Repurposing DNase I and alginate lyase to degrade the biofilm matrix of dual-species biofilms of Staphylococcus aureus and Pseudomonas aeruginosa grown in artificial sputum medium: In-vitro assessment of their activity in combination with broad-spectrum antibiotics.

BACKGROUND: Biofilm-associated pulmonary infections pose therapeutic challenges in cystic fibrosis patients, especially when involving multiple bacterial species. Enzymatic degradation of the biofilm matrix may offer a potential solution to enhance antibiotic efficacy. This study investigated the repurposing of DNase I, commonly used for its mucolytic activity in cystic fibrosis, to target extracellular DNA within biofilms, as well as potential synergies with alginate lyase and broad-spectrum antibiotics in dual-species biofilms of Pseudomonas aeruginosa and Staphylococcus aureus. METHODS: Dual-species biofilms were grown in artificial sputum medium using S. aureus and P. aeruginosa isolated by pairs from the same patients and exposed to various combinations of enzymes, meropenem, or tobramycin. Activity was assessed by measuring biofilm biomass and viable counts. Matrix degradation and decrease in bacterial load were visualized using confocal microscopy. Biofilm viscoelasticity was estimated by rheology. RESULTS: Nearly complete destruction of the biofilms was achieved only if combining the enzymatic cocktail with the two antibiotics, and if using supratherapeutic levels of DNase I and high concentrations of alginate lyase. Biofilms containing non-pigmented mucoid P. aeruginosa required higher antibiotic concentrations, despite low viscoelasticity. In contrast, for biofilms with pigmented mucoid P. aeruginosa, a correlation was observed between the efficacy of different treatments and the reduction they caused in elasticity and viscosity of the biofilm. CONCLUSIONS: In this complex, highly drug-tolerant biofilm model, enzymes prove useful adjuvants to enhance antibiotic activity. However, the necessity for high enzyme concentrations emphasizes the need for thorough concentration-response evaluations and safety assessments before considering clinical applications.

"Just Move It . . . Move It": A Multidisciplinary Motivational Approach to Improve Physical Activity in Children With Cystic Fibrosis.

Regular physical activity (PA) is essential in cystic fibrosis (CF). This study assessed the impact of a motivational interviewing (MI)-based project titled "Just move it . . . move it," aimed at improving the PA of pediatric CF patients. At baseline and month 6, body mass index, spirometric values, and duration of extracurricular sport activities were collected. Concurrently, the maximum oxygen uptake (VO2max) was estimated. MI was performed during each visit. Overall, 19 CF children were included. Ten patients (52.7%) increased their regular PA (mean 1.9 hours/week) between both visits (PA+ group), while 9 did not (PA- group). No significant differences in functional and nutritional values were observed between the groups, while extracurricular sport time significantly increased in the PA+ group. "Just move it . . . move it" seems to be an efficient approach, as it was able to motivate several CF patients to initiate or increase their PA, yet without improving functional parameters.

Real-world data on the efficacy and safety of tezacaftor-ivacaftor in adults living with cystic fibrosis homozygous for F508del and heterozygous for F508del and a residual function mutation.

