Pharmacokinetics and pharmacodynamics of mycophenolic acid and their relation to response to therapy of childhood-onset systemic lupus erythematosus.
OBJECTIVE
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).


CONCLUSIONS
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.
Sagcal-Gironella
Anna Carmela P
AC
Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA.
Fukuda
Tsuyoshi
T
Wiers
Kristina
K
Cox
Shareen
S
Nelson
Shannen
S
Dina
Blair
B
Sherwin
Catherine M T
CM
Klein-Gitelman
Marisa S
MS
Vinks
Alexander A
AA
Brunner
Hermine I
HI
D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D002648:Child; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use
D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid