Consensus conference on a composite endpoint for clinical trials on immunosuppressive drugs in lung transplantation.

BACKGROUND: In lung transplantation, diverse clinical events may impact patient outcome. In clinical trials comparing intervention strategies, single primary endpoints require large populations, or long study durations, whereas composite endpoints (CEPs) do not take into account the respective impact of their components on patient survival. The objective of this study was to propose consensus recommendations on endpoints for clinical trials on immunosuppressants in lung transplantation. METHODS: The consensus process was managed through the Internet using the Delphi method. Forty experts were invited by the pilot group with the help of the International Society for Heart and Lung Transplantation and The Transplantation Society. In the first round, a questionnaire was made available to the experts to complete, and the responses were analyzed. In each next round, a new questionnaire was developed from the previous responses and sent to the panel members. RESULTS: Consensus between 17 experts was achieved after five rounds. Two score-type CEPs were defined for immunosuppressive drug efficacy (7 items) and for toxicity (15 items). Death related to graft loss or immunosuppressive drug toxicity was attributed a maximum weight of 100. The weights of the items included in the efficacy and toxicity CEPs ranged between 10 and 80 and between 25 and 70, respectively. The CEP scores are calculated by adding the weights of all the items composing them, without exceeding 90 as long as the patient is alive. CONCLUSION: This consensus conference proposed two score-type CEPs including relevant endpoints. After validation, they should allow clinical trials with higher statistical power, improving the evaluation of the interventions tested.

IL-17A mediates early post-transplant lesions after heterotopic trachea allotransplantation in Mice.

Primary graft dysfunction (PGD) and bronchiolitis obliterans (BO) are the leading causes of morbidity and mortality after lung transplantation. Reports from clinical and rodent models suggest the implication of IL-17A in either PGD or BO. We took advantage of the heterotopic trachea transplantation model in mice to study the direct role of IL-17A in post-transplant airway lesions. Across full MHC barrier, early lesions were controlled in IL-17A(-/-) or anti-IL17 treated recipients. In contrast, IL-17A deficiency did not prevent subsequent obliterative airway disease (OAD). Interestingly, this early protection occurred also in syngeneic grafts and was accompanied by a decrease in cellular stress, as attested by lower HSP70 mRNA levels, suggesting the involvement of IL-17A in ischemia-reperfusion injury (IRI). Furthermore, persistence of multipotent CK14(+) epithelial stem cells underlined allograft protection afforded by IL-17A deficiency or neutralisation. Recipient-derived γδ(+) and CD4(+) T cells were the major source of IL-17A. However, lesions still occurred in the absence of each subset, suggesting a high redundancy between the innate and adaptive IL-17A producing cells. Notably, a double depletion significantly diminished lesions. In conclusion, this work implicated IL-17A as mediator of early post-transplant airway lesions and could be considered as a potential therapeutic target in clinical transplantation.

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.

Lung transplantation and lung volume reduction surgery.

Since the publication of the last edition of the Handbook of Physiology, lung transplantation has become widely available, via specialized centers, for a variety of end-stage lung diseases. Lung volume reduction surgery, a procedure for emphysema first conceptualized in the 1950s, electrified the pulmonary medicine community when it was rediscovered in the 1990s. In parallel with their technical and clinical refinement, extensive investigation has explored the unique physiology of these procedures. In the case of lung transplantation, relevant issues include the discrepant mechanical function of the donor lungs and recipient thorax, the effects of surgical denervation, acute and chronic rejection, respiratory, chest wall, and limb muscle function, and response to exercise. For lung volume reduction surgery, there have been new insights into the counterintuitive observation that lung function in severe emphysema can be improved by resecting the most diseased portions of the lungs. For both procedures, insights from physiology have fed back to clinicians to refine patient selection and to scientists to design clinical trials. This section will first provide an overview of the clinical aspects of these procedures, including patient selection, surgical techniques, complications, and outcomes. It then reviews the extensive data on lung and muscle function following transplantation and its complications. Finally, it reviews the insights from the last 15 years on the mechanisms whereby removal of lung from an emphysema patient can improve the function of the lung left behind.

Gravitational gradients in expiratory computed tomography examinations of patients with small airways disease: effect of body position on extent of air trapping.

PURPOSE: First, to test the hypothesis that air trapping in diseased patients follows a gravitational gradient and is more extensive in dependent than in nondependent lung regions. Second, to test the hypothesis that the dependent lung regions on combined supine and prone expiratory computed tomography (CT) examinations will show more air trapping than would a supine expiratory CT examination alone. MATERIALS AND METHODS: For this ethics committee-approved study, supine and prone multidetector-row CT (4×1 mm collimation, 0.5 s rotation time, 140 kVp, and effective 80 mAs) was performed at full end-expiration on 47 lung transplant recipients (mean age 41±12 y; 18 without bronchiolitis, 18 with potential bronchiolitis, and 11 with bronchiolitis). The extent of air trapping was visually quantified in the supine and prone positions, and in dependent and nondependent lung regions. Individual air trapping scores from these regions were thus available and could be combined for later analysis. Differences in the extent of air trapping between the positions and regions were tested with a Wilcoxon signed-rank test. RESULTS: Air trapping was significantly more extensive in the combined dependent lung regions than in the combined nondependent lung regions (15.00% vs. 5.77%; P<0.001). Air trapping was also significantly more extensive in the combined dependent regions than in the supine body position (15.00% vs. 7.50%; P<0.001). No statistically significant difference in the extent of air trapping was found between the supine and the prone positions (7.50% vs. 12.14%; P=0.735). CONCLUSIONS: In patients with suspected or overt small airways disease, air trapping follows a gravitational gradient. A change from the supine to the prone position can make air trapping visible in formerly nondependent lung regions. The combined readings from supine and prone CT examinations in dependent lung regions show more air trapping than a standard supine CT examination alone.

Disease-specific approach to lung transplantation.

PURPOSE OF REVIEW: The present review provides an update on the recent literature regarding disease-specific issues in lung transplantation. Some of the published data will help refine previously published candidate selection criteria and provide evidence-based data for choice of procedures. RECENT FINDINGS: Recent studies on lung transplant outcomes in older patients underline that satisfactory results can be obtained in patients older than 60 years but not in patients older than 70 years. Data from two large registry-based studies indicate that bilateral lung transplantation in patients with chronic obstructive pulmonary disease confers significantly longer survival than single lung transplantation, especially in patients younger than 60 years. Mathematical models to estimate survival benefit in chronic obstructive pulmonary disease lung transplant candidates have been developed and are being validated. The impact of Bcc colonization in cystic fibrosis patients on outcome has been nuanced; thus, cystic fibrosis lung transplant candidates colonized by particular Bcc strains may be transplanted with good outcomes. Novel surgical approaches to peculiar situations in end-stage cystic fibrosis have been described. Candidate selection criteria for retransplantation procedures have further been clarified. SUMMARY: This article attempts to provide an overview of some of the currently important topics for clinicians involved in referring and evaluating patients with end-stage lung disease for lung transplantation in 2009.

Effect of systemic inflammation on inspiratory and limb muscle strength and bulk in cystic fibrosis.

RATIONALE: Diaphragm thickness is increased in cystic fibrosis (CF), but it shows a marked variability between patients. The variable response of the diaphragm to loading may reflect the combined and opposite effects of training by the respiratory disease and systemic inflammation. OBJECTIVES: To assess the impact of systemic inflammation on diaphragm and limb muscle strength and bulk in adult patients with CF. METHODS: In 38 stable patients with CF and 20 matched control subjects, we measured fat-free mass (FFM), inspiratory muscle strength, diaphragm thickness, quadriceps and biceps strength and cross-sectional area, and circulating levels of leukocytes, C-reactive protein, IL-6, IL-8, IL-17, tumor necrosis factor-alpha, tumor necrosis factor-alpha soluble receptors, and immunoglobulin G. MEASUREMENTS AND MAIN RESULTS: Patients had increases in several inflammatory markers that correlated with the severity of lung disease and nutritional depletion. Compared with control subjects, patients with CF had increased diaphragm thickness and inspiratory muscle strength and showed a trend toward a reduction in limb muscle strength and bulk. Multiple regression analyses identified FFM and airway resistance as independent predictors of diaphragm thickness, but systemic inflammation had no (or only a minor) predictive effect on FFM, inspiratory muscle strength, diaphragm thickness, and limb muscle strength and bulk. CONCLUSIONS: In patients with CF, the intensity of systemic inflammation does not account significantly for the variance of FFM and diaphragm or limb muscle strength and bulk. Training of the diaphragm in CF occurs despite the presence of systemic inflammation.

Effect of lung transplant and volume reduction surgery on respiratory muscle function.

