outcome [6, 7]. This suggests that dose adjustment to the MPA target concentrations range in the LN patients may be more beneficial than standard fixed dosing protocol. It still needs to be evaluated as limited number of studies have been published so far [5]
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