Modeling of Body Weight Metrics for Effective and Cost-Efficient Conventional Factor VIII Dosing in Hemophilia A Prophylaxis

The total body weight-based dosing strategy currently used in the prophylactic treatment of hemophilia A may not be appropriate for all populations. The assumptions that guide weight-based dosing are not valid in overweight and obese populations, resulting in overdosing and ineffective resource utilization. We explored different weight metrics including lean body weight, ideal body weight, and adjusted body weight to determine an alternative dosing strategy that is both safe and resource-efficient in normal and overweight/obese adult patients. Using a validated population pharmacokinetic model, we simulated a variety of dosing regimens using different doses, weight metrics, and frequencies; we also investigated the implications of assuming various levels of endogenous factor production. Ideal body weight performed the best across all of the regimens explored, maintaining safety while moderating resource consumption for overweight and obese patients.Canadian HIV Trials NetworkCanadian Institutes of Health Researc

Cadomian S-type granites as basement rocks of the Variscan belt (Massif Central, France): Implications for the crustal evolution of the north Gondwana margin

International audienceFrom the Neoproterozoic to the early Paleozoic, the northern Gondwana margin was sequentially shaped by the Cadomian accretionary and the Variscan collisional orogens which offers the opportunity to investigate the relative extent of crust production/reworking in both geodynamic settings. In the eastern part of the Variscan French Massif Central (FMC), the Velay Orthogneiss Formation (VOF) represents a consistent lithological unit of the pre-Variscan basement and comprises augen gneisses and leucogneisses. Such rocks constitute a unique record of the pre-Variscan magmatic history and bear critical information on the crustal evolution of the northern Gondwana margin.Here, we present whole–rock major and trace element compositions indicating that: (i) the VOF shows a remarkable geochemical homogeneity; (ii) the protolith of the augen gneisses corresponds to strongly peraluminous, “S-type” porphyritic granites originating from partial melting of an Ediacaran sedimentary sequence; (iii) the leucogneisses are former leucogranites generated by fractionation of the magma at the origin of the porphyritic granites; and (iv) the whole suite emplaced at shallow crustal levels (< 7 km). U–Pb LA–(MC–)ICP–MS analyses on zircon yielded similar emplacement ages of c. 542 Ma and a narrow range of εHf(t) clustering around 0 for the protoliths of both augen and leucogneisses. This homogeneous Hf isotope signature, notably uncommon for S-type granites, would originate from a sequential process of: (i) inherited zircon dissolution during melting and ascent in the crust due to Zr-undersaturated conditions, (ii) isotopic homogenization of the melt by advection and elemental/isotopic diffusion, followed by (iii) early saturation upon emplacement owing to rapid cooling at shallow crustal levels.We propose that partial melting of Ediacaran sediments occurred during inversion of a Cadomian back-arc basin and was promoted by the high thermal gradient typical of thinned crust domains. Therefore, the VOF and other Cadomian S-type granitoids from the northern Gondwana margin are indicative of substantial crust reworking away from any proper continental collision zone

Toward a patient specific level of anti-haemophilic factor based on thrombin generation : Contributions of experimental approaches and dynamic modeling of the coagulation cascade

L’hémophilie est une maladie génétique se traduisant par la déficience des facteurs VIII et IX de la coagulation et conduisant à une tendance hémorragique. L’intensité des traitements substitutifs en facteur VIII et IX est définie essentiellement sur le taux basal du facteur déficitaire et non pas sur la capacité propre à chaque patient à générer de la thrombine qui est l’enzyme clé dans la formation du caillot de fibrine. Le test de génération de thrombine pourrait être utilisé pour permettre une individualisation du traitement anti-hémophilique. En effet, le taux de facteur VIII ou IX nécessaire à la normalisation de la génération de thrombine est potentiellement variable d’un patient à l’autre pour une même sévérité d’hémophilie. On peut donc se demander quelle approche expérimentale permettrait de mettre en exergue le lien entre taux de facteur anti-hémophilique et la génération de thrombine. Est-il possible de modéliser mathématiquement la coagulation pour obtenir une relation, soit explicite, soit implicite, entre taux de facteurs et génération de thrombine ? Les modèles existants permettent-ils d'obtenir une telle relation ? Une vaste campagne expérimentale a donc été menée pour mettre en place une base de données qui a permis d’identifier les facteurs déterminants de la génération de thrombine et la relation entre génération de thrombine et taux de facteur anti-hémophilique, de définir leurs valeurs de références, ainsi que d’évaluer et de paramétrer de manière sujet-spécifique des modèles mathématiques de la coagulation.Haemophilia is a genetic disease corresponding to the deficiency of coagulation factor VIII or IX and leading to a bleeding tendency. The current substitutive treatment is defined essentially by the basal level of deficient factor and not the individual capacity to generate thrombin, a key enzyme of the clot formation. The thrombin generation assay could help in the individualisation of the anti-haemophilia treatment. Indeed, the factor VIII or IX level needed to normalise the thrombin generation vary potentially from one patient to another for a same degree of severity. We can wonder which experimental approach could emphasise the relation between level of anti-haemophilic factor and thrombin generation. Is it possible to mathematically model coagulation to obtain a relation, either explicit, or implicit, between factor level and thrombin generation? Could existing models provide this relation? An extensive experimental campaign was carried out to build a database that has been used to identify the determinant coagulation factors of thrombin generation and the individual relation between thrombin generation and anti-haemophilic factor level, to define their reference values, and also to evaluate and parametrise subject-specifically mathematical models of the coagulation cascad

Vers une définition patient-spécifique du taux cible de facteur anti-hémophilique à partir de la génération de thrombine : Apports des approches expérimentales et des modèles dynamiques de la cascade de la coagulation

Haemophilia is a genetic disease corresponding to the deficiency of coagulation factor VIII or IX and leading to a bleeding tendency. The current substitutive treatment is defined essentially by the basal level of deficient factor and not the individual capacity to generate thrombin, a key enzyme of the clot formation. The thrombin generation assay could help in the individualisation of the anti-haemophilia treatment. Indeed, the factor VIII or IX level needed to normalise the thrombin generation vary potentially from one patient to another for a same degree of severity. We can wonder which experimental approach could emphasise the relation between level of anti-haemophilic factor and thrombin generation. Is it possible to mathematically model coagulation to obtain a relation, either explicit, or implicit, between factor level and thrombin generation? Could existing models provide this relation? An extensive experimental campaign was carried out to build a database that has been used to identify the determinant coagulation factors of thrombin generation and the individual relation between thrombin generation and anti-haemophilic factor level, to define their reference values, and also to evaluate and parametrise subject-specifically mathematical models of the coagulation cascadeL’hémophilie est une maladie génétique se traduisant par la déficience des facteurs VIII et IX de la coagulation et conduisant à une tendance hémorragique. L’intensité des traitements substitutifs en facteur VIII et IX est définie essentiellement sur le taux basal du facteur déficitaire et non pas sur la capacité propre à chaque patient à générer de la thrombine qui est l’enzyme clé dans la formation du caillot de fibrine. Le test de génération de thrombine pourrait être utilisé pour permettre une individualisation du traitement anti-hémophilique. En effet, le taux de facteur VIII ou IX nécessaire à la normalisation de la génération de thrombine est potentiellement variable d’un patient à l’autre pour une même sévérité d’hémophilie. On peut donc se demander quelle approche expérimentale permettrait de mettre en exergue le lien entre taux de facteur anti-hémophilique et la génération de thrombine. Est-il possible de modéliser mathématiquement la coagulation pour obtenir une relation, soit explicite, soit implicite, entre taux de facteurs et génération de thrombine ? Les modèles existants permettent-ils d'obtenir une telle relation ? Une vaste campagne expérimentale a donc été menée pour mettre en place une base de données qui a permis d’identifier les facteurs déterminants de la génération de thrombine et la relation entre génération de thrombine et taux de facteur anti-hémophilique, de définir leurs valeurs de références, ainsi que d’évaluer et de paramétrer de manière sujet-spécifique des modèles mathématiques de la coagulation

ALiBi : un exemple de modèle de transferts sol-végétation-atmosphère

National audienc

Comparison of single subject and population-based pharmacokinetics for optimizing prophylaxis with simoctocog alfa in patients with haemophilia A

Introduction: The use of pharmacokinetic assessment for optimal prophylactic dosing of factor concentrates in haemophilia has gained increasing enthusiasm over the last decade. However, blood sampling on several occasions is burdensome and limited sampling using population-based PK is appealing. Aim: To compare the pharmacokinetics and dosing recommendations for prophylaxis using six-point single subject versus population-based method (WAPPS-Hemo) for simoctocog alfa (Nuwiq®). Methods: Twelve adult patients with severe haemophilia A received a factor VIII (FVIII) dose of ≈50 IU/kg, and the activity was measured pre-infusion and at 30 min, 6, 9, 24 and 48 h post-infusion. Half-life (t1/2), weight-normalized AUC and time to troughs of 5%, 3% and 1% were calculated. The correlation between the PK algorithms was assessed using intraclass correlations (ICC) and dosing estimations were provided. Results: WAPPS-Hemo yielded a slightly longer mean t1/2, but the overall correlation between the methods was good (ICC ≥0.79) The time to troughs of 5%, 3% and 1% showed ICCs ≥0.86. For all variables, the most converging limited time point was 6+48 h. Additional time points did not improve the correlation. Despite similar pharmacokinetics, the mean estimated dose for a specific trough level varied from 60% less to 20% more using the population-based approach. The time to 1% and the corresponding dose was sensitive to the baseline assumption. Conclusion: Our data support the use of population-based PK for patients on simoctocog alfa prophylaxis but also indicates differences, stressing the importance of the sampling scheme and monitoring actual FVIII levels achieved

Development and evaluation of the population pharmacokinetic models for FVIII and FIX concentrates of the WAPPS-Hemo project.

BACKGROUND: The Web-Accessible Population Pharmacokinetic Service (WAPPS) project generates individually predicted pharmacokinetic (PK) profiles and tailored prophylactic treatment regimens for haemophilic patients, which rely on a set of population PK (PopPK) models providing concentrate-specific priors for the Bayesian forecasting methodology. AIM: To describe the predictive performance of the WAPPS PopPK models in use on the WAPPS-Hemo platform. METHODS: Data for modelling include dense PK data obtained from industry sponsored and independent PK studies, and dense and sparse data accumulated through WAPPS-Hemo. WAPPS PopPK models were developed via non-linear mixed-effect modelling taking into account the effects of covariates and between-individual-and sometimes between-occasion-variability. Model evaluation consisted of (a) prediction-corrected Visual Predictive Check (pcVPC), (b) Limited Sampling Analysis (LSA) and (c) repeated hold-out cross-validation. RESULTS: Thirty-three WAPPS PopPK models built on data from 3188 patients (ages 1-78 years) under treatment by factor VIII or IX products (FVIII, FIX) were evaluated. Overall, models exhibit excellent performance characteristics. The pcVPC shows that the observed PK data fall within acceptable 90% interpercentile predictive bands. A slight overprediction beyond the expected half-life, an anticipated result of using sparse data, occurs for some models. The LSA results in lower than 3% of relative error for FVIII and FIX products and 16% for engineered FIX products. Cross-Validation analysis yields relative errors lower than 1.5% and 1.4% in estimates of half-life and time to 0.02 IU/mL, respectively. CONCLUSION: The WAPPS-Hemo models consistently showed excellent performance characteristics for the intended use for Bayesian forecasting of individual PK profiles

Detrital zircon U–Pb–Hf systematics of Ediacaran metasediments from the French Massif Central:Consequences for the crustal evolution of the north Gondwana margin

International audienceCombining U–Pb and Lu-Hf isotopic data of detrital zircon grains has proven a powerful tool to unravel theprovenance of sediments and address continental crust evolution. In this study, we explore the origin of thicksiliciclastic metasedimentary units from the high-grade internal domains of the Variscan belt of Europe andexamine their significance for Neoproterozoic crust formation and evolution along the North Gondwana margin.We present data and U–Pb/Lu–Hf systematics of detrital zircons from five amphibolite-facies metasedimentssampled in the eastern French Massif Central, measured in situ by LA–(MC)–ICP–MS. The sedimentary protolithswere deposited in the Ediacaran as evidenced by field relationships and maximum depositional ages rangingbetween 592.4 ± 5.5 and 556.8 ± 5.1 Ma. All samples contain three main zircon populations in terms of agedistribution and Hf isotopes: (i) abundant 0.55–0.65 Ga zircons with considerably scattered εHf(t) from −19 to+14; (ii) varied amounts of 0.65–1.0 Ga zircons showing dominantly positive εHf(t) with the exception of the c.1.0 Ga zircons; and (iii) ≥1.8 Ga zircons (mostly between 1.9–2.1 and 2.5–2.8, up to 3.2 Ga) with εHf(t) rangingbetween +5 and −7. Multidimensional scaling of our U–Pb dataset and a data compilation of Ediacaran toLower Cambrian (meta)sediments from the North Gondwana margin reveals that the relative proportions of thethree age components carry discriminant provenance information. Geological data indicate that the Ediacaranbasins of the eastern French Massif Central collected the erosion products of two main source regions: (i) theNeoproterozoic Cadomian magmatic arc; and (ii) the cratonic hinterland, mostly from the Saharan Metacratonand the Arabian-Nubian Shield. Our dataset attests to the reworking of: (i) juvenile Neoproterozoic crust and, (ii)old Paleoproterozoic to Neoarchean crustal components, either as part of the detritus or incorporated inNeoproterozoic arc magmas. First-order estimates derived from the isotopic signature of S-type granitic magmassourced in the Ediacaran metasediments suggest that 60–75% of the detritus would correspond to youngNeoproterozoic crust and thus represent net additions to the continental crust volume

A method for the quantitative extraction of gold nanoparticles from human bronchoalveolar lavage fluids through a glycerol gradient

International audienceBronchoalveolar lavage (BAL) is a diagnostic procedure which samples the cellular and non-cellular components of the pulmonary epithelial surface. The inherent biological noise of BAL fluids inhibits their direct mineralogical analysis while currently available particle retrieval protocols are suspected to impose quantitative and qualitative bias on the studied particle load. This study presents a simple method for the near-lossless extraction of citrate-capped gold nanoparticles from human BAL fluids at sub-ppm levels which enables their quantitation and surface characterization. This procedure was modeled according to fundamental principles of particle sedimentation and liquid–liquid interdiffusion and was evaluated by a battery of analytical techniques. The extraction yield of gold nanoparticles ranged from 61 to 86%, with a quantitation limit at 0.5 μg ml−1, as measured by inductively-coupled optical emission spectroscopy. Dynamic light scattering could resolve the hydrodynamic size distribution of extracted particles which returned significantly different photon count rates at various concentrations. Their shape and primary size were easily observable by electron microscopy while atomic force microscopy, Auger electron spectroscopy and X-ray photoelectron spectroscopy could respectively probe the particles’ biomolecular corona, detect surface-adsorbed S- and N- species, and identify carbon-based covalent bonds

Biodistribution and Physiologically-Based Pharmacokinetic Modeling of Gold Nanoparticles in Mice with Interspecies Extrapolation

Gold nanoparticles (AuNPs) are a focus of growing medical research applications due to their unique chemical, electrical and optical properties. Because of uncertain toxicity, &#8220;green&#8222; synthesis methods are emerging, using plant extracts to improve biological and environmental compatibility. Here we explore the biodistribution of green AuNPs in mice and prepare a physiologically-based pharmacokinetic (PBPK) model to guide interspecies extrapolation. Monodisperse AuNPs were synthesized and capped with epigallocatechin gallate (EGCG) and curcumin. 64 CD-1 mice received the AuNPs by intraperitoneal injection. To assess biodistribution, groups of six mice were sacrificed at 1, 7, 14, 28 and 56 days, and their organs were analyzed for gold content using inductively coupled plasma mass spectrometry (ICP-MS). A physiologically-based pharmacokinetic (PBPK) model was developed to describe the biodistribution data in mice. To assess the potential for interspecies extrapolation, organism-specific parameters in the model were adapted to represent rats, and the rat PBPK model was subsequently evaluated with PK data for citrate-capped AuNPs from literature. The liver and spleen displayed strong uptake, and the PBPK model suggested that extravasation and phagocytosis were key drivers. Organ predictions following interspecies extrapolation were successful for rats receiving citrate-capped AuNPs. This work lays the foundation for the pre-clinical extrapolation of the pharmacokinetics of AuNPs from mice to larger species