BACKGROUND: To examine safety and efficacy of tezacaftor-ivacaftor (TEZ/IVA) in a real-life setting in adults living with cystic fibrosis. METHODS: A multicentre retrospective observational study, including adults living with cystic fibrosis (pwCF) eligible for TEZ/IVA, with assessments at baseline, 3 months (visit3mo) and 6 months (visit6mo) after start of treatment. Outcomes included change in FEV1, LCI, FeNO, CFQ-R, estimated number of annual acute exacerbations, BMI, dosage of pancreatic enzyme replacement therapy (PERT) and airway microbiology. We also assessed safety. RESULTS: Forty-eight adult pwCF (mean (±SD) age 33 (±12) years; mean FEV1 65 (±19) %P) were included. Three subgroups were identified: pwCF F/F CFTR modulator-naive (n = 28; 58%), pwCF F/F previously treated with lumacaftor-ivacaftor (n = 11; 23%) and pwCF F/RF (n = 9; 19%). Adverse events were described in 3 pwCF (6%) during the 6-month observation period (in one leading to treatment interruption). At visit3mo, FEV1 had improved in all subgroups. In the entire group, mean FEV1 had increased from 66 (±2.9) %P to 72 (±2.9) %P (p < 0.0001). Similarly, LCI improved by approximately one unit at visit3mo (p = 0.02). At visit6mo mean annual acute exacerbation rate decreased significantly (p = 0.02). Only in the CFQ-R social functioning domain score, a significant improvement was observed at visit6mo (p < 0.01). CONCLUSIONS: We showed that TEZ/IVA is safe, well tolerated and effective in terms of improvement of lung function, ventilation inhomogeneity, health-related social functioning, and reduction of estimated annual acute exacerbation rate, in adult pwCF F/F and F/RF. Results in this real-life study reflect those observed in RCTs.

Non-respiratory health-related quality of life in people with cystic fibrosis receiving elexacaftor/tezacaftor/ivacaftor.

Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in people with cystic fibrosis (CF) heterozygous for F508del and a minimal function mutation (F/MF) or homozygous for F508del (F/F) in two pivotal Phase 3 trials, significantly improving percentage predicted forced expiratory volume in 1 second, Cystic Fibrosis Questionnaire-Revised, Respiratory Domain (CFQ-R RD) scores, and sweat chloride concentration. Here, we analyzed the 11 non-respiratory domains (non-RDs) of the CFQ-R, which assess general health-related quality of life (i.e., Physical Functioning, Role Functioning, Vitality, Health Perceptions, Emotional Functioning, and Social Functioning) and quality of life impacted by CF (i.e., Body Image, Eating Problems, Treatment Burden, Weight, and Digestive Symptoms), for participants in these two Phase 3 trials. ELX/TEZ/IVA treatment led to higher scores in all CFQ-R non-RDs, with improvements in most domains compared with control treatments. These findings demonstrate that ELX/TEZ/IVA improves a range of CF-specific symptoms and general functioning and well-being.

ISHLT consensus document on lung transplantation in patients with connective tissue disease: Part II: Cardiac, surgical, perioperative, operative, and post-operative challenges and management statements.

Patients with connective tissue disease (CTD) present unique surgical, perioperative, operative, and postoperative challenges related to the often underlying severe pulmonary hypertension and right ventricular dysfunction. The International Society for Heart and Lung Transplantation-supported consensus document on lung transplantation in patients with CTD standardization addresses the surgical challenges and relevant cardiac involvement in the perioperative, operative, and postoperative management in patients with CTD.

Phenotypical diversity of airway morphology in chronic lung graft vs. host disease after stem cell transplantation.

Pulmonary graft vs. host disease is a diverse and underestimated complication following allogenic hematopoietic stem cell transplantation. We aimed to compare the airway architecture with chronic lung allograft dysfunction post lung transplantation. Inflated explant lungs from graft vs. host disease patients were compared with lungs with chronic lung allograft dysfunction following lung transplantation, and control lungs using a combination of CT, microCT, and histology (n = 6 per group) and pathology in the (small) airways was further quantified and analyzed. Following allogenic hematopoietic stem cell transplantation, three patients presented as bronchiolitis obliterans syndrome and three patients showed interstitial changes and restriction. The CT analysis demonstrated a strong similarity between bronchiolitis obliterans syndrome after lung transplantation and post allogenic hematopoietic stem cell transplantation, evidenced by severe ( > 50%) airway obstruction from generation 9, with 70.8% of the airways ending in obstruction. Further analysis indicated that the airways either collapsed or accumulated matrix along a segment of the airway. In patients with restriction and interstitial changes following allogenic hematopoietic stem cell transplantation, the degree of airway obstruction was lower compared with bronchiolitis obliterans syndrome post allogenic hematopoietic stem cell transplantation, but similar to restrictive allograft syndrome post lung transplantation, showing a lower proportion of airway obstruction (20-35%), decreased number of terminal bronchioles per lung (p < 0.01), and parenchymal fibrosis. We observed similarities in the airway and parenchymal morphometric changes in lung graft vs. host disease and with chronic lung allograft dysfunction following lung transplantation, suggesting similar pathophysiological mechanisms.

