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Current methods for therapeutic drug monitoring (TDM) have a long turnaround time as they involve collecting patients' blood samples followed by transferring the samples to medical laboratories where sample processing and analysis are performed. To enable real-time and minimally invasive TDM, a microneedle (MN) biosensor to monitor the levels of two important antibiotics, vancomycin (VAN) and gentamicin (GEN) is developed. The MN biosensor is composed of a hydrogel MN (HMN), and an aptamer-functionalized flexible (Flex) electrode, named HMN-Flex. The HMN extracts dermal interstitial fluid (ISF) and transfers it to the Flex electrode where sensing of the target antibiotics happens. The HMN-Flex performance is validated ex vivo using skin models as well as in vivo in live rat animal models. Data is leveraged from the HMN-Flex system to construct pharmacokinetic profiles for VAN and GEN and compare these profiles with conventional blood-based measurements. Additionally, to track pH and monitor patient's response during antibiotic treatment, an HMN is developed that employs a colorimetric method to detect changes in the pH, named HMN-pH assay, whose performance has been validated both in vitro and in vivo. Further, multiplexed antibiotic and pH detection is achieved by simultaneously employing the HMN-pH and HMN-Flex on live animals., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Aims: Use of infliximab (IFX) has improved outcomes in children with inflammatory bowel disease (IBD). However, a proportion of patients does not respond to IFX or loses response over time. Population pharmacokinetic (PopPK) modelling is a promising approach for IFX dose optimization, but with the increasing number of PopPK models in literature, model evaluation is essential. The aims of this study are: (i) to validate the predictive performance of existing IFX PopPK models using a cohort of children with IBD; and (ii) to perform a Bayesian estimation of the most suitable model to predict the next IFX concentrations., Methods: PubMed was searched for IFX PopPK models in children. Selected models were rebuilt and analysed using R. Model performance was assessed through goodness-of-fit-plots, residuals against time, prediction error and prediction-corrected visual predictive checks. The validation cohort consisted of 73 children with IBD who were treated with IFX in our centre between 2017 and 2023 (340 IFX measurements)., Results: We identified 9 PopPK models. Model bias for individual predicted values ranged from -9.29% to 8.01% compared to bias for population predicted values. The model by Vande Casteele et al. demonstrated superior performance (individual predicted bias 2.13, population predicted bias -6.11); upon Bayesian estimation, it predicted induction trough levels with median error of 12.95% but had a median error of -69% predicting maintenance concentrations., Conclusion: The model by Vande Casteele et al. displayed superior performance in initial evaluations but had a high error in estimating next IFX levels and can only be used in practice to predict induction levels., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Introduction: Web-Accessible Population-Pharmacokinetic Service-Haemophilia (WAPPS-Hemo) data are available to study factor-concentrate usage, defined as the required weekly dose to achieve a 3% trough (WD3T), across standard and extended half-life (SHL/EHL) products., Aim: To provide baseline usage data including (i) differences across plasma-derived (pdSHL) versus recombinant (rSHL) products, (ii) SHL versus EHL, and (iii) effect of age and positive inhibitor history., Methods: PK profiles (n = 14,416 patients, 0.3-85.2 years) and linear mixed effects models were used to estimate usage versus age, controlling for significant factors, using 95% confidence intervals to perform comparisons across all ages and posthoc tests to assess the differences., Results: Average usage was significantly higher for pdSHL versus rSHL in patients with a positive inhibitor history (PIH; 1.9-2.5 times higher), for SHL versus EHL (4-10 times), and was significantly associated with age., Conclusion: Baseline usage patterns from 2017 to early 2023 provide a benchmark for assessing the impact of emerging technologies in haemophilia., (© 2024 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Introduction: Plasminogen deficiency is an ultra rare disease whose patients may develop ligneous lesions if untreated. Prophylactic replacement therapy with plasma derived plasminogen, Ryplazim, is efficient in treating lesions and could benefit from pharmacokinetic (PK) tailoring., Aim: The objectives of this study are to develop, evaluate and integrate into the WAPPS-Hemo platform a Population PK model supporting prophylactic replacement therapy for Plasminogen deficient patients., Methods: Population PK modelling and evaluations followed the same protocol performed for factor VIII and IX concentrates. Limited sampling analysis used dosing and sampling scenarios in accordance with recommended treatment for Ryplazim., Results: The population PK model, derived from 16 participants included in previous clinical studies, was a 2-compartment model whose variability was best described by fat-free mass. Evaluations showed that the model described well the data and Bayesian forecasting in limited sampling environment led to acceptable precision for PK parameters relevant to plasminogen treatment., Conclusion: The model was integrated into the WAPPS-Hemo webservice to help individualize prophylactic treatment in plasminogen deficient patients. Prospective PK data to be collected through the WAPPS-Hemo database will be used to better understand plasminogen PK and improve patient care., (© 2024 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Introduction: Damoctocog alfa pegol (BAY 94-9027, Jivi®) is an extended half-life recombinant factor (F)VIII replacement, indicated for the treatment of haemophilia A in patients aged ≥12 years. Following introduction of damoctocog alfa pegol in Canada in 2020, there have been no reports on routine clinical effectiveness and satisfaction, when switching from a previous FVIII product in Canada., Aim: To report changes in pharmacokinetics, effectiveness, utilization and patient satisfaction when switching to damoctocog alfa pegol prophylaxis from previous standard half-life octocog alfa (BAY 81-8973, Kovaltry®) treatment., Methods: A single-centre, intra-patient comparison of pharmacokinetics and clinical outcomes was performed. Blood samples drawn once pre-dose and ≥2 times post-dose were measured by a one-stage assay to assess pharmacokinetic parameters including area under the curve (AUC, primary endpoint). Patient-reported outcomes data were collected using the Patient-Reported Outcomes, Burdens and Experiences questionnaire (PROBE). Clinical outcomes included annualized bleeding rate (ABR) and factor utilization., Results: Dose-normalized AUC was significantly increased after switch to damoctocog alfa pegol from octocog alfa. Median (quartile [Q]1; Q3) annualized bleeding rates were 0.67 (0.00; 1.33) with damoctocog alfa pegol and 1.33 (0.00; 2.67) with octocog alfa. Half of the patients receiving damoctocog alfa pegol prophylaxis experienced zero bleeds (n = 9, 50.0%) versus 38.9% (n = 7) of patients treated with octocog alfa. Patients' good quality of life was maintained., Conclusion: This study provides routine clinical evidence supporting the benefits of switching from octocog alfa to damoctocog alfa pegol for patients with severe haemophilia A., (© 2024 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Introduction: Hemophilia A is a bleeding disorder characterized by a deficiency of a coagulation factor VIII and optimally treated using pharmacokinetics (PK)-guided prophylactic replacement therapy. To decrease patient burden, PK can be estimated from sparse sampling leveraging population PK modeling. However, recommendations for sampling times meant for patients with hemophilia A as a group may not be optimal at the individual level., Objective: To evaluate a personalized limited sampling approach (Personalized LSA) that suggests a next sampling time point that would provide a more accurate estimation of terminal half-life of FVIII concentrates when using a population PK approach., Methods: 331 PK studies with rich sampling were extracted from the WAPPS-Hemo database. Two sampling approaches were evaluated and compared: 974 PK studies consisting of two samples were built from the rich sampling data including one sample selected using the personalized LSA prediction; 974 PK studies consisting of two samples were built from the rich sampling data including one sample selected randomly. Half-life values were estimated on the sparse data and compared within patients to the estimates obtained on the rich data for assessing the error on half-life values., Results: Relative errors between estimates from sparse sampling data using personalized LSA and from rich sampling data were always lower than 20% and significantly lower than the comparative approach that used random sampling (median-95th percentile were 3.8%-13.1% vs. 7.0%-23.5%, respectively, p-value < 10 -10 ). Moreover, less than 4% of the samples suggested by the personalized LSA were below the limit of quantification., Conclusions: Identifying the most informative sampling points for PK assessment using a Personalized LSA approach that accounts for individual differences in PK improves the precision of FVIII terminal half-life estimates in sparse sampling., (© 2022 International Society on Thrombosis and Haemostasis.)

