mycophenolic-acid and Cystic-Fibrosis

The objective of this work was to characterize and compare the population pharmacokinetics (PK) mycophenolic acid (MPA) in adult lung transplant recipients with cystic fibrosis (CF) and without the disease (NCF) following repeated oral administration of the prodrug mycophenolate mofetil (MMF) as an immunosuppressant.. Three separate 12-h PK visits were conducted for lung transplant patients with or without CF following repeated MPA treatment with at least a 2-week break between the visits. A population PK model was developed using nonlinear mixed effects modeling (NONMEM), and the contribution of physiological and pathological factors and time dependence of apparent oral clearance (CL/F) were assessed.. For both CF and NCF patients, MPA serum concentration-time profiles were best described by a two-compartment PK model with first-order absorption. CF patients had a slower absorption rate (Ka), and elevated CL/F and volume of distribution (Vd/F) compared with NCF patients. There is a significant contribution of body weight and CF disease to MPA CL/F, and both were included in the final model as covariates.. The population PK model developed from our study successfully characterizes the absorption, distribution, and elimination of MPA in lung transplant recipients with or without CF disease. The decrease of MPA absorption and increase of both oral clearance (CL/F) and volume of distribution (V2/F and V3/F) in the CF patients would suggest the importance of MPA therapeutic monitoring for this group.

Topics: Adult; Aged; Area Under Curve; Cystic Fibrosis; Female; Graft Rejection; Humans; Immunosuppressive Agents; Lung Transplantation; Male; Middle Aged; Models, Biological; Mycophenolic Acid; Transplant Recipients

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.. 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.. 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.. Given these results, the lower MPA exposure in CF patients may impact transplant outcome in this lung transplant population.

Topics: Adult; Case-Control Studies; Cystic Fibrosis; Female; Humans; Immunosuppressive Agents; Lung Transplantation; Male; Middle Aged; Mycophenolic Acid; Pilot Projects

The immunosuppressive drug mycophenolate mofetil is used to prevent rejection after organ transplantation. In kidney transplant recipients, it has been demonstrated that adjustment of the mycophenolate mofetil dose on the basis of the area under the concentration-time curve (AUC) of mycophenolic acid (MPA), the active moiety of mycophenolate mofetil, improves the clinical outcome. Because of the high risks of rejections and infections in lung transplant recipients, therapeutic drug monitoring of the MPA AUC might be even more useful in these patients. The aims of this study were to characterize the pharmacokinetics of MPA in lung and kidney transplant recipients, describe the differences between the two populations and develop a Bayesian estimator of the MPA AUC in lung transplant recipients.. In total, 460 MPA concentration-time profiles from 41 lung transplant recipients and 116 kidney transplant recipients were included. Nonlinear mixed-effects modelling was used to develop a population pharmacokinetic model. Patients were divided into an index dataset and a validation dataset. The pharmacokinetic model derived from the index dataset was used to develop a Bayesian estimator, which was validated using the 35 lung transplant recipients' profiles from the validation dataset.. MPA pharmacokinetics were described using a two-compartment model with lag time, first-order absorption and first-order elimination. The influence of ciclosporin co-treatment and the changes over time post-transplantation were included in the model. Lung transplant recipients had, on average, a 53% slower absorption rate and 50% faster MPA apparent oral clearance than kidney transplant recipients (p < 0.001). In lung transplant recipients, the bioavailability was, on average, 31% lower in patients with cystic fibrosis than in patients without cystic fibrosis (p < 0.001). The Bayesian estimator developed using the population pharmacokinetic model--and taking into account ciclosporin co-treatment, cystic fibrosis and time post-transplantation, with concentrations measured at 0, 1 and 4 hours after mycophenolate mofetil dose administration--resulted in a non-significant bias and mean imprecision of 5.8 mg · h/L. This higher imprecision compared with those of similar estimators that have previously been developed in kidney transplantation might have been caused by the high MPA pharmacokinetic variability seen in the lung transplant recipients and by the fact that a large proportion of the patients did not receive ciclosporin, which reduces variability in the elimination phase of MPA by blocking its enterohepatic cycling.. Lung transplant recipients have a slower MPA absorption rate and faster apparent oral clearance than kidney transplant recipients, while cystic fibrosis results in lower MPA bioavailability. A Bayesian estimator using MPA concentration-time samples at 0, 1 and 4 hours post-dose had the best predictive performance.

Topics: Adolescent; Adult; Aged; Area Under Curve; Bayes Theorem; Biological Availability; Cystic Fibrosis; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Lung Transplantation; Male; Middle Aged; Models, Biological; Mycophenolic Acid; Reproducibility of Results; Young Adult

Topics: alpha 1-Antitrypsin Deficiency; Cyclosporine; Cystic Fibrosis; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Infusions, Intravenous; Lung Transplantation; Male; Middle Aged; Mycophenolic Acid; Survival Rate

Topics: Adult; Antibiotics, Antineoplastic; Antirheumatic Agents; Autoimmune Diseases; Cataract; Cystic Fibrosis; Electroretinography; Humans; Hydroxychloroquine; Lupus Erythematosus, Systemic; Male; Mycophenolic Acid; Physical Examination; Retina; Retinal Diseases; Vision Disorders; Vision Tests; Visual Acuity

1. Cystic fibrosis (CF) is a disease affecting multiple organs that may reduce the systemic exposure of some drugs. The objective of this work was to characterize and compare the population pharmacokinetics (PK) of the immunosuppressant mycophenolic acid (MPA), and its glucuronide metabolite (MPAG) in adult lung transplant recipients with and without CF (NCF) following repeated oral administration of the prodrug mycophenolate mofetil (MMF). 2. A population PK model was developed, with simultaneous modeling of MPA and MPAG, using nonlinear mixed effects modeling. MPA and MPAG serum concentration-time data were adequately described by a compartmental model including enterohepatic recirculation (EHR). Both MPA and MPAG apparent clearance values were significantly elevated (>65%) in patients with CF (24.1 and 1.95 L/h, respectively) compared to the values in the NCF patients (14.5 and 1.12 L/h, respectively), suggesting a notable influence of CF on MPA absorption and disposition. 3. The population PK model developed from our study successfully characterized the absorption, distribution, elimination and EHR of MPA and the metabolite MPAG in lung transplant recipients with or without CF. This model may help to further understand the impact of CF to the overall clinical effects of MPA therapy including immunosuppression and gastrointestinal side effects.

Topics: Cystic Fibrosis; Glucuronides; Humans; Immunosuppressive Agents; Lung Transplantation; Mycophenolic Acid; Transplant Recipients

We present management strategies utilised for the first case of an urgent live-donor ABO incompatible B blood group renal transplant, in a patient with a prior A blood group lung transplant for cystic fibrosis. Three years on, renal function is excellent and stable, whilst lung function has improved.

Topics: ABO Blood-Group System; Acute Disease; Adult; Cystic Fibrosis; Disease-Free Survival; Female; Graft Rejection; HLA Antigens; Humans; Isoantigens; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Lung Transplantation; Middle Aged; Mothers; Mycophenolic Acid; Plasmapheresis; Prednisolone; Sepsis; Tacrolimus; Withholding Treatment

Advanced kidney disease is usually considered an absolute contraindication for lung transplantation due to the difficult management of these patients in the post-operative period. Combined lung-kidney transplantation, however, could offer an opportunity for selected patients with renal and pulmonary dysfunction. This study summarizes the long-term success of a double transplantation in a 38-year-old male patient with cystic fibrosis who presented respiratory and kidney failure. After a complicated post-operative period, the patient currently lives completely independently 46 months after the operation and he enjoys excellent pulmonary and renal function.

Topics: Acute Disease; Adult; Antibodies, Monoclonal; Basiliximab; Coinfection; Cystic Fibrosis; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lung Transplantation; Male; Mycophenolic Acid; Pneumonia; Prednisone; Recombinant Fusion Proteins; Recovery of Function; Renal Dialysis; Respiratory Insufficiency; Tacrolimus

Topics: Cystic Fibrosis; Drug Monitoring; Humans; Lung Transplantation; Mycophenolic Acid; Retrospective Studies

Pharmacologic interactions and absorption disturbances after transplantation may induce serologic fluctuation of immunosuppression and adversely affect outcome. We present data showing that trough levels of mycophenolic acid decreased by 50% during combined mycophenolate mofetil (MMF) and cyclosporine therapy compared with levels during combined MMF and tacrolimus therapy. In addition, cystic fibrosis patients required 30% higher doses of MMF to achieve the therapeutic levels of recipients without cystic fibrosis.

Topics: Adult; Calcineurin Inhibitors; Cyclosporine; Cystic Fibrosis; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Lung Transplantation; Mycophenolic Acid; Tacrolimus

Bronchiolitis obliterans (BO) is the most important long-term complication of lung transplantation. Treatment of this condition is often unsuccessful.. A patient presented with early BO. Despite OKT3 and the addition of methotrexate, the patient needed persistently high doses of prednisone to maintain lung function at a moderate level. Only the substitution of azathioprine by mycophenolate mofetil (MMF, 3 g/day) made it possible to reduce the dose of prednisone.. Reduction of the dose of MMF to 2 g/day resulted in a deterioration of lung function, which improved impressively after MMF was increased again to 3 g/day.. MMF may be a valuable therapy for lung transplant BO. However, the use of a high dose, i.e., 3 g/day, may be crucial.

Topics: Adult; Bronchiolitis Obliterans; Cystic Fibrosis; Dose-Response Relationship, Drug; Female; Humans; Immunosuppressive Agents; Lung Transplantation; Mycophenolic Acid; Salvage Therapy