Mycophenolic acid pharmacokinetics in lung transplant recipients with cystic fibrosis.
BACKGROUND
Lung transplantation is an established treatment for cystic fibrosis (CF) patients with end-stage lung disease. Current immunosuppression includes the prodrug mycophenolate mofetil (MMF), which has led to improved transplant outcomes. Given the pancreatic insufficiency and malabsorption in CF patients, some transplant centers give higher doses of MMF to these patients based on lower predose levels (C(0)), even though C(0) values correlate poorly with mycophenolic acid (MPA) exposure. The focus of this pilot study was to determine the pharmacokinetics (PK) of MPA in CF when compared with noncystic fibrosis (NCF) lung transplant recipients.


METHODS
Five CF and 5 NCF patients had 3 separate PK analyses performed through our clinical research center. In addition to MMF, all patients were on tacrolimus and prednisone and were diabetic on insulin. Twelve-hour total serum concentration-time profiles of MPA and MPA glucuronide (MPAG) were obtained after oral administration of MMF. Concentrations of total MPA and MPAG were determined by a validated liquid chromatography-tandem mass spectrometry method. PK parameters of MPA were calculated by the noncompartmental method. Student t test or Mann-Whitney test was used to assess the differences in the PK parameters between the 2 cohorts.


RESULTS
CF patients were significantly younger (30.6 versus 59.4 years; P < 0.001) and had significantly lower serum albumin (3.8 versus 4.1 g/dL; P = 0.0018) than NCF patients. CF patients had significantly lower MPA area under the curve (47.7 versus 83.1 mg·h·L(-1); P = 0.016) and MPAG area under the curve (569 versus 911 mg·h·L(-1); P = 0.047) when compared with NCF patients. In addition, C(0) (2.6 versus 4.6 mg/L; P = 0.026) and maximum serum concentration (9.2 versus 20.3 mg/L; P = 0.016) were significantly lower, and apparent oral clearance (0.26 versus 0.13 L·h·kg(-1); P = 0.009) was significantly higher in CF patients. T(max) was delayed in CF patients but not significantly. No difference between CF and NCF patients was observed for intra- and interindividual variability.


CONCLUSIONS
Given these results, the lower MPA exposure in CF patients may impact transplant outcome in this lung transplant population.
*Department of Pharmacy Services, College of Pharmacy; Departments of †Internal Medicine and ‡Pathology, University of Michigan, Ann Arbor.
Linda
L
Stuckey
Tammy
T
Clark Ojo
Jeong M
JM
Park
Thomas
T
Annesley
Cathy
C
Bartos
Diane M
DM
Cibrik
D000328:Adult; D016022:Case-Control Studies; D003550:Cystic Fibrosis / Q000097:blood / Q000188:drug therapy* / Q000601:surgery*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010865:Pilot Projects
D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid