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Background and Objective Mechanistic static and dynamic physiologically based pharmacokinetic models are used in clinical drug development to assess the risk of drug–drug interactions (DDIs). Currently, the use of mechanistic static models is restricted to screening DDI risk for an investigational drug, while dynamic physiologically based pharmacokinetic models are used for quantitative predictions of DDIs to support regulatory filing. As physiologically based pharmacokinetic model development by sponsors as well as a review of models by regulators require considerable resources, we explored the possibility of using mechanistic static models to support regulatory filing, using representative cases of successful physiologically based pharmacokinetic submissions to the US Food and Drug Administration under different classes of applications. Methods Drug–drug interaction predictions with mechanistic static models were done for representative cases in the different classes of applications using the same data and modelling workflow as described in the Food and Drug Administration clinical pharmacology reviews. We investigated the hypothesis that the use of unbound average steady-state concentrations of modulators as driver concentrations in the mechanistic static models should lead to the same conclusions as those from physiologically based pharmacokinetic modelling for non-dynamic measures of DDI risk assessment such as the area under the plasma concentration–time curve ratio, provided the same input data are employed for the interacting drugs. Results Drug–drug interaction predictions of area under the plasma concentration–time curve ratios using mechanistic static models were mostly comparable to those reported in the Food and Drug Administration reviews using physiologically based pharmacokinetic models for all representative cases in the different classes of applications. Conclusions The results reported in this study should encourage the use of models that best fit an intended purpose, limiting the use of physiologically based pharmacokinetic models to those applications that leverage its unique strengths, such as what-if scenario testing to understand the effect of dose staggering, evaluating the role of uptake and efflux transporters, extrapolating DDI effects from studied to unstudied populations, or assessing the impact of DDIs on the exposure of a victim drug with concurrent mechanisms. With this first step, we hope to trigger a scientific discussion on the value of a routine comparison of the two methods for regulatory submissions to potentially create a best practice that could help identify examples where the use of dynamic changes in modulator concentrations could make a difference to DDI risk assessment.

To investigate the effects of gas transport on ignition response of polymer-bonded explosives (PBXs) during slow cookoff, this study develops a thermo-mechanically coupled pyrolytic gas transport porous model. The model resolves dynamically coupled physical fields across thermal, mechanical, gas transport, and chemical reaction throughout the slow cook-off. Results are consistent with Sandia Instrumented Thermal Ignition (SITI) experiments for PBX 9501 in sealed and vented systems. It is revealed that porosity evolves in two stages: the first stage is dominated by thermal expansion, while the second is governed by decomposition. Gas transport pathways are controlled by the coupled evolution of porosity and temperature. Convective heat transfer from gas products contributes less of the total thermal transport, while the concentration effect of gas product within pores is identified as the dominant factor in ignition delay. This study provides a foundational framework for understanding gas transport in the slow cookoff of polymer-bonded explosives. •A thermomechanically coupled pyrolytic gas transport model is developed.•Good agreement is reached for both vented and sealed slow cook off scenarios.•Pore evolution is dominated by thermal expansion initially, followed by thermal decomposition.•Ignition delay is extremely dominated by concentration of gas products.

The majority of the projectiles used in the hypersonic penetration study are solid flat-nosed cylindrical projectiles with a diameter of less than 20 mm. This study aims to fill the gap in the experimental and analytical study of the evolution of the nose shape of larger hollow projectiles under hypersonic penetration. In the hypersonic penetration test, eight ogive-nose AerMet100 steel projectiles with a diameter of 40 mm were launched to hit concrete targets with impact velocities that ranged from 1351 to 1877 m/s. Severe erosion of the projectiles was observed during high-speed penetration of heterogeneous targets, and apparent localized mushrooming occurred in the front nose of recovered projectiles. By examining the damage to projectiles, a linear relationship was found between the relative length reduction rate and the initial kinetic energy of projectiles in different penetration tests. Furthermore, microscopic analysis revealed the forming mechanism of the localized mushrooming phenomenon for eroding penetration, i.e., material spall erosion abrasion mechanism, material flow and redistribution abrasion mechanism and localized radial upsetting deformation mechanism. Finally, a model of high-speed penetration that included erosion was established on the basis of a model of the evolution of the projectile nose that considers radial upsetting; the model was validated by test data from the literature and the present study. Depending upon the impact velocity, v0, the projectile nose may behave as undistorted, radially distorted or hemispherical. Due to the effects of abrasion of the projectile and enhancement of radial upsetting on the duration and amplitude of the secondary rising segment in the pulse shape of projectile deceleration, the predicted DOP had an upper limit. •Tests of the hypersonic penetration of concrete targets by large-sized ogival-nosed projectiles were completed.•Microscopic analysis revealed the mechanism for the localized mushrooming caused by projectile erosion during penetration.•A high-speed penetration model was established based on a projectile nose evolution model that considered radial upsetting.

Predictions of extreme near-field blast wave for cylindrical charge is crucial for designing sympathetic detonation protection structures, yet the quantitative analysis of detonation products and shock wave field are still insufficient. The present work conducted experiments and numerical simulations of near-field explosion for kilogram scale cylindrical charge, and investigated the propagation and spatial distribution characteristics of incident and reflected blast waves. The results show that near-field reflected overpressure exhibits multi-peak structures, which are primarily governed by reflections of detonation products and shock wave. The reflected peak overpressure dominated by detonation products shows higher sensitivity to scaled distance. Meanwhile, the Rayleigh-Taylor instability (RTI) effect induces the evolutions of detonation products and shock wave interface from smooth to random microjets, increasing dispersion of secondary reflected peak overpressure. In free-field explosion, the incident peak overpressure exhibits a dual-peak structure, governed by the shock wave front and detonation products flowing past the gauge points. The incident peak overpressure dominated by detonation products is sensitive to orientations due to the charge structures. As the aspect ratio of charge increases from 0.6 to 8, the dominant radial azimuth angle region expands from 60°–90° to 30°–90°. An empirical model was developed to predict the spatial distributions of incident peak loads at arbitrary orientations for cylindrical charge with 0.6 ≤ L/D ≤ 8.0 and 0.06 m·kg−1/3

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