Effects of Mycophenolate Mofetil in Cystic Fibrosis Lung Transplant Patients

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00908830
Recruitment Status : Unknown
Verified August 2011 by University of Michigan.
Recruitment status was:  Active, not recruiting
First Posted : May 27, 2009
Last Update Posted : August 4, 2011
Information provided by:
University of Michigan

May 26, 2009
May 27, 2009
August 4, 2011
June 2009
May 2011   (Final data collection date for primary outcome measure)
Characterize steady-state PK of MPA and MPAG in stable CF and non-CF lung transplant recipients. [ Time Frame: 3 weeks ]
Same as current
Complete list of historical versions of study NCT00908830 on Archive Site
Determine inter- and intra-patient variability of MPA exposure (AUC) in CF lung transplant recipients on tacrolimus based immunosuppression. [ Time Frame: 3 weeks ]
Same as current
Not Provided
Not Provided
Effects of Mycophenolate Mofetil in Cystic Fibrosis Lung Transplant Patients
Pharmacokinetics of Mycophenolic Acid in Cystic Fibrosis Lung Transplant Recipients
Lung transplantation is a life saving procedure for patients with a terminal lung disease such as cystic fibrosis. Approximately, one in 3,500 children in the United States are born with cystic fibrosis each year with the predicted survival reaching 36.9 years in 2006. Cystic fibrosis was the third lead indication for lung transplantation in 2006. Cystic fibrosis is a genetic disease that can affect the way the body can remove salt from various organs. It results in mucus blocking the ducts of the lungs and pancreas leading to inability to handle oxygen and malabsorption of nutrients. Malabsorption is a common complication of cystic fibrosis that can affect the way the anti-rejection medications are absorbed. One medication that is utilized after transplant to prevent rejection is mycophenolate mofetil. This medication may not be absorbed adequately in this population due to their disease thus placing these patients at increased risk of rejection. At the investigators' institution, all transplant patients are initiated at the same mycophenolate dose regardless of their underlying disease. The limited available literature regarding cystic fibrosis transplant patients and mycophenolate suggests that these patients require higher doses due to their erratic absorption. The purpose of this study is to evaluate the effects of mycophenolate mofetil on the body in lung transplant patients who have cystic fibrosis in efforts to improve survival outcomes.


Lung transplantation has been established as a viable treatment for cystic fibrosis (CF) patients who have end-stage lung disease. CF is a genetic disorder which is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene. These mutations cause abnormal transport of sodium chloride which affects various organs. In the lungs, there is a reduction in mucociliary clearance leading to viscous mucus that can block the airways. In addition to obstruction of the airways, the stagnant mucus provides a good medium for microorganisms leading to infectious complications.1,2 Approximately one in 3,500 children in the United States are born with CF each year with the predicted survival reaching 36.9 years in 2006.3 CF was the third leading indication (16%) for lung transplantation in 2006.4

The success of transplantation has been due to the advances in immunosuppression over the years. Within the past ten years, the substantial changes in the immunosuppression regimen include more transplant centers utilizing induction therapy (29% vs. 50% in 1995 and 2004, respectively); and baseline immunosuppression shifted from cyclosporine-based in 1995 (77%) to tacrolimus-based in 2004 (70%).5 In addition, mycophenolate mofetil (MMF) has been replacing azathioprine as the purine synthesis antagonist in maintenance regimens in the recent years.4

Gastrointestinal malabsorption is a common complication of CF that can affect the impact of immunosuppression. It has been shown that CF patients can have sub-therapeutic calcineurin inhibitors.6,7 However, little information regarding MMF pharmacokinetics (PK) exist in this population. One small observational study of 30 stable lung-transplant recipients demonstrated that the CF patients (n=7) required at least 30% higher doses to achieve similar pre-dose levels of mycophenolic acid (MPA) to that of non-CF patients (n=6).8 The authors did not include any other PK parameters in their results. In a second study, 12-hour PK of MPA and its glucuronide metabolites were characterized in 21 stable lung transplant recipients. The authors included 5 CF patients and found no significant difference in PK parameters except for the ratio of MPA glucuronide and MPA (MPAG/MPA) between the CF and non-CF patients. However, the CF patients tended to have a lower area under the curve (AUC) than non-CF patients. Inter- or intra-patient variability of MPA AUC was not determined in this study.9 In addition, these previous studies did not distinguish tacrolimus-based regimen from cyclosporine-based regimen.

