Effects of Mycophenolate Mofetil in Cystic Fibrosis Lung Transplant Patients
Condition: Cystic Fibrosis; Lung Transplant
MeSH terms: Cystic Fibrosis; Pulmonary Fibrosis; Fibrosis
Study type: Observational

Summary: 
      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.
    

Detailed description: 
      Background:

      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.
    

Observational model: Other
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Lung transplant patients with and without cystic fibrosis.