Pharmacokinetics and Pharmacodynamics of Mycophenolic Acid and Their Relation to Response to Therapy of Childhood-Onset Systemic Lupus Erythematosus

Objectives

Mycophenolic acid (MPA) is the active form of mycophenolate mofetil (MMF), which is currently used off-label as immunosuppressive therapy in childhood-onset SLE (cSLE). The objectives of this study were to (1) characterize the pharmacokinetics (MPA-PK) and pharmacodynamics (MPA-PD) of MPA and (2) explore the relationship between MPA-PK and cSLE disease activity.

Methods

MPA-PK [area under the curve from 0-12 hours (AUC_0-12)] and MPA-PD [inosine-monophosphate dehydrogenase (IMPDH) activity] were evaluated in cSLE patients on stable MMF dosing. Change in SLE disease activity while on MMF therapy was measured using the British Isles Lupus Assessment Group (BILAG) index.

Results

A total of 19 AUC_0-12 and 10 IMPDH activity profiles were included in the analysis. Large interpatient variability in MPA exposure (AUC_0-12) was observed (mean ± SE: 32 ± 4.2 mg h/L; coefficient of variation: 57%). Maximum MPA serum concentrations coincided with maximum IMPDH inhibition. AUC_0-12 and weight-adjusted MMF dosing were only moderately correlated (r = 0.56, P = 0.01). An AUC_0-12 of ≥30 mg h/L was associated with decreased BILAG scores while on MMF therapy (P = 0.002).

Conclusion

Weight-adjusted MMF dosing alone does not reliably allow for the prediction of exposure to biologically active MPA in cSLE. Individualized dosing considering MPA-PK appears warranted as this allows for better estimation of immunologic suppression (IMPDH activity). Additional controlled studies are necessary to confirm that an MPA AUC_0-12 of at least 30 mg h/L is required for cSLE improvement.

Keywords: systemic lupus erythematosus, mycophenolic acid, pharmacokinetics, pharmacodynamics, inosine 5′-monophosphate dehydrogenase (IMPDH)