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To rapidly achieve ceftazidime target concentrations, a 2 g loading dose (LD) is recommended before continuous infusion, but its adequacy in critically ill patients, given their unique pharmacokinetics, needs investigation. This study included patients from six ICUs in Saint-Etienne and Paris, France, who received continuous ceftazidime infusion with plasma concentration measurements. Using MONOLIX and R, a pharmacokinetic (PK) model was developed, and the literature on ICU patient PK models was reviewed. Simulations calculated the LD needed to reach a 60 mg/L target concentration and assessed ceftazidime exposure for various regimens. Among 86 patients with 223 samples, ceftazidime PK was best described by a one-compartment model with glomerular filtration rate explaining clearance variability. Typical clearance and volume of distribution were 4.45 L/h and 88 L, respectively. The literature median volume of distribution was 37.2 L. Simulations indicated that an LD higher than 2 g was needed to achieve 60 mg/L in 80% of patients, with a median LD of 4.9 g. Our model showed a 4 g LD followed by 6 g/day infusion reached effective concentrations within 1 h, while a 2 g LD caused an 18 h delay in achieving target steady state. [ABSTRACT FROM AUTHOR]

Background. Unfractionated heparin is administered in patients undergoing veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Anticoagulation monitoring is recommended, with an anti-activated factor X (anti-Xa) targeting 0.3 to 0.7 IU/mL. Owing to heparin's heterogeneous pharmacokinetic properties, anti-Xa is unpredictable, generating a challenge in anticoagulation practices. The aim of this study was to build a pharmacokinetic model of heparin accounting for potential confounders, and derive an optimized dosing regimen for a given anti-Xa target. Methods. Adult patients undergoing VA-ECMO were included between January 2020 and June 2021. Anticoagulation was managed with an initial 100 IU/kg heparin loading dose followed by a continuous infusion targeting 0.2 to 0.7 IU/mL anti-Xa. The data were split into model development and model validation cohorts. Statistical analysis was performed using a nonlinear mixed effects modeling population approach. Model-based simulations were performed to develop an optimized dosing regimen targeting the desired anti-Xa. Results. A total of 74 patients were included, with 1703 anti-Xa observations. A single-compartment model best fitted the data. Interpatient variability for distribution volume was best explained by body weight, C-reactive protein and ECMO indication (post-cardiotomy shock or medical cardiogenic shock), and interpatient variability for elimination clearance was best explained by serum creatinine and C-reactive protein. Simulations using the optimized regimen according to these covariates showed accurate anti-Xa target attainment. Conclusion. In adult patients on VA-ECMO, heparin's effect increased with serum creatinine and medical indication, whereas it decreased with body weight and systemic inflammation. We propose an optimized dosing regimen accounting for key covariates, capable of accurately predicting a given anti-Xa target. [ABSTRACT FROM AUTHOR]

The number of meta‐analyses of aggregate data has dramatically increased due to the facility of obtaining data from publications and the development of free, easy‐to‐use, and specialised statistical software. Even when meta‐analyses include the same studies, their results may vary owing to different methodological choices. Assessment of the replication of meta‐analysis provides an example of the variation of effect 'naturally' observed between multiple research projects. Reproducibility of results has mostly been reported using graphical descriptive representations. A quantitative analysis of such results would enable (i) breakdown of the total observed variability with quantification of the variability generated by the replication process and (ii) identification of which variables account for this variability, such as methodological quality or the statistical analysis procedures used. These variables might explain systematic mean differences between results and dispersion of the results. To quantitatively characterise the reproducibility of meta‐analysis results, a bivariate linear mixed‐effects model was developed to simulate both mean results and their corresponding uncertainty. Results were assigned to several replication groups, those assessing the same studies, outcomes, treatment indication and comparisons classified in the same replication group. A nested random effect structure was used to break down the total variability within each replication group and between these groups to enable calculation of an intragroup correlation coefficient and quantification of reproducibility. Determinants of variability were investigated by modelling both mean and variance parameters using covariates. The proposed model was applied to the example of meta‐analyses evaluating direct oral anticoagulants in the acute treatment of venous thromboembolism. [ABSTRACT FROM AUTHOR]

Apixaban and rivaroxaban have first-line use for many patients needing anticoagulation for venous thromboembolism (VTE). The pharmacokinetics of these drugs in non-obese subjects have been extensively studied, and, while changes in pharmacokinetics have been documented in obese patients, data remain scarce for these anticoagulants. The aim of this study was to perform an external validation of published population pharmacokinetic (PPK) models of apixaban and rivaroxaban in a cohort of obese patients with VTE. A literature search was conducted in the PubMed/MEDLINE, Scopus, and Embase databases following the PRISMA statement. External validation was performed using MonolixSuite software, using prediction-based and simulation-based diagnostics. An external validation dataset from the university hospitals of Brest and Rennes, France, included 116 apixaban pharmacokinetic samples from 69 patients and 121 rivaroxaban samples from 81 patients. Five PPK models of apixaban and 16 models of rivaroxaban were included, according to the inclusion criteria of the study. Two of the apixaban PPK models presented acceptable performances, whereas no rivaroxaban PPK model did. This study identified two published models of apixaban applicable to apixaban in obese patients with VTE. However, none of the rivaroxaban models evaluated were applicable. Dedicated studies appear necessary to elucidate rivaroxaban pharmacokinetics in this population. [ABSTRACT FROM AUTHOR]

Apixaban is a direct oral anticoagulant (DOAC). Many studies have shown that it shows high pharmacokinetic interindividual and intraindividual variability (IIV). The risk of hemorrhage is a major concern for patients treated with apixaban to undergo an operation or an invasive procedure. Due to this large pharmacokinetic variability, the current recommendations concerning the optimal duration of apixaban discontinuation before a high‐bleeding risk procedure concern the general population and not a specific patient. The aim of this study was (1) to investigate by simulation the distribution of decay time of apixaban concentration and (2) to develop and validate an easy‐to‐use web tool to estimate the individual decay time of apixaban in a "real‐life" situation. A systematic review of the literature was conducted to select the relevant pharmacokinetic models for the creation of the web tool. For each model, pharmacokinetic profiles were simulated and the time to reach concentrations below the threshold of 30 ng/ml (T30) was calculated. One of the selected models was chosen to perform a Bayesian estimation and predict the optimal duration of apixaban discontinuation before a high‐bleeding risk procedure. All these results were concatenated into the PrevBleed application developed with the R Shiny package. [ABSTRACT FROM AUTHOR]

Network meta‐analysis (NMA) allows the combination of direct and indirect evidence from a set of randomized clinical trials. Performing NMA using individual patient data (IPD) is considered as a "gold standard" approach as it provides several advantages over NMA based on aggregate data. For example, it allows to perform advanced modeling of covariates or covariate‐treatment interactions. An important issue in IPD NMA is the selection of influential parameters among terms that account for inconsistency, covariates, covariate‐by‐treatment interactions or nonproportionality of treatments effect for time to event data. This issue has not been deeply studied in the literature yet and in particular not for time‐to‐event data. A major difficulty is to jointly account for between‐trial heterogeneity which could have a major influence on the selection process. The use of penalized generalized mixed effect model is a solution, but existing implementations have several shortcomings and an important computational cost that precludes their use for complex IPD NMA. In this article, we propose a penalized Poisson regression model to perform IPD NMA of time‐to‐event data. It is based only on fixed effect parameters which improve its computational cost over the use of random effects. It could be easily implemented using existing penalized regression package. Computer code is shared for implementation. The methods were applied on simulated data to illustrate the importance to take into account between trial heterogeneity during the selection procedure. Finally, it was applied to an IPD NMA of overall survival of chemotherapy and radiotherapy in nasopharyngeal carcinoma. [ABSTRACT FROM AUTHOR]

Aim: For patients with severe haemophilia A, guidelines recommend prophylactic treatment with FVIII, with dose calculations targeting a predetermined FVIII trough level. However, this pharmacokinetic (PK) approach is suboptimal, with some patients experiencing breakthrough bleeds. We aimed to improve FVIII dosing by incorporating the thrombin generation assay, a global haemostasis assay whose main pharmacodynamic (PD) parameter, endogenous thrombin potential (ETP), predicts spontaneous bleeding risk. Methods: We performed post hoc combined PK‐PD modelling using data from 66 adults who received human‐cl rhFVIII (Nuwiq®, Octapharma AG) in a phase IIIb study. Time‐to‐event analyses simulated the probability of spontaneous bleeding for different FVIII exposures and baseline ETPs. Results: Ninety‐one spontaneous bleeds occurred in 20/66 patients. The relationship between FVIII:C and ETP was non‐linear, and the sigmoid Emax model adequately described the data. Individual PK‐PD Bayesian estimation significantly improved predictive performance. Simulations showed that the mean spontaneous annual bleeding rate decreased with increasing baseline ETP or dosing: with ETP values of 200, 400 and 600 (nmol/L)·min annual bleeding rates were 2.36, 1.25 and 0.66, respectively, on 40 IU/kg human‐cl rhFVIII every 3 days; and annual bleeding rates were 2.09, 1.10, and 0.60, respectively, on 60 IU/kg every 3 days. Conclusion: Prophylactic FVIII dosing is more clinically meaningful when incorporating ETP alongside FVIII level. For the first time, FVIII dosing can be personalized with the aim of eliminating spontaneous breakthrough bleeds. [ABSTRACT FROM AUTHOR]

Background: Phase II trials are designed to assess the efficacy/toxicity ratio of experimental treatments and select those worth being tested in phase III trials. Although crucial limitations were identified when concurrent chemoradiation (cCRT) phase III trials characteristics were assessed, features of cCRT phase II trials have never been reported. The objective was to describe features of all cCRT phase II trials. Methods and material: Requests were performed in the Medline database (via PubMed). The latest update was performed in April 2016, using the following MESH terms: 'clinical trials: phase II as topic', 'chemoradiotherapy'. Results: Four hundred and fifty-eight cCRT phase II trials were identified. They were mainly multicenter (51.5%), single arm studies (77.7%) published after 2011 (55.0%). The median number of included patients was 52. Primary endpoints were mainly response rate (20.5%), pathological complete response (14.4%) and overall survival (12.6%). The primary endpoint was not defined in 22% of studies. Tumors were mostly lung (23.1%), head and neck (20.3%), colorectal (16.6%) and esophagogastric cancer (14.6%) treated at a locally advanced setting (81.7%). 55.2% of trials used 3D-conformal radiotherapy and 9.1% intensity-modulated radiotherapy, mainly with normo-fractionation (82.0% of the 573 arms with radiotherapy). Radiation technique was not reported in 19.9% of studies. Associated anticancer drugs (563 arms) were mainly conventional chemotherapies (559 arms): cisplatin (46.2%) and 5-fluorouracil (28.3%). Non cytotoxic agents (targeted therapies, immunotherapies) were tested in 97 arms (17%). With a median follow-up of 31 months, acute grades 3–5 were reported in 98.5% of studies and late toxicities in 44.5%. Follow-up was not reported in 17% of studies. Conclusions: cCRT phase II trials featured severe limitations, with outdated radiation techniques, insufficient reporting of crucial data and a small number of included patients. This certainly limited the impact of conclusions and hindered the development of successful phase III trials. [ABSTRACT FROM AUTHOR]

Aim: Previous pharmacokinetic (PK) studies have proposed various dosing regimens for vancomycin in intensive care unit (ICU) patients undergoing renal replacement therapy (RRT), but all are restricted to specific RRT modalities. To be useful in practice, a population PK model would need to predict vancomycin clearance during any RRT modality. Development of such a model is feasible using meta‐analysis of published summarized estimates of vancomycin PK parameters. Our aims were: (i) to develop and validate a population PK model for vancomycin that takes into account any RRT modalities, and (ii) to predict vancomycin dosing for RRT patients in ICU. Methods: Vancomycin pharmacokinetics were assumed to be two‐compartmental, total body clearance being the sum of non‐RRT clearance and RRT‐induced clearance. Drug disposition and non‐RRT clearance parameters were estimated by systematic review and meta‐analysis of previously published parameter estimates. The relationship between RRT‐induced clearance and RRT flowrate settings was assessed using a model‐based meta‐analysis. Prediction performances of the PK model were assessed using external data. Results: The meta‐analyses of disposition parameters, non‐RRT clearance and RRT‐induced clearance included 11, 6 and 38 studies (84 RRT clearance measurements) respectively. The model performed well in predicting external individual PK data. Individual vancomycin concentrations during RRT were accurately predicted using Bayesian estimation based solely on pre‐RRT measurements. Conclusions: The PK model allowed accurate prediction of the vancomycin pharmacokinetics during RRT in ICU patients. Based on the model of RRT‐induced clearance, an appropriate adjustment of the vancomycin dosing regimen could be proposed for any kind of flowrate settings. [ABSTRACT FROM AUTHOR]

Aims: The use of factor VIII (FVIII) prophylaxis in haemophilia A is considered the standard of care, particularly in children. Despite adjustment of doses for body weight and/or age, a large pharmacokinetic (PK) variability between patients has been observed. PK‐tailored prophylaxis may help clinicians adjust coagulation factor FVIII activity (FVIII:C) to the desired level, which may differ in individual patients. The objective was to develop a population PK model for simoctocog alfa based on pooled clinical trial data and to develop a Bayesian estimator to allow PK parameters in individual patients to be estimated using a reduced number of blood samples. Methods: PK data from 86 adults and 29 children/adolescents with severe haemophilia A were analysed. The FVIII data measured using 2 different assays (chromogenic and the 1‐stage clotting assay) were fit to separate develop population PK models using nonlinear mixed‐effect models. A Bayesian estimator was then developed to estimate the time above the threshold of 1%. Results: The PK data for chromogenic and the 1‐stage clotting assays were both best described by a 2‐compartment models. Simulations demonstrated good predictive capacity. The limited sampling strategy using blood sample at 3 and 24 hours allowed an accurate estimation of the time above the threshold of 1% FVIII:C (mean bias 0.01 and 0.11, mean precision 0.18 and 0.45 for 2 assay methods). Conclusion: In this study, we demonstrated that a Bayesian approach can help to reduce the number of samples required to estimate the time above the threshold of 1% FVIII:C with good accuracy. [ABSTRACT FROM AUTHOR]

Understanding how tumors develop resistance to chemotherapy is a major issue in oncology. When treated with temozolomide ( TMZ), an oral alkylating chemotherapy drug, most low-grade gliomas ( LGG) show an initial volume decrease but this effect is rarely long lasting. In addition, it has been suggested that TMZ may drive tumor progression in a subset of patients as a result of acquired resistance. Using longitudinal tumor size measurements from 121 patients, the aim of this study was to develop a semi-mechanistic mathematical model to determine whether resistance of LGG to TMZ was more likely to result from primary and/or from chemotherapy-induced acquired resistance that may contribute to tumor progression. We applied the model to a series of patients treated upfront with TMZ ( n = 109) or PCV (procarbazine, CCNU, vincristine) chemotherapy ( n = 12) and used a population mixture approach to classify patients according to the mechanism of resistance most likely to explain individual tumor growth dynamics. Our modeling results predicted acquired resistance in 51% of LGG treated with TMZ. In agreement with the different biological effects of nitrosoureas, none of the patients treated with PCV were classified in the acquired resistance group. Consistent with the mutational analysis of recurrent LGG, analysis of growth dynamics using mathematical modeling suggested that in a subset of patients, TMZ might paradoxically contribute to tumor progression as a result of chemotherapy-induced resistance. Identification of patients at risk of developing acquired resistance is warranted to better define the role of TMZ in LGG. [ABSTRACT FROM AUTHOR]

The treatment of acute venous thromboembolism (VTE) is being completely modified with the development of direct oral anticoagulants (DOACs). Rivaroxaban, apixaban and edoxaban directly inhibit factor Xa, whereas dabigatran inhibits factor IIa. All these drugs are proposed orally, and share pharmacological similarities: fixed doses without any therapeutic drug monitoring, key role of the transporter proteins P-glycoprotein for all of them and metabolism mediated by CYP3A4 for the anti-Xa, short half-life with variable rate of renal elimination. More than 25 000 patients with acute VTE were included in phase-III studies. Rivaroxaban and apixaban challenged all the conventional therapy (parenteral heparins followed by anti-vitamin K antagonists) whereas edoxaban and dabigatran challenged only anti-vitamin K antagonists. All the DOACs met the non-inferiority efficacy endpoint (recurrent VTE during treatment), whereas the large non-inferiority margin was debated for dabigatran. However, they were associated with better safety and a decreased risk of major bleeding. According to indirect comparisons, there were no statistically significant differences between DOACs in terms of efficacy but some differences are not excluded in term of safety. Although DOACs allow for simplification of treatment in the majority of patients with acute VTE, their risk/benefit ratio is questioned in elderly patients, patients with mild-to-severe renal impairment, and in some clinical subgroups such as cancer or chronic thromboembolic pulmonary hypertension. Validated reversal strategies (potentially based on laboratory monitoring) are expected for patients with major bleeding, overdose or with a need for surgery. [ABSTRACT FROM AUTHOR]

Background: The diagnostic role of circulating anti-phospholipase A2 receptor antibodies (anti-PLA2R Abs) is now well recognized in idiopathic membranous nephropathy (iMN). These Abs could also be interesting as predictors of clinical outcome. In this study, we explored the prognostic value of anti-PLA2R Abs measured in a cohort of iMN patients, with a special focus on their ability to detect patients achieving spontaneous remission. Methods: All adult patients with biopsy-proven iMN diagnosed between 1978 and 2007 were retrospectively screened in our centre. Using a validated enzyme-linked immunosorbent assay, levels of anti-PLA2R Abs were measured from serum samples obtained at the time of renal biopsy and stored at -80° C until processing. Clinical data on disease activity, treatments and outcomes were collected by reviewing patients' medical records. The association between anti-PLA2R Ab titres and clinical activity/outcome was assessed by Cox proportional hazard and Kaplan-Meier methods. Results: In this retrospective study, 68 patients were included in the final analysis (median follow-up of 81 months). No significant association was found between anti-PLA2R Ab titres at diagnosis with baseline proteinuria, baseline estimated glomerular filtration rate or chronic kidney disease progression. Spontaneous remission was observed in 22% of patients. Ab titres were significantly and gradually correlated in a dose-response manner with the likelihood of spontaneous remission. Conclusions: While Ab titres measured at diagnosis were not found to predict the activity of iMN, evaluation of anti-PLA2R Ab titres might prove useful in the early identification of patients likely to achieve spontaneous remission. [ABSTRACT FROM AUTHOR]