Pharmacocinétique de population dans l'évaluation et l'optimisation des schémas posologiques en médecine péri-opératoire

Population pharmacokinetics is a useful tool to evaluate drugs, and bring information about regimen optimization in special populations. It aims to identify and quantify the factors and covariates that may affect pharmacokinetic inter individual variability, in order to propose individualized drugs regimen adapted to patients’ characteristics. This work aims to evaluate the strengths and limitations of this approach to evaluate and optimize drugs regimen in the field of perioperative medicine. A first section displays the benefits of this approach to evaluate tranexamic acid pharmacokinetic variability in total hip arthroplasty surgery, in order to evaluate the relationship between drug exposure and postoperative bleeding. A second section displays the benefits to quantify cefuroxime pharmacokinetic variability in cardiac surgery under cardiopulmonary bypass, in order to propose an individualized drug regimen. A last section displays the benefits of this approach to evaluate cefazolin exposure in obese patients undergoing total hip arthroplasty surgery. To propose relevant pharmacokinetics models, statistic methods should be used with precision. The results of these studies aim to propose individualized drugs regimen, adapted to patients’ characteristics without pharmacokinetic variability. Anyway, the relevance of these results should be compared to the expected benefits in terms of drugs exposure and effect optimization in the studied populations.La pharmacocinétique de population est un outil d’évaluation des médicaments permettant d’apporter une information concernant l’optimisation des schémas posologiques dans les populations spéciales. Cette approche consiste à identifier et quantifier les différentes sources de variabilité des traitements pour proposer une administration individualisée en fonction des caractéristiques des patients. Ce travail est consacré à l’évaluation des avantages et des limites de cette approche dans l’évaluation et l’optimisation des schémas posologiques en médecine péri-opératoire. Une première partie présente l’intérêt de cette approche dans l’estimation de la variabilité pharmacocinétique de l’acide tranexamique dans la prothèse de hanche pour évaluer la relation entre l’exposition au traitement et le saignement postopératoire. Une deuxième partie présente l’intérêt de cette approche dans la quantification de la variabilité pharmacocinétique de la céfuroxime en chirurgie cardiaque sous circulation extracorporelle pour proposer un protocole d’administration individualisé. Une dernière partie présente l’utilisation de la pharmacocinétique de population dans l’évaluation de l’exposition à la céfazoline chez l’obèse dans la prothèse de hanche. Afin de proposer des modèles pertinents, la méthodologie pharmaco-statistique requise doit être appréhendée avec rigueur. Les résultats obtenus permettent de proposer des schémas posologiques adaptés aux caractéristiques des patients en s’amendant de la variabilité pharmacocinétique. Mais leur pertinence doit être confrontée aux réels bénéfices en termes d’optimisation d’exposition et d’effet des médicaments dans les populations étudiées

Pharmacocinétique de population dans l'évaluation et l'optimisation des schémas posologiques en médecine péri-opératoire

Population pharmacokinetics is a useful tool to evaluate drugs, and bring information about regimen optimization in special populations. It aims to identify and quantify the factors and covariates that may affect pharmacokinetic inter individual variability, in order to propose individualized drugs regimen adapted to patients’ characteristics. This work aims to evaluate the strengths and limitations of this approach to evaluate and optimize drugs regimen in the field of perioperative medicine. A first section displays the benefits of this approach to evaluate tranexamic acid pharmacokinetic variability in total hip arthroplasty surgery, in order to evaluate the relationship between drug exposure and postoperative bleeding. A second section displays the benefits to quantify cefuroxime pharmacokinetic variability in cardiac surgery under cardiopulmonary bypass, in order to propose an individualized drug regimen. A last section displays the benefits of this approach to evaluate cefazolin exposure in obese patients undergoing total hip arthroplasty surgery. To propose relevant pharmacokinetics models, statistic methods should be used with precision. The results of these studies aim to propose individualized drugs regimen, adapted to patients’ characteristics without pharmacokinetic variability. Anyway, the relevance of these results should be compared to the expected benefits in terms of drugs exposure and effect optimization in the studied populations.La pharmacocinétique de population est un outil d’évaluation des médicaments permettant d’apporter une information concernant l’optimisation des schémas posologiques dans les populations spéciales. Cette approche consiste à identifier et quantifier les différentes sources de variabilité des traitements pour proposer une administration individualisée en fonction des caractéristiques des patients. Ce travail est consacré à l’évaluation des avantages et des limites de cette approche dans l’évaluation et l’optimisation des schémas posologiques en médecine péri-opératoire. Une première partie présente l’intérêt de cette approche dans l’estimation de la variabilité pharmacocinétique de l’acide tranexamique dans la prothèse de hanche pour évaluer la relation entre l’exposition au traitement et le saignement postopératoire. Une deuxième partie présente l’intérêt de cette approche dans la quantification de la variabilité pharmacocinétique de la céfuroxime en chirurgie cardiaque sous circulation extracorporelle pour proposer un protocole d’administration individualisé. Une dernière partie présente l’utilisation de la pharmacocinétique de population dans l’évaluation de l’exposition à la céfazoline chez l’obèse dans la prothèse de hanche. Afin de proposer des modèles pertinents, la méthodologie pharmaco-statistique requise doit être appréhendée avec rigueur. Les résultats obtenus permettent de proposer des schémas posologiques adaptés aux caractéristiques des patients en s’amendant de la variabilité pharmacocinétique. Mais leur pertinence doit être confrontée aux réels bénéfices en termes d’optimisation d’exposition et d’effet des médicaments dans les populations étudiées

Population pharmacokinetics to evaluate and optimize drugs regimen in perioperative medicine

La pharmacocinétique de population est un outil d’évaluation des médicaments permettant d’apporter une information concernant l’optimisation des schémas posologiques dans les populations spéciales. Cette approche consiste à identifier et quantifier les différentes sources de variabilité des traitements pour proposer une administration individualisée en fonction des caractéristiques des patients. Ce travail est consacré à l’évaluation des avantages et des limites de cette approche dans l’évaluation et l’optimisation des schémas posologiques en médecine péri-opératoire. Une première partie présente l’intérêt de cette approche dans l’estimation de la variabilité pharmacocinétique de l’acide tranexamique dans la prothèse de hanche pour évaluer la relation entre l’exposition au traitement et le saignement postopératoire. Une deuxième partie présente l’intérêt de cette approche dans la quantification de la variabilité pharmacocinétique de la céfuroxime en chirurgie cardiaque sous circulation extracorporelle pour proposer un protocole d’administration individualisé. Une dernière partie présente l’utilisation de la pharmacocinétique de population dans l’évaluation de l’exposition à la céfazoline chez l’obèse dans la prothèse de hanche. Afin de proposer des modèles pertinents, la méthodologie pharmaco-statistique requise doit être appréhendée avec rigueur. Les résultats obtenus permettent de proposer des schémas posologiques adaptés aux caractéristiques des patients en s’amendant de la variabilité pharmacocinétique. Mais leur pertinence doit être confrontée aux réels bénéfices en termes d’optimisation d’exposition et d’effet des médicaments dans les populations étudiées.Population pharmacokinetics is a useful tool to evaluate drugs, and bring information about regimen optimization in special populations. It aims to identify and quantify the factors and covariates that may affect pharmacokinetic inter individual variability, in order to propose individualized drugs regimen adapted to patients’ characteristics. This work aims to evaluate the strengths and limitations of this approach to evaluate and optimize drugs regimen in the field of perioperative medicine. A first section displays the benefits of this approach to evaluate tranexamic acid pharmacokinetic variability in total hip arthroplasty surgery, in order to evaluate the relationship between drug exposure and postoperative bleeding. A second section displays the benefits to quantify cefuroxime pharmacokinetic variability in cardiac surgery under cardiopulmonary bypass, in order to propose an individualized drug regimen. A last section displays the benefits of this approach to evaluate cefazolin exposure in obese patients undergoing total hip arthroplasty surgery. To propose relevant pharmacokinetics models, statistic methods should be used with precision. The results of these studies aim to propose individualized drugs regimen, adapted to patients’ characteristics without pharmacokinetic variability. Anyway, the relevance of these results should be compared to the expected benefits in terms of drugs exposure and effect optimization in the studied populations

Stability and precision of the fish metrics obtained using CEN multi-mesh gillnet in natural and artificial lakes in France

International audienceThe stability and the precision of fish metrics obtained using CEN multi-mesh benthic nets are compared between twenty-seven natural and artificial French lakes. We show that the natural or artificial origin of the lake has no impact on the precision of the fish metrics provided by the method and it provides more precise catch data in French lakes than in the Nordic countries. The precision of abundances and biomass depends on fish density, and thus on the trophic status of the lake sampled. We also show that the sampling effort advocated by standard is appropriate in French lakes despite its underestimation of species number and disregard of marginal habitats. Nevertheless in deep lakes, the sampling effort could be reduced in the deeper layers which are never informative

Pharmacokinetics of enoxaparin in COVID-19 critically ill patients

International audienc

Effect of Activated Charcoal on Rivaroxaban Complex Absorption.

