Influence of clinical and demographic variables on mycophenolic acid pharmacokinetics in antineutrophil cytoplasmic antibody-associated vasculitis.
BACKGROUND
Mycophenolic acid (MPA) is used off-label to treat many forms of glomerulonephritis.


OBJECTIVE
To evaluate the pharmacokinetics of MPA and its glucuronide (MPAG) in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis patients with renal manifestations and to determine the effects of clinical (urinary protein excretion, serum albumin, creatinine clearance) and demographic (age, race, sex) variables on MPA and MPAG pharmacokinetics.


METHODS
Twenty-three patients taking MPA at steady-state were evaluated. Plasma and urine samples were collected over 24 hours. Analyses included noncompartmental pharmacokinetics and statistics including Mann-Whitney U test and univariate/multiple regression.


RESULTS
MPA clearance (Cl/F 288 +/- 154 mL/min) was approximately 2-fold higher than previously reported from transplant patients and predicted by weight and race (ranked MPA Cl/F = -11.766 + 0.2035 [wt] + 4.9578 [race]; R(2) 41.8%; p = 0.005). Creatinine clearance (CrCl) less than 60 mL/min resulted in higher MPA exposure, total area under the curve (AUC)(0-12), and AUC(6-12), as well as unbound AUC(0-12). The metabolic ratio (MPAG(AUC)/MPA(AUC)) of 8.67 +/- 5.57 was lower than that previously reported in renal transplant recipients.


CONCLUSIONS
Diminished kidney function (eg, CrCl <60 mL/min) demonstrated enhanced MPA and MPAG exposure in patients with ANCA vasculitis. However, unlike renal transplant recipients, patients with ANCA vasculitis had enhanced Cl/F and diminished metabolic ratio, suggesting the need to comprehensively evaluate the role of disease-specific factors on MPA pharmacokinetics.
Joy
Melanie S
MS
School of Medicine, University of North Carolina (UNC) at Chapel Hill, Chapel Hill, NC 27599, USA.
Hilliard
Tandrea
T
Hu
Yichun
Y
Hogan
Susan L
SL
Wang
Jinzhao
J
Falk
Ronald J
RJ
Smith
Philip C
PC
D000328:Adult; D000368:Aged; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000276:immunology; D019540:Area Under Curve; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D005260:Female; D020719:Glucuronides / Q000493:pharmacokinetics*; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D012044:Regression Analysis; D051437:Renal Insufficiency / Q000150:complications; D018709:Statistics, Nonparametric; D014657:Vasculitis / Q000150:complications / Q000188:drug therapy* / Q000276:immunology
D019268:Antibodies, Antineutrophil Cytoplasmic; D004791:Enzyme Inhibitors; D020719:Glucuronides; C113145:mycophenolic acid glucuronide; D009173:Mycophenolic Acid