Lung transplantation after allogeneic stem cell transplantation: a pan-European experience.

Late-onset noninfectious pulmonary complications (LONIPCs) affect 6% of allogeneic stem cell transplantation (SCT) recipients within 5 years, conferring subsequent 5-year survival of 50%. Lung transplantation is rarely performed in this setting due to concomitant extrapulmonary morbidity, excessive immunosuppression and concerns about recurring malignancy being considered contraindications. This study assesses survival in highly selected patients undergoing lung transplantation for LONIPCs after SCT.SCT patients undergoing lung transplantation at 20 European centres between 1996 and 2014 were included. Clinical data pre- and post-lung transplantation were reviewed. Propensity score-matched controls were generated from the Eurotransplant and Scandiatransplant registries. Kaplan-Meier survival analysis and Cox proportional hazard regression models evaluating predictors of graft loss were performed.Graft survival at 1, 3 and 5 years of 84%, 72% and 67%, respectively, among the 105 SCT patients proved comparable to controls (p=0.75). Sepsis accounted for 15 out of 37 deaths (41%), with prior mechanical ventilation (HR 6.9, 95% CI 1.0-46.7; p<0.001) the leading risk factor. No SCT-specific risk factors were identified. Recurring malignancy occurred in four patients (4%). Lung transplantation <2 years post-SCT increased all-cause 1-year mortality (HR 7.5, 95% CI 2.3-23.8; p=0.001).Lung transplantation outcomes following SCT were comparable to other end-stage diseases. Lung transplantation should be considered feasible in selected candidates. No SCT-specific factors influencing outcome were identified within this carefully selected patient cohort.

Development of a Multivariate Prediction Model for Early-Onset Bronchiolitis Obliterans Syndrome and Restrictive Allograft Syndrome in Lung Transplantation.

BACKGROUND: Chronic lung allograft dysfunction and its main phenotypes, bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), are major causes of mortality after lung transplantation (LT). RAS and early-onset BOS, developing within 3 years after LT, are associated with particularly inferior clinical outcomes. Prediction models for early-onset BOS and RAS have not been previously described. METHODS: LT recipients of the French and Swiss transplant cohorts were eligible for inclusion in the SysCLAD cohort if they were alive with at least 2 years of follow-up but less than 3 years, or if they died or were retransplanted at any time less than 3 years. These patients were assessed for early-onset BOS, RAS, or stable allograft function by an adjudication committee. Baseline characteristics, data on surgery, immunosuppression, and year-1 follow-up were collected. Prediction models for BOS and RAS were developed using multivariate logistic regression and multivariate multinomial analysis. RESULTS: Among patients fulfilling the eligibility criteria, we identified 149 stable, 51 BOS, and 30 RAS subjects. The best prediction model for early-onset BOS and RAS included the underlying diagnosis, induction treatment, immunosuppression, and year-1 class II donor-specific antibodies (DSAs). Within this model, class II DSAs were associated with BOS and RAS, whereas pre-LT diagnoses of interstitial lung disease and chronic obstructive pulmonary disease were associated with RAS. CONCLUSION: Although these findings need further validation, results indicate that specific baseline and year-1 parameters may serve as predictors of BOS or RAS by 3 years post-LT. Their identification may allow intervention or guide risk stratification, aiming for an individualized patient management approach.

Blood Gene Expression Predicts Bronchiolitis Obliterans Syndrome.

