An observational study in Cystic Fibrosis and Lung Transplant, sponsored by University of Michigan. Completed. Open to participants aged 18 Years to 70 Years. Per ClinicalTrials.gov, last updated 2018-08-06.
Sponsored by University of Michigan · Observational
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.
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.
1,581 studies on the registry are indexed under Cystic Fibrosis; 190 are open to participants now.
This study's enrollment of 10 is below the median of 85 across 482 observational studies indexed under Cystic Fibrosis.
Browse Cystic Fibrosis studies →University of Michigan is the lead sponsor of 1,475 studies on the registry; 196 are open to participants now.
Of its 162 completed or terminated interventional studies of FDA-regulated products, 128 (79%) have results posted.
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Lung transplant patients with and without cystic fibrosis.
Exclusion Criteria:
Lung transplant patients with cystic fibrosis. Measuring MPA levels in cystic fibrosis lung transplant patients for pharmacokinetic parameters.
Non-cystic fibrosis lung transplant patients. Non-cystic fibrosis lung transplant patients will have MPA levels drawn after their dose to determine pharmacokinetic parameters.
Steady-state Pharmacokinetics of Mycophenolic Acid and Mycophenolic Acid Glucuronide in Stable Cystic Fibrosis and Non-Cystic Fibrosis Lung Transplant Recipients.
The AUC is the area under the concentration-time curve from time 0 to 12 hours. The AUC is measured in units of micrograms of mycophenolic acid (MPA) per milliliter of plasma (mcg/mL) multiplied by time in hours (mg\*h/L) and in units of micrograms of mycophenolic acid glucuronide (MPAG) per milliliter of plasma (mcg/mL) multiplied by time in hours (mg\*h/L). Apparent oral clearance (CL/F) was calculated by dose/AUC0-12.
Time frame: 0 hours pre-dose and again at 0.5, 1, 1.5, 2, 4, 6, 9, and 12 hours post-dose
Inter- and Intra-patient Variability of Mycophenolic Acid Exposure (AUC) in Cystic Fibrosis Lung Transplant Recipients on Tacrolimus Based Immunosuppression.
Inter- and intra-patient variability will be calculated by the coefficients of variation (CV) of the MPA AUC (mg\*h/L). To analyze the intra- and interindividual variability, the coefficient of variation (CV) was calculated by dividing the standard deviation by the mean of the PK parameters from the 3 PK visits and the 5 study patients in each group, respectively. Inter-individual CVs presented are only comparing within the individuals per arm, not across or between arms.
Time frame: 0 hours pre-dose and again at 0.5, 1, 1.5, 2, 4, 6, 9, and 12 hours post-dose
| Milestone | Cystic Fibrosis | Non-cystic Fibrosis Lung Transplant |
|---|---|---|
| Started | 5 | 5 |
| Completed | 5 | 5 |
| Not completed | 0 | 0 |
The AUC is the area under the concentration-time curve from time 0 to 12 hours. The AUC is measured in units of micrograms of mycophenolic acid (MPA) per milliliter of plasma (mcg/mL) multiplied by time in hours (mg\*h/L) and in units of micrograms of mycophenolic acid glucuronide (MPAG) per milliliter of plasma (mcg/mL) multiplied by time in hours (mg\*h/L). Apparent oral clearance (CL/F) was calculated by dose/AUC0-12.
| mg*h/L | Cystic Fibrosis | Non-cystic Fibrosis Lung Transplant |
|---|---|---|
| MPA AUC | 47.7 ± 13.7 | 83.1 ± 27.9 |
| MPAG AUC | 569 ± 204 | 911 ± 249 |
Inter- and intra-patient variability will be calculated by the coefficients of variation (CV) of the MPA AUC (mg\*h/L). To analyze the intra- and interindividual variability, the coefficient of variation (CV) was calculated by dividing the standard deviation by the mean of the PK parameters from the 3 PK visits and the 5 study patients in each group, respectively. Inter-individual CVs presented are only comparing within the individuals per arm, not across or between arms.
| percent CV | Cystic Fibrosis | Non-cystic Fibrosis Lung Transplant |
|---|---|---|
| MPA AUC..Intraindividual | 16.6 ± 6.1 | 13.8 ± 5.3 |
| MPA AUC..Interindividual | 31.2 ± 1.5 | 36.3 ± 5.6 |
| MPAG AUC..Intraindividual | 16.6 ± 6.5 | 15.9 ± 6.7 |
| MPAG AUC..Interindividual | 37.3 ± 6.1 | 27.8 ± 3.2 |
Collected over Up to 4 weeks. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Cystic Fibrosis | — | 0/5 (0%) | 0/5 (0%) |
| Non-cystic Fibrosis Lung Transplant | — | 0/5 (0%) | 0/5 (0%) |
| Age, Continuous(years) | Cystic Fibrosis | Non-cystic Fibrosis Lung Transplant | Total |
|---|---|---|---|
| Mean | 30.6 ± 6.8 | 59.4 ± 9.0 | 45.0 ± 16.9 |
| Sex: Female, Male(Participants) | Cystic Fibrosis | Non-cystic Fibrosis Lung Transplant | Total |
|---|---|---|---|
| Female | 3 | 3 | 6 |
| Male | 2 | 2 | 4 |
| Region of Enrollment(participants) | Cystic Fibrosis | Non-cystic Fibrosis Lung Transplant | Total |
|---|---|---|---|
| United States | 5 | 5 | 9 |
No study locations are listed for this record.
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