Tacrolimus Population Pharmacokinetic-Pharmacogenetic Analysis and Bayesian Estimation in Renal Transplant Recipients

Objectives: The aims of this study were (i) to investigate the population pharmacokinetics of tacrolimus in renal transplant recipients, including the influence of biological and pharmacogenetic covariates; and (ii) to develop a Bayesian estimator able to reliably estimate the individual pharmacokinetic parameters and inter-dose area under the blood concentration-time curve (AUC) from 0 to 12 hours (AUC12) in renal transplant patients. Methods: Full pharmacokinetic profiles were obtained from 32 renal transplant patients at weeks 1 and 2, and at months 1, 3 and 6 post-transplantation. The population pharmacokinetic analysis was performed using the nonlinear mixed-effect modelling software NONMEM® version VI. Patients’ genotypes were characterized by allelic discrimination for PXR −25385C>T genes. Results: Tacrolimus pharmacokinetics were well described by a two-compartment model combined with an Erlang distribution to describe the absorption phase, with low additive and proportional residual errors of 1.6 ng/mL and 9%, respectively. Both the haematocrit and PXR −25385C>T single nucleotide polymorphism (SNP) were identified as significant covariates for apparent oral clearance (CL/F) of tacrolimus, which allowed improvement of prediction accuracy. Specifically, CL/F decreased gradually with the number of mutated alleles for the PXR −25385C>T SNP and was inversely proportional to the haematocrit value. However, clinical criteria of relevance, mainly the decrease in interindividual variability and residual error, led us to retain only the haematocrit in the final model. Maximum a posteriori Bayesian forecasting allowed accurate prediction of the tacrolimus AUC12 using only three sampling times (at 0 hour [predose] and at 1 and 3 hours postdose) in addition to the haematocrit value, with a nonsignificant mean AUC bias of 2% and good precision (relative mean square error = 11%). Conclusion: Population pharmacokinetic analysis of tacrolimus in renal transplant recipients showed a significant influence of the haematocrit on its CL/F and led to the development of a Bayesian estimator compatible with clinical practice and able to accurately predict tacrolimus individual pharmacokinetic parameters and the AUC12

Utilisation des techniques d'imagerie pour la cartographie des vitesses à la surface d'une avalanche dense

Research on the dynamics of dense snow avalanches has resulted in the development of numerous digital models. The difficulty of measuring the parameters provided by these models has prevented their validation by comparing them with other real phenomena. Image processing is a primary validation approach. For fifteen years, high speed stereophotogrammetry has been used by the Cemagref's Nivology Division to determine the 3-D morphology of a snow flow. We are proposing the use of a treatment of video images of dense snow avalanches to measure the surface speeds of these flows. The problem related to this process is due to the non-distinction of shapes and to a movement blur at high speeds. We show that a good estimation of the speed distribution can be obtained with different techniques using image intercorrelation. / La recherche sur la dynamique des avalanches de neige dense a produit de nombreux modèles numériques. La difficulté de mesurer les paramètres fournis par ces modèles a empêché leur validation par comparaison avec des phénomènes réels. Le traitement d'images est une première approche de cette validation. Depuis une quinzaine d'années, la stéréophotogrammétrie à cadence rapide a été utilisée par la division Nivologie du Cemagref pour déterminer la morphologie tridimensionnelle d'un écoulement. Nous nous proposons d'utiliser le traitement d'images vidéo des avalanches de neige dense pour mesurer le champ des vitesses à la surface des écoulements. La difficulté du traitement est due à l'indétermination des formes et à un "flou de bougé" qui apparaît pour les vitesses élevées. Nous montrons que différentes techniques utilisant l'intercorrélation des images permet d'obtenir une bonne estimation de la distribution des vitesses

Variability in clinical presentation of diabetes mellitus during anti-PD-1 immunotherapy

International audienceNo abstract availabl

Three-Year Outcomes in Kidney Transplant Patients Randomized to Steroid-Free Immunosuppression or Steroid Withdrawal, with Enteric-Coated Mycophenolate Sodium and Cyclosporine: The Infinity Study

International audienceIn a six-month, multicenter, open-label trial, de novo kidney transplant recipients at low immunological risk were randomized to steroid avoidance or steroid withdrawal with IL-2 receptor antibody (IL-2RA) induction, enteric-coated mycophenolate sodium (EC-MPS: 2160 mg/day to week 6, 1440 mg/day thereafter), and cyclosporine. Results from a 30-month observational follow-up study are presented. Of 166 patients who completed the core study on treatment, 131 entered the follow-up study (70 steroid avoidance, 61 steroid withdrawal). The primary efficacy endpoint of treatment failure (clinical biopsy-proven acute rejection (BPAR) graft loss, death, or loss to follow-up) occurred in 21.4% (95% CI 11.8-31.0%) of steroid avoidance patients and 16.4% (95% CI 7.1-25.7%) of steroid withdrawal patients by month 36 (P = 0.46). BPAR had occurred in 20.0% and 11.5%, respectively (P = 0.19). The incidence of adverse events with a suspected relation to steroids during months 6-36 was 22.9% versus 37.1% (P = 0.062). By month 36, 32.4% and 51.7% of patients in the steroid avoidance and steroid withdrawal groups, respectively, were receiving oral steroids. In conclusion, IL-2RA induction with early intensified EC-MPS dosing and CNI therapy in de novo kidney transplant patients at low immunological risk may achieve similar three-year efficacy regardless of whether oral steroids are withheld for at least three month