Bronchiolitis obliterans syndrome (BOS), the main manifestation of chronic lung allograft dysfunction, leads to poor long-term survival after lung transplantation. Identifying predictors of BOS is essential to prevent the progression of dysfunction before irreversible damage occurs. By using a large set of 107 samples from lung recipients, we performed microarray gene expression profiling of whole blood to identify early biomarkers of BOS, including samples from 49 patients with stable function for at least 3 years, 32 samples collected at least 6 months before BOS diagnosis (prediction group), and 26 samples at or after BOS diagnosis (diagnosis group). An independent set from 25 lung recipients was used for validation by quantitative PCR (13 stables, 11 in the prediction group, and 8 in the diagnosis group). We identified 50 transcripts differentially expressed between stable and BOS recipients. Three genes, namely POU class 2 associating factor 1 (POU2AF1), T-cell leukemia/lymphoma protein 1A (TCL1A), and B cell lymphocyte kinase, were validated as predictive biomarkers of BOS more than 6 months before diagnosis, with areas under the curve of 0.83, 0.77, and 0.78 respectively. These genes allow stratification based on BOS risk (log-rank test p < 0.01) and are not associated with time posttransplantation. This is the first published large-scale gene expression analysis of blood after lung transplantation. The three-gene blood signature could provide clinicians with new tools to improve follow-up and adapt treatment of patients likely to develop BOS.

Stent-in-Stent Technique for the Treatment of Proximal Bronchial Restenosis after Insertion of Metallic Stents: A Report of Two Cases.

Endoscopic treatment of a bronchial restenosis previously treated by insertion of a partially covered self-expandable metallic stent (SEMS) can be difficult. Classically, after recanalization of the bronchus, the stent is removed and replaced by a more adapted one. We report on two cases of proximal bronchial restenosis treated by insertion of an additional stent inside the lumen of the previously inserted stent using the stent-in-stent (SIS) technique. The indications for the initial stent were malignancy in Patient 1 and posttransplant bronchial stenosis in Patient 2. Restenosis occurred at the proximal end of the stent within months in both cases. Stent removal and insertion of a new stent were considered, but this option was discarded because of an excessive risk of bronchial perforation and preference towards an alternative approach. In both cases, a second customized SEMS was placed using the SIS technique after ablation of the proximal end stenosis of the stent by argon plasma coagulation and/or dilation with a balloon. Recanalization of the bronchus was achieved in both cases without complications. The SIS technique is a valuable alternative to removal of SEMS in case of proximal bronchial restenosis.

