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

Terminal half-life of FVIII and FIX according to age, blood group and concentrate type: data from the WAPPS database

Background Real-life data on pharmacokinetics of factor (F) VIII/IX concentrates, especially extended half-life (EHL), concentrates in large cohorts of persons with hemophilia are currently lacking. Objectives This cross-sectional study aimed to establish reference values for terminal half-life (THL) for FVIII/IX concentrates according to concentrate type, age, blood group and inhibitor history. Patients/Methods Data were extracted from the Web-Accessible Population Pharmacokinetics Service database. Groups were compared by nonparametric tests. THL was modelled according to patient characteristics and concentrate type. Results Infusion data (n = 8022) were collected from 4832 subjects (including 2222 children) with severe hemophilia (age: 1 month–85 years; 89% hemophilia A; 34% using EHL concentrates, 9.8% with history of inhibitors). THL of FVIII-EHL was longer than of FVIII standard half-life (SHL; median 15.1 vs. 11.1 h). FVIII-THL was dependent on age, concentrate type, blood group, and inhibitor history. THL of FIX-EHL was longer than of FIX-SHL (median 106.9 vs. 36.5 h). FIX-THL increased with age until 30 years and remained stable thereafter. FVIII-THL was shorter in subjects with blood group O. THL was decreased by 1.3 h for FVIII and 22 h for FIX in subjects with a positive inhibitor history. Conclusions We established reference values for FVIII/IX concentrates according to patient characteristics and concentrate type in a large database of hemophilia patients. These reference values may inform clinical practice (e.g., assessment of immune tolerance success), economic implications of procurement processes and value attribution of novel treatments (e.g., mimetics, gene therapy)

Predicting Individual Changes in Terminal Half-Life After Switching to Extended Half-Life Concentrates in Patients With Severe Hemophilia

Predicting individual effects of switching from standard half-life (SHL) to extended half-life (EHL) FVIII/FIX concentrates is pivotal in clinical care, but large-scale individual data are scarce. The aim of this study was to assess individual changes in terminal half-life (THL) after switching to EHL concentrates and identifying determinants of a clinically relevant THL extension in people with severe hemophilia. Data from participants with pharmacokinetic studies on both SHL and EHL were extracted from the Web-Accessible Population Pharmacokinetics Service (WAPPS) database and stratified according to hemophilia type and age groups (children/adults). A 30% increase in THL was considered clinically relevant. Predictors of a relevant increase were identified using logistic regression. Data from 688 persons with severe hemophilia (2174 infusions) were included: 89% hemophilia A; median age: 21.7 (interquartile range [IQR]: 11.5-37.7); positive inhibitor history: 11.7%. THL increased by 38% (IQR: 17%-67%) and 212% (139%-367%) for hemophilia A and B, respectively. All EHL-FIX concentrate users showed clinically relevant THL extension. However, 40% (242/612) of people with hemophilia A showed limited extension or decrease in THL after switching. Relevant FVIII-THL extension was predicted by short baseline THL and blood group non-O in both children and adults. In conclusion, clinically relevant THL extension was observed in all 75/76 participants switching to EHL-FIX, and in 60% of 612 switching to EHL-FVIII. Short THL on SHL-FVIII and blood group non-O were identified as predictors for a relevant THL increase after switching to EHL-FVIII. Individualized pharmacokinetic assessment may guide clinical decision-making when switching from SHL to EHL-FVIII

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

Use of population PK/PD approach to model the thrombin generation assay: assessment in haemophilia A plasma samples spiked by a TFPI antibody

International 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