Lung transplantation and lung volume reduction surgery have opened a new therapeutic era for patients with advanced emphysema. In addition to providing impressive clinical benefits, they have helped us better understand how the chest wall and respiratory muscles adapt to chronic hyperinflation. This article reviews the effects of these procedures on respiratory muscle and chest wall function. Inspiratory (including diaphragm) and expiratory muscle strength are often close to normal after unilateral and bilateral transplantation, although some patients have marked weakness. After bilateral transplantation for emphysema, graft volume is normal at full inflation but remains greater than normal at end expiration, which results from structural changes in the chest wall. In contrast, patients with unilateral transplantation have a reduction in graft volume at full inflation. The mediastinum is displaced toward the graft at end expiration, which reduces the surface area of the diaphragm on the transplanted side, and it moves toward the native lung during tidal and full inspiration and toward the graft during tidal and forced expiration. Lung volume reduction produces an increase in contractility, length and surface area of the diaphragm, and increases its contribution to tidal volume; at the same time, neural drive to the muscle and respiratory load are reduced, such that diaphragm neuromechanical coupling is improved. Diaphragm configuration and rib cage dimensions are only minimally affected by the procedure. Single-lung transplantation and lung volume reduction favorably impact on the disadvantageous size interaction by which the lungs are functionally restricted by the chest wall in emphysema.

Regional heterogeneity of air trapping at expiratory thin-section CT of patients with bronchiolitis: potential implications for dose reduction and CT protocol planning.

PURPOSE: To prospectively determine whether the regional distribution of air trapping in patients with suspected or overt bronchiolitis is heterogeneous, and to determine the effect that a simulated reduction of computed tomographic (CT) sections and of scanned anatomic regions would have on the assessment of the extent of air trapping. MATERIALS AND METHODS: For this Ethical Committee-approved study, multi-detector row CT (collimation, 4 x 1 mm; rotation time, 0.5 second; 140 kVp; and 80 effective mAs) was performed in 47 lung transplant recipients (23 women, 24 men; mean age, 41 years +/- 12 [standard deviation]; 18 without bronchiolitis, 18 with potential bronchiolitis, and 11 with bronchiolitis, as determined by lung function measurements). Images were reconstructed with a thickness of 1 mm at an increment of 10 mm. The extent of air trapping in the upper, middle, and lower lung regions was correlated. Differences between regions and the interaction between patients and regions were tested with an analysis of variance. The extent of air trapping was calculated for six simulated examination protocols. RESULTS: Correlations between the upper and middle (r = 0.930), the upper and lower (r = 0.756), and the middle and lower lung regions (r = 0.863) were significant (P < .001). The extent of air trapping increased from the upper to the lower lung region, with significant differences between regions (P < .001). There was a significant interaction between patients and lung regions (P < .001). Simulated examination protocols resulted in significantly different extents of air trapping (P < .001). CONCLUSION: The regional distribution of the extent of air trapping in suspected or overt bronchiolitis is heterogeneous. Because the extent of air trapping can depend on the examination protocol, identical protocols are needed when air trapping is being compared within and between patients.

Single-breath test in lateral decubitus reflects function of single lungs grafted for interstitial lung disease.

After single-lung transplantation (SLT) for emphysema, heterogeneity of ventilation distribution in the graft can be assessed by measuring the slope of the alveolar plateau, computed from a single-breath test, performed in lateral decubitus with this lung in the nondependent position. We tested the validity of this technique in patients with SLT for interstitial lung diseases (ILD). Twelve patients with SLT for ILD, 12 nontransplanted patients with ILD, and 10 healthy control subjects performed single-breath washouts in right and left lateral decubitus; nitrogen slope (S(N(2))) and the difference between SF(6) and He slopes (S(SF(6))-S(He)) were measured between 75 and 100% of expired volume. In 10 transplant recipients, the volume of each lung was measured in both postures by computerized tomography. Slopes were unaffected by posture in normal control subjects and patients with ILD. On the other hand, S(N(2)) and S(SF(6))-S(He) in transplant recipients were smaller with the graft in the nondependent than in the dependent position (0.366 +/- 0.445 vs. 1.035 +/- 0.498 for S(N(2)); 0.094 +/- 0.201 vs. 0.218 +/- 0.277 for S(SF(6))-S(He)). Values of S(N(2)) and S(SF(6))-S(He) obtained in the former position were similar to those obtained in normal controls, while values obtained in the latter position were similar to those obtained in nontransplanted patients with ILD. Computerized tomography studies with the graft in the nondependent position indicated that this lung contributed 82% of the volume expired below functional residual capacity. We conclude that, in patients with SLT for ILD, the slope of the alveolar plateau obtained with the graft in the nondependent position reflects heterogeneity of ventilation distribution in this lung.