Ataluren for the treatment of nonsense-mutation cystic fibrosis: a randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Ataluren was developed to restore functional protein production in genetic disorders caused by nonsense mutations, which are the cause of cystic fibrosis in 10% of patients. This trial was designed to assess the efficacy and safety of ataluren in patients with nonsense-mutation cystic fibrosis. METHODS: This randomised, double-blind, placebo-controlled, phase 3 study enrolled patients from 36 sites in 11 countries in North America and Europe. Eligible patients with nonsense-mutation cystic fibrosis (aged ≥ 6 years; abnormal nasal potential difference; sweat chloride >40 mmol/L; forced expiratory volume in 1 s [FEV1] ≥ 40% and ≤ 90%) were randomly assigned by interactive response technology to receive oral ataluren (10 mg/kg in morning, 10 mg/kg midday, and 20 mg/kg in evening) or matching placebo for 48 weeks. Randomisation used a block size of four, stratified by age, chronic inhaled antibiotic use, and percent-predicted FEV1. The primary endpoint was relative change in percent-predicted FEV1 from baseline to week 48, analysed in all patients with a post-baseline spirometry measurement. This study is registered with ClinicalTrials.gov, number NCT00803205. FINDINGS: Between Sept 8, 2009, and Nov 30, 2010, 238 patients were randomly assigned, of whom 116 in each treatment group had a valid post-baseline spirometry measurement. Relative change from baseline in percent-predicted FEV1 did not differ significantly between ataluren and placebo at week 48 (-2.5% vs -5.5%; difference 3.0% [95% CI -0.8 to 6.3]; p=0.12). The number of pulmonary exacerbations did not differ significantly between treatment groups (rate ratio 0.77 [95% CI 0.57-1.05]; p=0.0992). However, post-hoc analysis of the subgroup of patients not using chronic inhaled tobramycin showed a 5.7% difference (95% CI 1.5-10.1) in relative change from baseline in percent-predicted FEV1 between the ataluren and placebo groups at week 48 (-0.7% [-4.0 to 2.1] vs -6.4% [-9.8 to -3.7]; nominal p=0.0082), and fewer pulmonary exacerbations in the ataluern group (1.42 events [0.9-1.9] vs 2.18 events [1.6-2.7]; rate ratio 0.60 [0.42-0.86]; nominal p=0.0061). Safety profiles were generally similar for ataluren and placebo, except for the occurrence of increased creatinine concentrations (ie, acute kidney injury), which occurred in 18 (15%) of 118 patients in the ataluren group compared with one (<1%) of 120 patients in the placebo group. No life-threatening adverse events or deaths were reported in either group. INTERPRETATION: Although ataluren did not improve lung function in the overall population of nonsense-mutation cystic fibrosis patients who received this treatment, it might be beneficial for patients not taking chronic inhaled tobramycin. FUNDING: PTC Therapeutics, Cystic Fibrosis Foundation, US Food and Drug Administration's Office of Orphan Products Development, and the National Institutes of Health.

Cystic fibrosis: unenhanced CT description of the appendix in asymptomatic adults.

OBJECTIVE: The purpose of this study was to describe the unenhanced CT appearance of the appendix in adults with cystic fibrosis. SUBJECTS AND METHODS: Among adults with cystic fibrosis undergoing follow-up at our hospital, 71 patients (35 women, 36 men; mean age, 33 years; range, 18-59 years) without a history of appendectomy or current abdominal pain were prospectively included in this study and underwent unenhanced abdominopelvic MDCT. Two readers coded visualization of the appendix, measured the diameter of the appendix, and described the attenuation of its contents in relation to the intestinal wall. They also coded the presence of colonic wall redundancy, pancreatic fatty replacement, and cirrhosis. Lung transplant status and CFTR gene mutations were recorded. Analysis of variance, linear regression analysis, Student t test, and Pearson test were used. RESULTS: The appendix was detected in all patients. The mean diameter was recorded as 10.6 ± 3.5 mm. The mean diameter was larger when the appendix contained hyperattenuating material (p = 0.001). There was no association between diameter and the other coded CT findings (p = 0.076-0.466), transplant status (p = 0.788), or CFTR mutation (p = 0.078). In 75% of the patients, the appendix contained hyperattenuating material with a higher proportion in homozygous ΔF508 mutation (p = 0.029) without any significant effect of the other CT features (p = 0.056-0.392), or transplant status (p = 1.000). CONCLUSION: The appendix is larger in adults with cystic fibrosis than in those without it and appears hyperattenuating at unenhanced CT in 75% of patients, more commonly in those with ΔF508 homozygous mutation.

Small airways diseases, excluding asthma and COPD: an overview.

This review is the summary of a workshop on small airways disease, which took place in Porquerolles, France in November 2011. The purpose of this workshop was to review the evidence on small airways (bronchiolar) involvement under various pathophysiological circumstances, excluding asthma and chronic obstructive pulmonary disease. Histopathological patterns associated with small airways disease were reviewed, including cellular and obliterative bronchiolitis. Many pathophysiological conditions have been associated with small airways disease including airway infections, connective tissue diseases and inflammatory bowel diseases, bone marrow and lung transplantation, common variable immunodeficiency disorders, diffuse panbronchiolitis, and diseases related to environmental exposures to pollutants, allergens and drugs. Pathogenesis, clinical presentation, a computed tomography scan and pulmonary function test findings are reviewed, and therapeutic options are described with the objective of providing an integrative approach to these disorders.