ClinicalTrial.gov registration no. NCT02657512.International audienceObjective. To quantify the impact of activated charcoal (AC) on rivaroxaban exposure in healthy volunteers.Methods. This was an open-label study with an incomplete cross-over design of single-dose rivaroxaban (40 mg) administered alone or with AC in 12 healthy volunteers. The study comprised three treatment periods in randomised sequence, one with rivaroxaban administered alone and two with AC given at 2, 5 or 8 h post-dose. Rivaroxaban plasma concentration was measured in blood samples drawn at 16 time points. The pharmacokinetic model of rivaroxaban alone or with AC administration was built using a non-linear mixed-effect modelling approach.Results. The pharmacokinetic model was based on a one-compartment model with an absorption rate described by the sum of three inverse Gaussian densities to reproduce multiphasic and prolonged absorption. The inclusion in the model of each AC administration schedule significantly improved objective function value. AC reduced the area under the rivaroxaban concentration-time curve by 43% when administered 2 h post-dose, by 31% when administered 5 h post-dose and by 29% when administered 8 h post-dose. Based on the estimated pharmacokinetic model, simulations suggested that AC might have an impact even after 8 h post-dose.Conclusion. AC administration significantly reduces exposure to rivaroxaban even if AC is administered 8 h after rivaroxaban. These results suggest that AC could be used in rivaroxaban overdose and accidental ingestion to antagonise absorption

Factors Influencing Unfractionated Heparin Pharmacokinetics and Pharmacodynamics During a Cardiopulmonary Bypass

International audienceBackground: Unfractionated heparin (UFH) is commonly used during cardiac surgery with a cardiopulmonary bypass to prevent blood clotting. However, empirical administration of UFH leads to variable responses. Pharmacokinetic and pharmacodynamic modeling can be used to optimize UFH dosing and perform real-time individualization. In previous studies, many factors that could influence UFH pharmacokinetics/pharmacodynamics had not been taken into account such as hemodilution or the type of UFH. Few covariates were identified probably owing to a lack of statistical power. This study aims to address these limitations through a meta-analysis of individual data from two studies.Methods: An individual patient data meta-analysis was conducted using data from two single-center prospective observational studies, where different UFH types were used for anticoagulation. A pharmacodynamic/pharmacodynamic model of UFH was developed using a non-linear mixed-effects approach. Time-varying covariates such as hemodilution and fluid infusions during a cardiopulmonary bypass were considered.Results: Activities of UFH's anti-activated factor/anti-thrombin were best described by a two-compartment model. Unfractionated heparin clearance was influenced by body weight and the specific UFH type. Volume of distribution was influenced by body weight and pre-operative fibrinogen levels. Pharmacodynamic data followed a log-linear model, accounting for the effect of hemodilution and the pre-operative fibrinogen level. Equations were derived from the model to personalize UFH dosing based on the targeted activated clotting time level and patient covariates.Conclusions: The population model effectively characterized UFH's pharmacokinetics/pharmacodynamics in cardiopulmonary bypass patients. This meta-analysis incorporated new covariates related to UFH's pharmacokinetics/pharmacodynamics, enabling personalized dosing regimens. The proposed model holds potential for individualization using a Bayesian estimation

P-202 Evaluation de l[StQuote]efficacité des transfusions des concentrés plaquettaires traités par Amotosalen/UVA en chirurgie cardiaque

National audienc

Management of Severe Bleeding in Patients Treated with Direct Oral Anticoagulants

International audienceThe use of prothrombin complex concentrates and the role of plasma concentration of anticoagulants in the management of bleeding in patients treated with direct oral anticoagulants are still debated. Our aim was to describe management strategies and outcomes of severe bleeding events in patients treated with direct oral anticoagulants.METHODS:We performed a prospective cohort study of 732 patients treated with dabigatran, rivaroxaban, or apixaban hospitalized for severe bleeding, included prospectively in the registry from June 2013 to November 2015.RESULTS:Bleeding was gastrointestinal or intracranial in 37% (212 of 732) and 24% (141 of 732) of the cases, respectively. Creatinine clearance was lower than 60 ml/min in 61% (449 of 732) of the cases. The plasma concentration of direct oral anticoagulants was determined in 62% (452 of 732) of the cases and was lower than 50 ng/ml or higher than 400 ng/ml in 9.2% (41 of 452) and in 6.6% (30 of 452) of the cases, respectively. Activated or nonactivated prothrombin complex concentrates were administered in 38% of the cases (281 of 732). Mortality by day 30 was 14% (95% CI, 11 to 16).CONCLUSIONS:Management of severe bleeding in patients treated with direct oral anticoagulants appears to be complex. The use of prothrombin complex concentrates differs depending on bleeding sites and direct oral anticoagulant plasma concentrations. Mortality differs according to bleeding sites and was similar to previous estimates