Development of an integrated multi-species and multi-dose route PBPK model for volatile methyl siloxanes – D4 and D5

AbstractThere are currently seven published physiologically based pharmacokinetic (PBPK) models describing aspects of the pharmacokinetics of octamethylcyclotetrasiloxane (D4) and decamethylcyclopentasiloxane (D5) for various exposure routes in rat and human. Each model addressed the biological and physico-chemical properties of D4 and D5 (highly lipophilic coupled with low blood: air partition coefficient and high liver clearance) that result in unique kinetic behaviors as well differences between D4 and D5. However, the proliferation of these models resulted in challenges for various risk assessment applications when needing to determine the optimum model for estimating dose metrics. To enhance the utility of these PBPK models for risk assessment, we integrated the suite of structures into one coherent model capable of simulating the entire set of existing data equally well as older more limited scope models. In this paper, we describe the steps required to develop this integrated model, the choice of physiological, partitioning and biochemical parameters for the model, and the concordance of the model behavior across key data sets. This integrated model is sufficiently robust to derive relevant dose metrics following individual or combined dermal and inhalation exposures of workers, consumer or the general population to D4 and D5 for route-to-route, interspecies and high to low dose extrapolations for risk assessment

A CFD parametric study on the performance of a low-temperature-differential γ-type Stirling engine

An in-house CFD code has been applied to a low-temperature-differential (LTD) γ-type Stirling engine to understand the effects posed by several geometrical and operational parameters on engine performance. The results include variations of pressure, temperature, and heat transfer rates within an engine cycle as well as variations of engine's power and efficiency versus these parameters. It is found that power piston stroke and radius influence engine performance very similarly, and power and efficiency both increase as these two parameters increase. In fact, the effects of the two parameters can be assimilated into those by the parameter of compression ratio. The stroke of displacer is observed to affect strongly on heat input but weakly on power, thus causing the efficiency to decrease as it increases. As expected, both power and efficiency increase as temperature difference between the hot and cold ends increases. Lastly, engine speed is observed to pose strong positive effects on power but exert weak effects on efficiency. This study reveals the effects produced by several important parameters on engine performance, and such information is very useful for the design of new LTD Stirling engines. © 2015 Published by Elsevier Ltd

Regulatory utility of physiologically based pharmacokinetic modeling for assessing food impact in bioequivalence studies: A workshop summary report

Abstract This workshop report summarizes the presentations and panel discussion related to the use of physiologically based pharmacokinetic (PBPK) modeling approaches for food effect assessment, collected from Session 2 of Day 2 of the workshop titled “Regulatory Utility of Mechanistic Modeling to Support Alternative Bioequivalence Approaches.” The US Food and Drug Administration in collaboration with the Center for Research on Complex Generics organized this workshop where this particular session titled “Oral PBPK for Evaluating the Impact of Food on BE” presented successful cases of PBPK modeling approaches for food effect assessment. Recently, PBPK modeling has started to gain popularity among academia, industries, and regulatory agencies for its potential utility during bioavailability (BA) and/or bioequivalence (BE) studies of new and generic drug products to assess the impact of food on BA/BE. Considering the promises of PBPK modeling in generic drug development, the aim of this workshop session was to facilitate knowledge sharing among academia, industries, and regulatory agencies to understand the knowledge gap and guide the path forward. This report collects and summarizes the information presented and discussed during this session to disseminate the information into a broader audience for further advancement in this area