Inhaled aztreonam lysine vs. inhaled tobramycin in cystic fibrosis: a comparative efficacy trial.

BACKGROUND: Open-label, parallel-group, international trial comparing aztreonam for inhalation solution (AZLI) and tobramycin nebulizer solution (TNS) for cystic fibrosis patients with airway Pseudomonas aeruginosa. METHODS: 273 patients (≥ 6 years); randomized to three 28-day courses (AZLI 75 mg [three-times/day] or TNS 300 mg [twice/day]); 28 off-days separated each course. RESULTS: 268 patients were treated (AZLI/TNS: 136/132). Mean baseline FEV1 was 52% predicted. Mean relative changes after 1 course (AZLI: 8.35%; TNS: 0.55%; p<0.001) and mean actual changes across 3 courses (AZLI: 2.05%; TNS: -0.66%; p=0.002) indicated AZLI statistical superiority vs. TNS. AZLI-treated patients had fewer respiratory hospitalizations (p=0.044) and respiratory events requiring additional antipseudomonal antibiotics (p=0.004); both treatments were well tolerated. 133 patients received 1 to 3 courses of AZLI treatment in the open-label extension-period (28-day courses separated by 28 days off-treatment); lung function improvements were comparable regardless of whether patients had received TNS or AZLI in the preceding comparative period. CONCLUSIONS: AZLI demonstrated statistical superiority in lung function and a reduction in acute pulmonary exacerbations compared to TNS over 3 treatment courses (ClinicalTrials.gov: NCT00757237).

Tacrolimus and cyclosporine have differential effects on the risk of development of bronchiolitis obliterans syndrome: results of a prospective, randomized international trial in lung transplantation.

BACKGROUND: Chronic lung allograft dysfunction, which manifests as bronchiolitis obliterans syndrome (BOS), is recognized as the primary cause of morbidity and mortality after lung transplantation. In this study we assessed the efficacy and safety of two de novo immunosuppression protocols to prevent BOS. METHODS: Our study approach was a multicenter, prospective, randomized (1:1) open-label superiority investigation of de novo tacrolimus vs cyclosporine, with both study arms given mycophenolate mofetil and prednisolone after lung transplantation. Cytolytic induction therapy was not employed. Patients were stratified at entry for cystic fibrosis. Primary outcome was incidence of BOS 3 years after transplant (intention-to-treat analysis). Secondary outcomes were survival and incidence of acute rejection, infection and other adverse events. RESULTS: Group demographic data were well matched: 110 of 124 tacrolimus vs 74 of 125 cyclosporine patients were treated per protocol (p < 0.01 by chi-square test). Cumulative incidence of BOS Grade ≥1 at 3 years was 11.6% (tacrolimus) vs 21.3% (cyclosporine) (cumulative incidence curves, p = 0.037 by Gray's test, pooled over strata). Univariate proportional sub-distribution hazards regression confirmed cyclosporine as a risk for BOS (HR 1.97, 95% CI 1.04 to 3.77, p = 0.039). Three-year cumulative incidence of acute rejection was 67.4% (tacrolimus) vs 74.9% (cyclosporine) (p = 0.118 by Gray's test). One- and 3-year survival rates were 84.6% and 78.7% (tacrolimus) vs 88.6% and 82.8% (cyclosporine) (p = 0.382 by log-rank test). Cumulative infection rates were similar (p = 0.91), but there was a trend toward new-onset renal failure with tacrolimus (p = 0.09). CONCLUSIONS: Compared with cyclosporine, de novo tacrolimus use was found to be associated with a significantly reduced risk for BOS Grade ≥1 at 3 years despite a similar rate of acute rejection. However, no survival advantage was detected.

