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Background:
Anti-TNFα monoclonal antibodies (mAbs) are a well-established treatment for patients with Crohn’s disease (CD). However, subtherapeutic concentrations of mAbs have been related to a loss of response during the first year of therapy1. Therefore, an appropriate dosing strategy is crucial to prevent the underexposure of mAbs for those patients. The aim of our study was to assess the impact of different dosing strategies (fixed dose or body size descriptor adapted) on drug exposure and the target concentration attainment for two different anti-TNFα mAbs: infliximab (IFX, body weight (BW)-based dosing) and certolizumab pegol (CZP, fixed dosing). For this purpose, a comprehensive pharmacokinetic (PK) simulation study was performed.
Methods:
A virtual population of 1000 clinically representative CD patients was generated based on the distribution of CD patient characteristics from an in-house clinical database (n = 116). Seven dosing regimens were investigated: fixed dose and per BW, lean BW (LBW), body surface area, height, body mass index and fat-free mass. The individual body size-adjusted doses were calculated from patient generated body size descriptor values. Then, using published PK models for IFX and CZP in CD patients2,3, for each patient, 1000 concentration–time profiles were simulated to consider the typical profile of a specific patient as well as the range of possible individual profiles due to unexplained PK variability across patients. For each dosing strategy, the variability in maximum and minimum mAb concentrations (Cmax and Cmin, respectively), area under the concentration-time curve (AUC) and the per cent of patients reaching target concentration were assessed during maintenance therapy.
Results:
For IFX and CZP, Cmin showed the highest variability between patients (CV ≈110% and CV ≈80%, respectively) with a similar extent across all dosing strategies. For IFX, the per cent of patients reaching the target (Cmin = 5 µg/ml) was similar across all dosing strategies (~15%). For CZP, the per cent of patients reaching the target average concentration of 17 µg/ml ranged substantially (52–71%), being the highest for LBW-adjusted dosing.
Conclusion:
By using a PK simulation approach, different dosing regimen of IFX and CZP revealed the highest variability for Cmin, the most commonly used PK parameter guiding treatment decisions, independent upon dosing regimen. Our results demonstrate similar target attainment with fixed dosing of IFX compared with currently recommended BW-based dosing. For CZP, the current fixed dosing strategy leads to comparable percentage of patients reaching target as the best performing body size-adjusted dosing (66% vs. 71%, respectively).
In this paper, we present the convergence rate analysis of the modified Landweber method under logarithmic source condition for nonlinear ill-posed problems. The regularization parameter is chosen according to the discrepancy principle. The reconstructions of the shape of an unknown domain for an inverse potential problem by using the modified Landweber method are exhibited.
The rational Krylov subspace method (RKSM) and the low-rank alternating directions implicit (LR-ADI) iteration are established numerical tools for computing low-rank solution factors of large-scale Lyapunov equations. In order to generate the basis vectors for the RKSM, or extend the low-rank factors within the LR-ADI method, the repeated solution to a shifted linear system of equations is necessary. For very large systems this solve is usually implemented using iterative methods, leading to inexact solves within this inner iteration (and therefore to "inexact methods"). We will show that one can terminate this inner iteration before full precision has been reached and still obtain very good accuracy in the final solution to the Lyapunov equation. In particular, for both the RKSM and the LR-ADI method we derive theory for a relaxation strategy (e.g. increasing the solve tolerance of the inner iteration, as the outer iteration proceeds) within the iterative methods for solving the large linear systems. These theoretical choices involve unknown quantities, therefore practical criteria for relaxing the solution tolerance within the inner linear system are then provided. The theory is supported by several numerical examples, which show that the total amount of work for solving Lyapunov equations can be reduced significantly.
Concurrent observation technologies have made high-precision real-time data available in large quantities. Data assimilation (DA) is concerned with how to combine this data with physical models to produce accurate predictions. For spatial-temporal models, the ensemble Kalman filter with proper localisation techniques is considered to be a state-of-the-art DA methodology. This article proposes and investigates a localised ensemble Kalman Bucy filter for nonlinear models with short-range interactions. We derive dimension-independent and component-wise error bounds and show the long time path-wise error only has logarithmic dependence on the time range. The theoretical results are verified through some simple numerical tests.
We describe a new, original approach to the modelling of the Earth's magnetic field. The overall objective of this study is to reliably render fast variations of the core field and its secular variation. This method combines a sequential modelling approach, a Kalman filter, and a correlation-based modelling step. Sources that most significantly contribute to the field measured at the surface of the Earth are modelled. Their separation is based on strong prior information on their spatial and temporal behaviours. We obtain a time series of model distributions which display behaviours similar to those of recent models based on more classic approaches, particularly at large temporal and spatial scales. Interesting new features and periodicities are visible in our models at smaller time and spatial scales. An important aspect of our method is to yield reliable error bars for all model parameters. These errors, however, are only as reliable as the description of the different sources and the prior information used are realistic. Finally, we used a slightly different version of our method to produce candidate models for the thirteenth edition of the International Geomagnetic Reference Field.
We present a new model of the geomagnetic field spanning the last 20 years and called Kalmag. Deriving from the assimilation of CHAMP and Swarm vector field measurements, it separates the different contributions to the observable field through parameterized prior covariance matrices. To make the inverse problem numerically feasible, it has been sequentialized in time through the combination of a Kalman filter and a smoothing algorithm. The model provides reliable estimates of past, present and future mean fields and associated uncertainties. The version presented here is an update of our IGRF candidates; the amount of assimilated data has been doubled and the considered time window has been extended from [2000.5, 2019.74] to [2000.5, 2020.33].
The purpose of this paper is to build an algebraic framework suited to regularize branched structures emanating from rooted forests and which encodes the locality principle. This is achieved by means of the universal properties in the locality framework of properly decorated rooted forests. These universal properties are then applied to derive the multivariate regularization of integrals indexed by rooted forests. We study their renormalization, along the lines of Kreimer's toy model for Feynman integrals.
For the time stationary global geomagnetic field, a new modelling concept is presented. A Bayesian non-parametric approach provides realistic location dependent uncertainty estimates. Modelling related variabilities are dealt with systematically by making little subjective apriori assumptions. Rather than parametrizing the model by Gauss coefficients, a functional analytic approach is applied. The geomagnetic potential is assumed a Gaussian process to describe a distribution over functions. Apriori correlations are given by an explicit kernel function with non-informative dipole contribution. A refined modelling strategy is proposed that accommodates non-linearities of archeomagnetic observables: First, a rough field estimate is obtained considering only sites that provide full field vector records. Subsequently, this estimate supports the linearization that incorporates the remaining incomplete records. The comparison of results for the archeomagnetic field over the past 1000 yr is in general agreement with previous models while improved model uncertainty estimates are provided.