At our institution, CF patients are managed the same as any other lung transplant patients in regards to immunosuppression. Standard starting dose for MMF is 1000mg twice daily within our institution, and pre-dose MPA levels are not routinely measured since they do not reflect MPA exposure. In contrast, other transplant centers dose MMF higher in CF patients based on the limited reports above. The purpose of this study is to determine PK of MPA and MPAG in CF patients on tacrolimus and compare them to a cohort of non-CF lung transplant patients.

Outline of the study:

We will conduct an open-label, PK study in stable CF lung transplant patients. Our study will also evaluate non-CF patients as the control group. Each patient will have three biweekly PK study visits. On the PK study days, patients will be admitted to the Michigan Clinical Research Unit (MCRU) at the University of Michigan Health Center. After administration of morning dose of MMF, serial blood samples will be collected at the following time intervals: immediately before and 0.5, 1, 1.5, 2, 4, 6, 9, and 12 hours after dosing. Serum creatinine and serum albumin will also be drawn. Vial of blood will be also collected to measure the function of IMPDH. Standardized meals will be provided on PK study days. Serum concentrations of total MPA and MPAG will be determined by a validated liquid chromatography with tandem mass spectrometry method.10

Outcome Measures:

Pharmacokinetic parameters of MPA and MPAG will be determined by noncompartmental methods. The area under the plasma concentration-time curve from time 0 to 12 hours (AUC) will be calculated by the trapezoidal rule. Maximum serum concentration (Cmax) and time to reach Cmax (Tmax) will be determined from visual inspection of the concentration-time profile. Clearance (CL/F) will be calculated by dose divided by AUC. Samples will be obtained to measure IMPDH and correlated with PK parameters. These tests will be assayed by Les Shaw at the University of Pennsylvania.

Statistical Analysis and Sample Size All PK parameters will be reported as mean and standard deviation. To analyze the inter- and intra-patient variability, coefficients of variation of the MPA AUC's will be calculated. Differences in the variables between the CF and non-CF patients will be determined by Student's t-test or Wilcoxon signed rank test. A two-sided p-value less than 0.05 will be considered significant.

Our sample size will be five CF and non-CF lung transplant patients.

Not Applicable
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
  • Cystic Fibrosis
  • Lung Transplant Patients
Drug: mycophenolate mofetil
Patients will take thier own 500-mg tablets of mycophenolate mofetil
Other Name: Brand name = cellcept
  • Active Comparator: Cystic fibrosis
    Lung transplant patients with cystic fibrosis. Measuring MPA levels in cystic fibrosis lung transplant patients for pharmacokinetic parameters.
    Intervention: Drug: mycophenolate mofetil
  • Active Comparator: Non-cystic fibrosis lung transplant
    Non-cystic fibrosis lung transplant patients. Non-cystic fibrosis lung transplant patients will have MPA levels drawn after their dose to determine pharmacokinetic parameters.
    Intervention: Drug: mycophenolate mofetil
Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Unknown status
Same as current
March 2012
May 2011   (Final data collection date for primary outcome measure)

Inclusion Criteria:

  • Ability and willingness to provide informed consent and be compliant with the study procedures
  • Between 18-70 years of age
  • Greater than 1 year post-transplant
  • Have no evidence of acute rejection at 1 year post-transplant biopsy or within three months of study entry
  • Stable mycophenolate mofetil dose
  • Stable renal function

Exclusion Criteria:

  • Serum creatinine greater than 2 mg/dl
  • Received pulse steroids within 3 months of the study entry
  • Chronic diarrhea
  • Concurrently on interacting medications (cholestyramine, etc)
Sexes Eligible for Study: All
18 Years to 70 Years   (Adult, Older Adult)
Contact information is only displayed when the study is recruiting subjects
Not Provided
UM 20989
Not Provided
Not Provided
Tammy Ojo, MD; Transplant Pulmonologist, University of Michigan Hospital
University of Michigan
Not Provided
Principal Investigator: Tammy Ojo, MD University of Michigan
University of Michigan
August 2011

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP