Pharmacokinetics of mycophenolic acid in patients with lupus nephritis.
OBJECTIVE
To evaluate and describe the pharmacokinetics of mycophenolic acid and its metabolite, mycophenolic acid glucuronide (MPAG), in patients with lupus nephritis, and to determine the effects of clinical parameters (urinary protein excretion as measured by the urinary protein:creatinine ratio, serum albumin level, and creatinine clearance) and demographic variables (age, race, sex) on the pharmacokinetics of total and unbound mycophenolic acid and MPAG.


METHODS
Pharmacokinetic analysis.


METHODS
University-affiliated general clinical research center.


METHODS
Eighteen patients with biopsy-confirmed lupus nephritis who were receiving maintenance therapy with mycophenolic acid for at least 2 weeks.


METHODS
Plasma and urine samples were collected for 24 hours and were assayed by high-performance liquid chromatography with ultraviolet detection.


RESULTS
Time to maximum concentration was variable (0.5-8 hrs). Mean +/- SD fraction of unbound mycophenolic acid was 2.6 +/- 1.9%, and oral clearance (Cl/F) was about 2-fold higher (343 +/- 200 ml/min) than previously reported. Multiple regression analysis showed that Cl/F of mycophenolic acid was predicted by creatinine clearance and serum albumin level: ln Cl/F = 5.358 + 0.0092 (creatinine clearance) - 0.078 (ranked albumin), R(2)=51.1%, p=0.0195. Patients with urinary protein excretion of 1 g/day or higher had lower minimum (trough) concentrations and area under the concentration-time curve (AUC(0-12)) profiles and higher Cl/F values compared with patients with urinary protein excretion of less than 1 g/day. Patients with serum albumin levels less than 4 g/dl had higher mycophenolic acid unbound clearance and MPAG renal clearance from 0-12 hours versus those with serum albumin levels of 4 g/dl or greater. Recycling AUC (AUC(6-12)), as well as sex and age (both equally), predicted renal clearance of MPAG.


CONCLUSIONS
Both creatinine clearance and serum albumin level were identified as primary contributors to mycophenolic acid exposure and should be considered when evaluating dosages. The results of future studies should clarify the interactions of other variables on drug exposure and treatment responses. Clinicians need to be mindful of clinical changes that occur throughout the course of lupus nephritis in order to maintain efficacy and reduce toxicity from mycophenolic acid therapy.
Joy
Melanie S
MS
University of North Carolina Kidney Center, Chapel Hill, North Carolina 27599-7155, USA. Melanie_Joy@med.unc.edu
Hilliard
Tandrea
T
Hu
Yichun
Y
Hogan
Susan L
SL
Dooley
Mary Anne
MA
Falk
Ronald J
RJ
Smith
Philip C
PC
D000328:Adult; D000367:Age Factors; D003404:Creatinine / Q000652:urine; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D005006:Ethnicity; D005260:Female; D020719:Glucuronides / Q000493:pharmacokinetics; D006801:Humans; D008181:Lupus Nephritis / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D011507:Proteinuria / Q000175:diagnosis; D012709:Serum Albumin; D012737:Sex Factors
D004791:Enzyme Inhibitors; D020719:Glucuronides; D012709:Serum Albumin; C113145:mycophenolic acid glucuronide; D003404:Creatinine; D009173:Mycophenolic Acid