Studies of patients afflicted by neurodegenerative diseases suggest that misfolded proteins spread through the brain along anatomically-connected networks, prompting progressive decline. Recently, mouse models have recapitulated the cell-to-cell transmission of pathogenic proteins and neuron death observed in patients. However, factors regulating spread of pathogenic proteins remain a matter of debate due to an incomplete understanding of how vulnerability functions in the context of spread. Here, we use quantitative pathology mapping in the mouse brain combined with network modeling to understand the spatiotemporal pattern of spread. α-Synuclein pathology patterns are well-described by a network model based on two factors—anatomical connectivity and endogenous α-Synuclein expression. The map and model allow assessment of selective vulnerability to α-Synuclein pathology development and neuron death. Finally, we use quantitative pathology to understand how the G2019S LRRK2 genetic risk factor impacts the spread and toxicity of α-Synuclein pathology.

Patient groups prone to polypharmacy and special subpopulations are susceptible to suboptimal treatment. Refined dosing in special populations is imperative to improve therapeutic response and/or lowering the risk of toxicity. Model-informed precision dosing (MIPD) may improve treatment outcomes by achieving the optimal dose for an individual patient. There is however relatively little published evidence of large-scale utility and impact of MIPD, where it is often implemented as local collaborative efforts between academia and healthcare.This manuscript highlights some successful applications of bringing MIPD to clinical care and proposes strategies for wider integration of MIPD in healthcare.Considerations are brought up herein that will need addressing to see MIPD become 'widespread clinical practice': amongst those, wider interdisciplinary collaborations and the necessity for further evidence-based efficacy and cost-benefit analysis of MIPD in healthcare. The implications of MIPD on regulatory policies and pharmaceutical development are also discussed as part of the roadmap.This article is protected by copyright. All rights reserved. 4 PRELUDEThis article appears in the so called 'State of the Art' section of the journal. 'State of the Art' is often considered to be cutting edge and the highest level of development in a given area. However, coining something as 'State of the Art' is a subliminal admission to the fact that the subject area has not yet become 'popular'. This article is a culmination of discussions and debates between many key opinion leaders, beyond the authorship, on the issue of model-informed precision dosing (MIPD), and why it has remained and is treated as 'State of the Art' rather than being used as 'widespread' clinical practice. It is hoped that the report provides a roadmap to advance the position of MIPD to a common clinical practice under the umbrella of precision medicine.

Bioavailability of orally administered drugs can be influenced by a number of factors including release from the formulation, dissolution, stability in the gastrointestinal (GI) environment, permeability through the gut wall and first-pass gut wall and hepatic metabolism. Although there are various enzymes in the gut wall which may contribute to gut first pass metabolism, Cytochrome P450 (CYP) 3A has been shown to play a major role. The efflux transporter P-glycoprotein (P-gp; MDR1/ABCB1) is the most extensively studied drug efflux transporter in the gut and might have a significant role in the regulation of GI absorption. Although not every CYP3A substrate will have a high extent of gut wall first-pass extraction, being a substrate for the enzyme increases the likelihood of a higher first-pass extraction. Similarly, being a P-gp substrate does not necessarily pose a problem with the gut wall absorption however it may reduce bioavailability in some cases (e.g. when drug has low passive permeability). An on-going debate has focused on the issue of the interplay between CYP3A and P-gp such that high affinity to P-gp increases the exposure of drug to CYP3A through repeated cycling via passive diffusion and active efflux, decreasing the fraction of drug that escapes first pass gut metabolism (F(G)). The presence of P-gp in the gut wall and the high affinity of some CYP3A substrates to this transporter are postulated to reduce the potential for saturating the enzymes, thus increasing gut wall first-pass metabolism for compounds which otherwise would have saturated CYP3A. Such inferences are based on assumptions in the modelling of oral drug absorption. These models should be as mechanistic as possible and tractable using available in vitro and in vivo information. We review, through simulation, this subject and examine the interplay between gut wall metabolism and efflux transporters by studying the fraction of dose absorbed into enterocytes (F(a)) and F(G) via systematic variation of drug characteristics, in accordance with the Biopharmaceutics Classification System (BCS) within one of the most physiological models of oral drug absorption currently available, respectively ADAM. Variables studied included the intrinsic clearance (CLint) and the Michaelis-Menten Constant (Km) for CYP3A4 and P-gp (C(Lint-CYP3A4) and K(m-CYP3A4), CL(int-P-gp) and K(m-P-gp)). The impact of CYP3A4 and P-gp intracellular topography were not investigated since a well-stirred enterocyte is assumed within ADAM. An increased CLint-CYP3A4 resulted in a reduced F(G) whereas an increase in C(Lint-P-gp) resulted in a reduced F(a), but interestingly decreased F(G) too. The reduction in FG was limited to certain conditions and was modest. Non-linear relationships between various parameters determining the permeability (e.g. P(app), C(Lint-P-gp,) and K(m-P-gp)) and gut wall metabolism (e.g. C(Lint-CYP3A4,) K(m-CYP3A4)) resulted in disproportionate changes in F(G) compared to the magnitude of singular effects. The results suggest that P-gp efflux decre...

Due to the rapid turnover of the small intestinal epithelia, the rate at which enterocyte renewal occurs plays an important role in determining the level of drug-metabolizing enzymes in the gut wall. Current physiologically based pharmacokinetic (PBPK) models consider enzyme and enterocyte recovery as a lumped first-order rate. An assessment of enterocyte turnover would enable enzyme and enterocyte renewal to be modeled more mechanistically. A literature review together with statistical analysis was employed to establish enterocyte turnover in human and preclinical species. A total of 85 studies was identified reporting enterocyte turnover in 1602 subjects in six species. In mice, the geometric weighted combined mean (WX) enterocyte turnover was 2.81 6 1.14 days (n = 169). In rats, the weighted arithmetic mean enterocyte turnover was determined to be 2.37 days (n = 501). Humans exhibited a geometric WX enterocyte turnover of 3.48 6 1.55 days for the gastrointestinal epithelia (n = 265), displaying comparable turnover to that of cytochrome P450 enzymes in vitro (0.96-4.33 days). Statistical analysis indicated humans to display longer enterocyte turnover as compared with preclinical species. Extracted data were too sparse to support regional differences in small intestinal enterocyte turnover in humans despite being indicated in mice. The utilization of enterocyte turnover data, together with in vitro enzyme turnover in PBPK modeling, may improve the predictions of metabolic drug-drug interactions dependent on enzyme turnover (e.g., mechanism-based inhibition and enzyme induction) as well as absorption of nanoparticle delivery systems and intestinal metabolism in special populations exhibiting altered enterocyte turnover.