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Background: Infliximab (IFX), an anti-TNF monoclonal antibody approved for the treatment of inflammatory bowel disease, is dosed per kg body weight (BW). However, the rationale for body size adjustment has not been unequivocally demonstrated [1], and first attempts to improve IFX therapy have been undertaken [2]. The aim of our study was to assess the impact of different dosing strategies (i.e. body size-adjusted and fixed dosing) on drug exposure and pharmacokinetic (PK) target attainment. For this purpose, a comprehensive simulation study was performed, using patient characteristics (n=116) from an in-house clinical database.
Methods: IFX concentration-time profiles of 1000 virtual, clinically representative patients were generated using a previously published PK model for IFX in patients with Crohn's disease [3]. For each patient 1000 profiles accounting for PK variability were considered. The IFX exposure during maintenance treatment after the following dosing strategies was compared: i) fixed dose, and per ii) BW, iii) lean BW (LBW), iv) body surface area (BSA), v) height (HT), vi) body mass index (BMI) and vii) fat-free mass (FFM)). For each dosing strategy the variability in maximum concentration Cmax, minimum concentration Cmin (= C8weeks) and area under the concentration-time curve (AUC), as well as percent of patients achieving the PK target, Cmin=3 μg/mL [4] were assessed.
Results: For all dosing strategies the variability of Cmin (CV ≈110%) was highest, compared to Cmax and AUC, and was of similar extent regardless of dosing strategy. The proportion of patients reaching the PK target (≈⅓ was approximately equal for all dosing strategies.
As a potentially toxic agent on nervous system and bone, the safety of aluminium exposure from adjuvants in vaccines and subcutaneous immune therapy (SCIT) products has to be continuously reevaluated, especially regarding concomitant administrations. For this purpose, knowledge on absorption and disposition of aluminium in plasma and tissues is essential. Pharmacokinetic data after vaccination in humans, however, are not available, and for methodological and ethical reasons difficult to obtain. To overcome these limitations, we discuss the possibility of an in vitro-in silico approach combining a toxicokinetic model for aluminium disposition with biorelevant kinetic absorption parameters from adjuvants. We critically review available kinetic aluminium-26 data for model building and, on the basis of a reparameterized toxicokinetic model (Nolte et al., 2001), we identify main modelling gaps. The potential of in vitro dissolution experiments for the prediction of intramuscular absorption kinetics of aluminium after vaccination is explored. It becomes apparent that there is need for detailed in vitro dissolution and in vivo absorption data to establish an in vitro-in vivo correlation (IVIVC) for aluminium adjuvants. We conclude that a combination of new experimental data and further refinement of the Nolte model has the potential to fill a gap in aluminium risk assessment. (C) 2017 Elsevier Inc. All rights reserved.
We present a project combining lidar, photometer and particle counter data with a regularization software tool for a closure study of aerosol microphysical property retrieval. In a first step only lidar data are used to retrieve the particle size distribution (PSD). Secondly, photometer data are added, which results in a good consistency of the retrieved PSDs. Finally, those retrieved PSDs may be compared with the measured PSD from a particle counter. The data here were taken in Ny Alesund, Svalbard, as an example.
S-test results for the USGS and RELM forecasts. The differences between the simulated log-likelihoods and the observed log-likelihood are labelled on the horizontal axes, with scaling adjustments for the 40year.retro experiment. The horizontal lines represent the confidence intervals, within the 0.05 significance level, for each forecast and experiment. If this range contains a log-likelihood difference of zero, the forecasted log-likelihoods are consistent with the observed, and the forecast passes the S-test (denoted by thin lines). If the minimum difference within this range does not contain zero, the forecast fails the S-test for that particular experiment, denoted by thick lines. Colours distinguish between experiments (see Table 2 for explanation of experiment durations). Due to anomalously large likelihood differences, S-test results for Wiemer-Schorlemmer.ALM during the 10year.retro and 40year.retro experiments are not displayed. The range of log-likelihoods for the Holliday-et-al.PI forecast is lower than for the other forecasts due to relatively homogeneous forecasted seismicity rates and use of a small fraction of the RELM testing region.
For a singularly perturbed parabolic - ODE system we construct the asymptotic expansion in the small parameter in the case, when the degenerate equation has a double root. Such systems, which are called partly dissipative reaction-diffusion systems, are used to model various natural processes, including the signal transmission along axons, solid combustion and the kinetics of some chemical reactions. It turns out that the algorithm of the construction of the boundary layer functions and the behavior of the solution in the boundary layers essentially differ from that ones in case of a simple root. The multizonal initial and boundary layers behaviour was stated.