Population pharmacokinetic modelling and design of a Bayesian estimator for therapeutic drug monitoring of tacrolimus in lung transplantation.

BACKGROUND: Therapeutic drug monitoring of tacrolimus is a major support to patient management and could help improve the outcome of lung transplant recipients, by minimizing the risk of rejections and infections. However, despite the wide use of tacrolimus as part of maintenance immunosuppressive regimens after lung transplantation, little is known about its pharmacokinetics in this population. Better knowledge of the pharmacokinetics of tacrolimus in lung transplant recipients, and the development of tools dedicated to its therapeutic drug monitoring, could thus help improve their outcome. OBJECTIVES: The aims of this study were (i) to characterize the population pharmacokinetics of tacrolimus in lung transplant recipients, including the influence of biological and pharmacogenetic covariates; and (ii) to develop a Bayesian estimator of the tacrolimus area under the blood concentration-time curve from time zero to 12 hours (AUC(12)) for its therapeutic drug monitoring in lung transplant recipients. METHODS: A population pharmacokinetic model was developed by nonlinear mixed-effects modelling using NONMEM® version VI, from 182 tacrolimus full concentration-time profiles collected in 78 lung transplant recipients within the first year post-transplantation. Patient genotypes for the cytochrome P450 3A5 (CYP3A5) A6986G single nucleotide polymorphism (SNP) were characterized by TaqMan allelic discrimination. Patients were divided into an index dataset (n = 125 profiles) and a validation dataset (n = 57 profiles). A Bayesian estimator was derived from the final model using the index dataset, in order to determine the tacrolimus AUC(12) on the basis of a limited number of samples. The predictive performance of the Bayesian estimator was evaluated in the validation dataset by comparing the estimated AUC(12) with the trapezoidal AUC(12). RESULTS: Tacrolimus pharmacokinetics were described using a two-compartment model with Erlang absorption and first-order elimination. The model included cystic fibrosis (CF) and CYP3A5 polymorphism as covariates. The relative bioavailability in patients with CF was approximately 60% of the relative bioavailability observed in patients without CF, and the transfer rate constant between the transit compartments was 2-fold smaller in patients with CF than in those without CF (3.32 vs 7.06 h-1). The apparent clearance was 40% faster in CYP3A5 expressers than in non-expressers (24.5 vs 17.5 L/h). Good predictive performance was obtained with the Bayesian estimator developed using the final model and concentrations measured at 40 minutes and at 2 and 4 hours post-dose, as shown by the mean bias (1.1%, 95% CI -1.4, 3.7) and imprecision (9.8%) between the estimated and the trapezoidal AUC(12). The bias was >20% in 1.8% of patients. CONCLUSION: Population pharmacokinetic analysis showed that lung transplant patients with CF displayed lower bioavailability and a smaller transfer rate constant between transit compartments than those without CF, while the apparent clearance was faster in CYP3A5 expressers than in non-expressers. The Bayesian estimator developed in this study provides an accurate prediction of tacrolimus exposure in lung transplant patients, with and without CF, throughout the first year post-transplantation. This tool may allow routine tacrolimus dose individualization and may be used to conduct clinical trials on therapeutic drug monitoring of tacrolimus after lung transplantation.

Bayesian estimation of mycophenolate mofetil in lung transplantation, using a population pharmacokinetic model developed in kidney and lung transplant recipients.

BACKGROUND AND OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Chronic allograft dysfunction.

Chronic, progressive, and irreversible loss of lung function is the major medium-term and long-term complication after lung transplantation and the leading cause of death. Over the past decade, progress has been made in understanding the pathogenesis of bronchiolitis obliterans. Alloimmune factors and nonalloimmune factors may contribute to its development. Understanding the precise mechanism of each type of chronic allograft dysfunction may open up the field for new preventive and therapeutic interventions. This article reviews major new insights into the clinical aspects, pathophysiology, risk factors, diagnosis, and management of chronic allograft dysfunction after lung transplantation.