Early detection of chronic pulmonary allograft dysfunction by exhaled biomarkers.

RATIONALE: Early detection of bronchiolitis obliterans syndrome (BOS) is important because therapies are more likely to be effective if employed early in the disease process. OBJECTIVES: To compare the performance of exhaled NO and CO (which reflect airway inflammation) and the slope of the alveolar plateau for helium (which reflects heterogeneity of ventilation distribution) for detection of BOS stages 0-p and 1. METHODS: Recipients of bilateral (n=64) and single (n=1) lung grafts were prospectively monitored for 1,249 days; the helium slope was derived from single-breath washouts and exhaled NO and CO were measured by chemiluminescence on 933 occasions. MEASUREMENTS AND MAIN RESULTS: At the end of follow-up, 9 patients were in stage 0-p and 16 patients were in BOS stage 1 or higher; 21 patients had at least one measurement made in BOS stage 0-p. All markers increased in BOS stage 0-p, but only the helium slope increased in BOS stage 1. The helium slope had better sensitivity for detection of stages 0-p and 1 than either exhaled NO or CO, but considering exhaled NO and CO together improved their sensitivity; the best sensitivity was found with the three markers in combination. The biomarkers had high negative predictive values, but low specificity and positive predictive values. CONCLUSIONS: After lung transplantation, (1) the helium slope and exhaled NO, but also exhaled CO, increase in BOS stage 0-p, (2) the helium slope has better sensitivity than exhaled NO and CO for the detection of BOS stages 0-p and 1, and (3) exhaled biomarkers have high negative predictive values, but low specificity and positive predictive values.

Acute and chronic rejection after lung transplantation.

Over the last decade, improvements in surgical techniques, lung preservation, immunosuppression, and management of ischemia-reperfusion injury and infections have contributed to increase the 1 year patient survival after lung transplantation to 70 to 80%. However, the incidence of acute rejection remains higher than after other types of solid organ transplantation, and long-term survival is threatened by bronchiolitis obliterans, which is thought to be a form of chronic allograft rejection. This article reviews major aspects of clinical presentation, risk factors, diagnosis, and management of acute and chronic rejection after lung transplantation.

Disseminated Scedosporium apiospermum infection in a cystic fibrosis patient after double-lung transplantation.

Scedosporium apiospermum is a saprophytic ubiquitous filamentous fungus. It can cause a wide spectrum of diseases, from localized to invasive infections. S apiospermum has been described as one of the major fungal agents of chronic colonization of airways in cystic fibrosis (CF) patients. Invasive infections due to S apiospermum are only rarely reported in CF after lung transplantation. A 26-year-old woman with CF and chronic bronchial colonization by S apiospermum developed bilateral chorioretinitis and subcutaneous nodules 4 weeks after double-lung transplantation (LTx). Isolates of S apiospermum from sputum samples before and after LTx and from vitreal fluid were typed by random amplification of polymorphic DNA (RAPD). The patient was treated with voriconazole (VRC). The patient improved with VRC given orally for 6 months. Two days after VRC discontinuation, she developed sub-acute meningitis (isolation of S apiospermum from the cerebrospinal fluid). She was again given VRC, but died 23 days later from uncontrolled fungal infection. Molecular typing of clinical isolates of S apiospermum performed by RAPD demonstrated that all isolates belonged to the same genotype. S apiospermum is a frequent, but late colonizing fungal agent in CF patients. In the case of LTx, these patients can develop invasive infection due to the colonizing strain, as confirmed by molecular typing.

Post-transplant lymphoproliferative disorders after lung transplantation: first-line treatment with rituximab may induce complete remission.

BACKGROUND: Post-transplant lymphoproliferative disorders (PTLD) are potentially lethal complications of solid organ transplantation. We, here, report on our experience with rituximab, an anti-CD20 monoclonal antibody, as first-line treatment for PTLD in six lung transplant recipients. PATIENTS AND METHODS: Two of the patients developed PTLD during the first year after transplantation, while four developed late-onset PTLD. One patient presented with PTLD localized to the graft, one had unilateral cervical lymph nodes, and the others presented with multi-organ involvement. All patients had diffuse large B-cell lymphoma. Immunosuppressive therapy was reduced and rituximab was administered at a dose of 375 mg/m(2)/wk for 4 wk. RESULTS: One patient did not respond to the first two courses of rituximab, received conventional chemotherapy, and achieved complete remission; four patients achieved complete remission after four courses with a median relapse-free survival of 34 months (range: 14-55); and one patient did not respond and died. The diagnosis of complete remission was established by conventional imaging techniques combined to whole-body positron emission tomography scan. CONCLUSIONS: We conclude that reduction in immunosuppression combined to first-line treatment with rituximab may induce long-term complete remission in lung transplant recipients presenting PTLD.

Single-breath test in lateral decubitus reflects function of single lungs grafted for emphysema.

The slope of alveolar plateau for nitrogen derived from the single-breath test is useful to assess the function of bilateral lung grafts, but this technique is not applicable to patients with single-lung grafts due to the confounding influence of the native lung. We tested the hypothesis that the nitrogen slope measured in lateral decubitus with the graft in nondependent position may primarily reflect the distribution of ventilation in this lung. Fifteen patients with single-lung transplantation for emphysema, 10 healthy controls, and 7 patients with advanced emphysema performed single-breath washouts in right and left lateral decubitus; nitrogen slope was measured between 75 and 100% of expired volume. In 10 transplant recipients, the volume of each lung was measured in the two postures by computerized tomography. Nitrogen slope was unaffected by posture in normal controls and emphysema patients. On the other hand, nitrogen slope in transplant recipients was invariably smaller, with the graft in nondependent vs. in dependent position. Values of nitrogen slope with the graft in nondependent position were similar to those obtained in normal controls but significantly smaller than those obtained in emphysema patients. Computerized tomography studies in this position indicated that the volume expired below functional residual capacity was exclusively contributed by the graft. We conclude that, in patients with single-lung transplantation for emphysema, 1) measuring nitrogen slope in lateral decubitus allows to distinguish between the graft and the native lung, and 2) nitrogen slope obtained with the graft in nondependent position reflects ventilation distribution in this lung.

Pharmacokinetic study of tacrolimus in cystic fibrosis and non-cystic fibrosis lung transplant patients and design of Bayesian estimators using limited sampling strategies.

OBJECTIVES: To: (i) test different pharmacokinetic models to fit full tacrolimus concentration-time profiles; (ii) estimate the tacrolimus pharmacokinetic characteristics in stable lung transplant patients with or without cystic fibrosis (CF); (iii) compare the pharmacokinetic parameters between these two patient groups; and (iv) design maximum a posteriori Bayesian estimators (MAP-BE) for pharmacokinetic forecasting in these patients using a limited sampling strategy. METHODS: Tacrolimus blood concentration-time profiles obtained on three occasions within a 5-day period in 22 adult lung transplant recipients (11 with CF and 11 without CF) were retrospectively studied. Three different one-compartment models with first-order elimination were tested to fit the data: one with first-order absorption, one convoluted with a gamma distribution to describe the absorption phase, and one convoluted with a double gamma distribution able to describe secondary concentration peaks. Finally, Bayesian estimation using the best model and a limited sampling strategy was tested in the two groups of patients for its ability to provide accurate estimates of the main tacrolimus pharmacokinetic parameters and exposure indices. RESULTS: The one-compartment model with first-order elimination convoluted with a double gamma distribution gave the best results in both CF and non-CF lung transplant recipients. The patients with CF required higher doses of tacrolimus than those without CF to achieve similar drug exposure, and population modelling had to be performed in CF and non-CF patients separately. Accurate Bayesian estimates of area under the blood concentration-time curve from 0 to 12 hours (AUC12), AUC from 0 to 4 hours, peak blood concentration (Cmax) and time to reach Cmax were obtained using three blood samples collected at 0, 1 and 3 hours in non-CF patients (correlation coefficient between observed and estimated AUC12, R2 = 0.96), and at 0, 1.5 and 4 hours in CF patients (R2 = 0.91). CONCLUSION: A particular pharmacokinetic model was designed to fit the complex and highly variable tacrolimus blood concentration-time profiles. Moreover, MAP-BE allowing tacrolimus therapeutic drug monitoring based on AUC12 were developed.