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NEPHROLOGY

Influence of Clinical and Demographic Variables on Mycophenolic Acid Pharmacokinetics in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

Associate Professor, School of Medicine, University of North Carolina (UNC) at Chapel Hill; UNC Kidney Center and Division of Nephrology and Hypertension, School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, Chapel Hill, NC

Tandrea Hilliard, BS

Research Associate, School of Medicine, University of North Carolina at Chapel Hill; UNC Kidney Center and Division of Nephrology and Hypertension

Yichun Hu, MS

Statistician, University of North Carolina at Chapel Hill; UNC Kidney Center and Division of Nephrology and Hypertension

Susan L Hogan, PhD MPH

Assistant Professor, School of Medicine, University of North Carolina at Chapel Hill; UNC Kidney Center and Division of Nephrology and Hypertension

Jinzhao Wang, BS

Research Associate, School of Medicine, University of North Carolina at Chapel Hill; UNC Kidney Center and Division of Nephrology and Hypertension

Ronald J Falk, MD

Professor, School of Medicine, University of North Carolina at Chapel Hill; UNC Kidney Center and Division of Nephrology and Hypertension

Philip C Smith, PhD

Associate Professor, School of Pharmacy, University of North Carolina at Chapel Hill; Division of Molecular Pharmaceutics

Reprints: Dr. Joy, School of Medicine, University of North Carolina at Chapel Hill, UNC Kidney Center and Division of Nephrology and Hypertension, CB 7155, 7005 Burnett Womack Bldg. Chapel Hill, NC 27599, fax 919/966-4251, Melanie_Joy{at}med.unc.edu

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]; R² 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.

Key Words: antineutrophil cytoplasmic antibody-associated vasculitis, individualized therapy, mycophenolic acid, pharmacokinetics

Published Online, June 2, 2009. www.theannals.com, DOI 10.1345/aph.1L699