Background: Nonacog alfa, a standard half-life recombinant factor IX (FIX), is used as a prophylactic treatment in severe haemophilia B (SHB) patients. Its half-life determined in clinical studies involving a limited sampling (72 h) was shown to be rather short. In our clinical practice, we suspected that its half-life could have been underestimated., Objectives: We aimed to evaluate nonacog alfa pharmacokinetics in real world clinical practice based on FIX levels in patients receiving prophylaxis., Methods: We retrospectively collected data on patients with SHB receiving prophylaxis from eight centres across France. The terminal half-life (THL), time to reach 5-2 IU/dl and FIX activity at 48, 72 and 96 h were derived by Bayesian estimations using NONMEM analysis., Results and Conclusions: Infusion data (n = 455) were collected from 64 patients with SHB. The median THL measured in 92 pharmacokinetic (PK) studies was 43.4 h. In 26 patients ≤12 years of age, 51 PK studies showed a median time to reach 5 IU/dl of FIX of 70.5 h and a median time to reach 2 IU/dl of 121.5 h. In 38 patients 13-75 years of age, 41 PK studies showed a median time to reach 5 IU/dl of FIX of 92.0 h and a median time to reach 2 IU/dl of 167.5 h. Extending the sampling beyond 72 h makes it possible to observe a plateau, with FIX remaining between 2 and 5 IU/dl for several days and shows that the THL of nonacog alfa might be longer than previously described., Essentials: Nonacog alfa terminal half-life (THL) in patients receiving regular prophylaxis was evaluated in clinical practice. The median THL was estimated to be 36.9 h for patients aged .8-12 years. The median THL was estimated to be 49.9 h for patients aged 13-75 years. For patients aged ≤12 and >12 years, the median times to reach 5 IU/dl were 70.5 and 92 h, respectively; to reach 3 IU/dl, 95.5 and 131.5 h, respectively; to reach 2 IU/dl, 121.5 and 167.5 h, respectively. We suggest that the half-life of nonacog alfa might be longer than previously described in both younger and older patients., (© 2022 John Wiley & Sons Ltd.)

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., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Background: Existing adult patient pharmacokinetic (PK) data from the published Advate vs Kovaltry PK crossover study were used for this validation study. This data set is appropriate for qualification, given that it has not been previously submitted to Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) and will not have impacted the WAPPS-Hemo models for Kovaltry., Objective: To compare the population PK parameters for Kovaltry (BAY 81-8973) derived from the WAPPS-Hemo models with PK parameters derived from noncompartmental analysis (NCA), using a validation PK dataset., Methods: The qualification data set included Kovaltry factor activity (10 samples per infusion) and anthropometric data for 18 patients. Two analyses were performed comparison of Bayesian forecasting from the WAPPS-Hemo models versus NCA using the full 10-sample data set; and comparison of Bayesian forecasting using the full versus reduced 4- and 3-sample data sets. Agreement between outcomes was assessed by quantifying the variability and bias of the error., Results: Comparison of WAPPS-Hemo models versus NCA led to well-correlated outcomes despite a systematic overprediction of clearance. Population PK models demonstrated greater consistency with NCA on one-stage data, compared with chromogenic data. WAPPS-Hemo model results were consistent in reduced sampling compared to full sampling. Inclusion of a 48-hour time point in the reduced sampling greatly improved the consistency with full sampling., Discussion: Qualification of population PK models and their use for Bayesian forecasting in full and reduced sampling is an essential step toward their validation. The evaluations performed in this study support the confidence of PK parameter estimates provided by the models., (© 2021 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

The thrombin generation (TG) assay is a well-established tool to capture the clotting potential of any healthy or haemophiliac subject. It measures ex vivo the kinetics of thrombin activation throughout the coagulation. Clinical studies allowed to create two databases gathering the coagulation factor levels and the thrombin generation profile of 40 healthy and 40 haemophiliac A (HA) subjects. Besides, portions of all HA samples were spiked with increasing levels of a TFPI antibody (considered as a possible therapeutic target) and corresponding TG profiles were determined. The non-linear mixed-effect (NLME) modelling aims at describing and explaining the experimentally observed important variability of the TG curves between subjects and the individual effects of spiking with a TFPI antibody. The models consist of an empirical description of the TG kinetics, accounting for an additive residual error and between-subject variability on its parameters. Factor VIII and TFPI were found to significantly explain and reduce the variability of the TG of haemophilia A samples. Besides, the model is shown to correctly reproduce the variability in the response to the ex vivo spiking with the TFPI antibody, by combining the empirical description of TG to a simple Hill equation that accounts for the binding between TFPI and different doses of its antibody. Such models can be useful for clinical practice, with the analysis and comparison of the distributions of TG profiles in healthy and haemophilia populations; and also for research, with the analysis of the effect of TFPI and its neutralization on individual TG profiles.

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)., (© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

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 (t 1 / 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 t 1 / 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., (© 2021 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

In selecting optimal dosing regimens in support of the clinical use of monoclonal antibodies and other therapeutic proteins in pediatric indications, the unique pharmacokinetic properties of this class of biologics, as well as the underlying physiologic and pathophysiologic processes and their modulation by childhood growth and development, needs to be appreciated. During drug development, first-in-pediatric dose selection is a capstone event in the pediatric investigation plan that relies heavily on extrapolation of pharmacokinetic and pharmacodynamic data from adult to pediatric populations. It is facilitated by combinations of pharmacometric approaches, including allometry, physiologically based pharmacokinetic modeling, and population pharmacokinetic analyses, although data on reliability and qualification of some of these tools in the context of therapeutic proteins are still limited but emerging. Presented data suggest nonlinear relationships between body weight and both clearance and volume of distribution for therapeutic proteins in pediatric populations, with allometric exponents of 0.75 and 0.8, respectively. For newborns and infants (<1 year), even higher nonlinearity seems to occur. Translation of the quantitative characterization of the pediatric pharmacokinetics of therapeutic proteins into dosing regimens for the drug label requires compromising between precision dosing and clinical practicability, with tiered dosing algorithms based on size or age strata being the currently most frequently applied methodology., (© 2021, The American College of Clinical Pharmacology.)

Introduction: Emicizumab is dosed as mg/kg and, according to the label, any unused drug left in the vial(s) must be discarded, thereby wasting expensive resources. The aim of this study was to use population pharmacokinetics to illustrate the implications of changing the dosing interval to avoid wastage., Methods: We used a previously published emicizumab PopPK model after extending its validation to children. We simulated PK parameters for labelled dosing regimens and for regimens using full vials with infusion frequency varied to keep the steady-state drug concentration unchanged. Cost and drug savings were calculated., Results: The model evaluation was successful. When rounding up, the average individual below 53, 47 and 39 has a time-to-trough increase of up to 5.7, 7.9 and 5.8 days for the QW, Q2 W and Q4 W regimen, respectively. This resulted in an annual cost reduction of up to $173,136, $75,747 and $61,319 USD per patient. At higher body weights, rounding down the dose to the nearest vial resulted in negligible changes in the steady state concentration and cost savings of up to $93,781, $46,891 and $23,446 USD per patient, respectively., Conclusion: Individuals with a lower body weight may benefit from increasing dose intervals and rounding up dose up to the nearest vial, and individuals with a higher body weight from maintaining the injection frequency and rounding dose down to the nearest vial without significant change in emicizumab levels. Administering the entire vial may result in a reduction of vials used annually and potential cost savings., (© 2021 John Wiley & Sons Ltd.)

Background: Extended half-life (EHL) factor VIII (FVIII) products may decrease the burden of prophylactic treatment in haemophilia A by reducing infusion frequency. However, these products still exhibit wide inter-patient variability and benefit from pharmacokinetic (PK) tailoring., Objective: Identify limited sampling strategies for rFVIIIFc, an EHL FVIII product, that produce accurate estimates of PK parameters and relevant troughs., Methods: We performed a limited sampling analysis on simulated populations of adults, adolescents, and children based on published population PK data. Sampling strategies were evaluated by comparing the error in estimates of half-life, clearance, and trough levels, to a full 6-sample design. Furthermore, we assessed the impact of incorporating knowledge about prior doses, and the day of the PK study within the regimen. We also evaluated the potential inappropriate dose adjustment rate (IDAR) among the modelled sampling strategies., Results: Many sampling strategies, including several 2-sample designs, accurately predicted the PK and exposure measures (median absolute error <10%). When samples are only collected during a single visit (i.e., predose + peak), inclusion of prior dose information reduces median half-life error from >20% to ~5% for adults/adolescents. In this same scenario, appropriate scheduling of the PK study decreases likelihood of unmeasurable predose samples, reducing median error on the 72-h trough from 25% to <12% in the youngest population., Conclusions: The PK of rFVIIIFc can be accurately estimated using only peak and trough samples, provided that knowledge of prior doses is incorporated and the PK study is planned on an appropriate day within the dosing regimen., (© 2021 John Wiley & Sons Ltd.)

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., (© 2020 John Wiley & Sons Ltd.)

The use of enhanced half-life (EHL) FVIII has improved the quality of prophylaxis in haemophilia A, but with a benefit that may vary from one patient to another. We analysed the pharmacokinetic data obtained with efmoroctocog alfa (rFVIII-Fc) in 114 patients and, in 47 cases, compared them to those previously measured with non-EHL FVIII. The in vivo recovery (IVR) of rFVIII-Fc measured with one stage clotting assay (OSA) and chromogenic assay (CSA) was 2.2 and 2.8 IU/mL per IU/kg, respectively. The median half-life (T 1/2 ) of rFVIII-Fc was 14.5 hours whatever the FVIII:C assay used, but variable and correlated with preinfusion VWF:Ag levels (r = .76). Both IVR and T 1/2 were lower in patients under 12 years old (2.4 IU/mL per IU/kg and 11.1 hours, respectively; CSA). PK study of rFVIII-Fc vs non-EHL FVIII showed a T 1/2 ratio of 1.4 in favour of rFVIII-Fc, regardless of the patient's age. However the relative increase in T 1/2 with rFVIII-Fc was lower than 30% in one-third of patients evaluated, particularly when the previous FVIII administered was a BHK-derived product. This study therefore suggests that analysis of individual PK profile in response to a specific FVIII concentrate is potentially useful before a switch in haemophilia A patients., (© 2020 John Wiley & Sons Ltd.)

Background and Objective: Rurioctacog alfa pegol (Adynovate) is a modified recombinant factor VIII concentrate used for treating hemophilia A. Aiming to improve treatment tailoring on the Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) platform for patients of all ages treated with Adynovate, we have developed and evaluated a population pharmacokinetic (PopPK) model. On the platform, PopPK models are used as priors for Bayesian forecasting that derive individual PK of hemophilia patients and are subsequently used for personalized dose regimen design., Methods: Factor activity measurements and demographic covariate data from patients infused with Adynovate were extracted from the WAPPS-Hemo database. Evaluations testing the appropriateness of Bayesian forecasting included 10-fold cross validation, a limited sampling analysis (LSA), and an external evaluation using additional independent data extracted from the WAPPS-Hemo database at a later date., Results: The model was constructed using 650 plasma factor activity observations (555 one stage assay and 95 chromogenic assay - 4.6% below limit of quantification) measured in 154 patients from 36 hemophilia centres. A two-compartment model including between subject variability on clearance and central volume was selected as the base model. Covariates were fat free mass on clearance and central volume, age on clearance and assay type on activity. The final model was well-suited to predict PK parameters of new individuals (n = 26) from sparse observations., Conclusions: The development of a PopPK model for Adynovate using real-world data increases the covariate space (e.g. age) beyond what is possible from clinical trial data. This model is available on the WAPPS-Hemo platform for tailoring treatment in hemophilia A patients.

Introduction: This study proposes a method to predict individual pharmacokinetics of a future product by using the individual pharmacokinetic profile on the current product and the PopPK models of the current and future product., Methods: Individual dense data was collected from two PK crossover studies, one enrolling 29 patients switching from Advate to Eloctate and one enrolling 15 patients switching from Advate to Novoeight. Three methods were designed to predict the second product's individual PK parameters (CL, V1, Q, and V2). Method 1 used the second product's typical population value of PK parameters from its PopPK model. Method 2 used the second product's calculated PK parameters based on individual covariates and its PopPK model. Method 3 used method 2, along with the predicted η-values of CL and V1 from the first product and its PopPK model. Each method was used to assess PK prediction during switching from Advate to Novoeight, Novoeight to Advate, and Advate to Eloctate., Results: The three methods produced different outcomes. The mean absolute relative errors for half-life were lowest for method 3 for each study (11.6%, 13.1%, 13.6%). The regression line between predicted and observed half-life for method 3 was closest to the line of identity for each study (0.84, 0.67, 0.66)., Conclusion: Taking into account individual PK from a previous clotting factor product was shown to provide better means of estimating individual PK for a new product. This may improve regimen design across switches and reduce the time to tailor optimal dose of FVIII products., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Hemophilia A is a rare bleeding disorder resulting from a lack of functional factor VIII (FVIII). Therapy consists of replacement with exogenous FVIII, but is complicated by high inter-patient variability. A population pharmacokinetics (PopPK) approach can facilitate the uptake of an individualized approach to hemophilia therapy. We developed a PopPK model using data from seven brands of standard half-life FVIII products. The final model consists of a 2-compartment structure, with a proportional residual error model and between-subject variability on clearance and central volume. Fat-free mass, age, and brand were found to significantly affect pharmacokinetic (PK) parameters. Internal and external evaluations found that the model is fit for Bayesian forecasting and capable of predicting PK for brands not included in the modelling dataset, and useful for determining individualized prophylaxis regimens for hemophilia A patients.

Fanhdi/Alphanate is a plasma derived factor VIII concentrate used for treating hemophilia A, for which there has not been any dedicated model describing its pharmacokinetics (PK). A population PK model was developed using data extracted from the Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) project. WAPPS-Hemo provided individual PK profiles for hemophilia patients using sparse observations as provided in routine clinical care by hemophilia centers. Plasma factor activity measurements and covariate data from hemophilia A patients on Fanhdi/Alphanate were extracted from the WAPPS-Hemo database. A population PK model was developed using NONMEM and evaluated for suitability for Bayesian forecasting using prediction-corrected visual predictive check (pcVPC), cross validation, limited sampling analysis and external evaluation against a population PK model developed on rich sampling data. Plasma factor activity measurements from 92 patients from 12 centers were used to derive the model. The PK was best described by a 2-compartment model including between subject variability on clearance and central volume, fat free mass as a covariate on clearance, central and peripheral volumes, and age as covariate on clearance. Evaluations showed that the developed population PK model could predict the PK parameters of new individuals based on limited sampling analysis and cross and external evaluations with acceptable precision and bias. This study shows the feasibility of using real-world data for the development of a population PK model. Evaluation and comparison of the model for Bayesian forecasting resulted in similar results as a model developed using rich sampling data.

Essentials The PK parameters of Eloctate vs Adynovate were compared using one-stage and chromogenic assays in 25 boys (12-18 years). The FVIII levels were taken at 3, 24, 48, and 72 hours following a dose of either FVIII; levels analyzed by WAPPS PK program. The PK profiles (half-life, clearance, and time to 5%, 3%, and 1%) were not statistically different for the two EHL FVIIIs. The significant interpatient variability in PK is mainly related to VWF levels (and blood group)., Background: A head-to-head comparison of the pharmokinetcs (PK) of extended half-life (EHL) factor VIII (FVIII) concentrates in the same subjects has not been reported. Recently, boys (ages 12-18 years) with hemophilia A in Canada were required to switch from Eloctate to Adynovate., Objectives: Compare the PK profiles of Eloctate vs Adynovate in the same boys., Methods: Boys switching from Eloctate to Adynovate prophylaxis had FVIII levels sampled at 3, 24, 48, and 72 hours following a regular prophylactic infusion of Eloctate and then 1-3 months later, of Adynovate. Testing was done by one-stage assay (OSA) and chromogenic assay (CA). The PK parameters were determined with the Web Accessible Population Pharmacokinetic Service (WAPPS)-Hemo PK tool., Results: Twenty-five boys (mean age 15.3 years; range: 12.1-18.4; 9 O blood group) underwent switching. Mean (range) terminal half-lives with the OSA were 16.1 hours (10.4 to 23.4; Eloctate) and 16.7 hours (11.0 to 23.6; Adynovate) (NS). With the CA, these were 18.0 hours (12.0 to 25.5; Eloctate) and 16.0 hours (10.3 to 22.9; Adynovate) (P = 0.001). There were no significant differences between the two EHL-FVIIIs in clearance, area under the concentration vs time curve (AUC), Vss, or time for FVIII levels to drop to 5%, 3%, and 1%. At the 72-h time point, mean observed FVIII levels following a mean dose of 39.3 IU/kg of Eloctate were 4.4% (OSA) and 4.4% (CA). For Adynovate, these were 5.1% (OSA) and 5.3% (CA) following similar doses. There was considerable interpatient variation in PK, mainly explained by differences in blood group/von Willebrand factor (VWF) levels., Conclusions: Eloctate and Adynovate have almost identical PK parameters. When switching from one to another no prophylaxis regimen change is needed., (© 2019 International Society on Thrombosis and Haemostasis.)

Gold nanoparticles (AuNPs) are a focus of growing medical research applications due to their unique chemical, electrical and optical properties. Because of uncertain toxicity, "green" 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.

The thrombin generation (TG) assay evaluates haemostatic balance, which is influenced by the levels of many coagulation factors and inhibitors. Our objective was to identify the determinant factors of TG in haemophilia A (HA) and haemophilia B (HB) patients and to compare them to those in healthy controls. Coagulation factor and inhibitor levels, and TG, were measured in platelet-poor plasma from 40 patients with HA, 32 patients with HB and 40 healthy subjects. Data were analysed using multiple regression models. In HA patients, factor VIII was a positive determinant of endogenous thrombin potential (ETP) and peak, whereas tissue factor pathway inhibitor (TFPI) and factor V were negative determinants of ETP and peak. In HB patients, FIX was a positive determinant of ETP and peak, FVII being a positive determinant of peak. Antithrombin and protein S (PS) were negative determinants of ETP while FX was a negative determinant of peak. Above all, in HB patients, TFPI was a negative determinant of ETP and peak. In healthy subjects, FVIII was a positive determinant of ETP and peak, whereas FX and protein S were negative determinants of these parameters. TFPI was not a negative determinant of either peak or ETP. In haemophilic patients, the determinant factors of TG are all implicated in FXa generation and inhibition, the crucial determinant factor being TFPI whatever the type of haemophilia, A or B. These findings contribute to the rationale that recently place TFPI as a target for innovative therapies of haemophilia., (© 2019 John Wiley & Sons Ltd.)

The coagulation cascade comprises numerous chemical reactions between many proteins, that finally lead to the formation of a clot to stop bleeding. Many numerical models have attempted to translate understanding of this cascade into mathematical equations that simulate the chain reactions. However, their predictions have not been validated against clinical data stemming from patients. In this paper, we propose an extensive validation of five available models, by comparing in healthy and haemophilic subjects, thrombin generation measured in vitro to thrombin generation predicted by the models in silico. In order to render the models more predictive, we calibrated the models to have an acceptable agreement between the experimental and estimated data. Optimization processes based on genetic algorithms were developed to search for those calibrated kinetic parameters. Our results show that the thrombin generation kinetics are so complex that they cannot be predicted by a unique set of kinetic parameters for all patients: the calibration of only three parameters in a subject-specific way allows reaching good model estimations for different experimental conditions realized on the same patient.

Bronchoalveolar 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.

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., Competing Interests: The authors declare no conflict of interest.