Micro-damage formation within the skeleton is an important stimulant for bone remodeling, however abnormal build-up of micro-damage can lead to skeletal fragility. In this study, µCT imaging based micro finite element (μFE) models were used to evaluate tissue level damage criteria in whole healthy and metastatically-involved vertebrae. T13-L2 spinal segments were excised from osteolytic (n=3) and healthy (n=3) female athymic rnu/rnu rats. Osteolytic metastasis was generated by intercardiac injection of HeLa cancer cells. Micro-mechanical axial loading was applied to the spinal motion segments under μCT imaging. Vertebral samples underwent BaSO4 staining and sequential calcein/fuchsin staining to identify load induced micro-damage. μCT imaging was used generate specimen specific μFE models of the healthy and osteolytic whole rat vertebrae. Model boundary conditions were generated through deformable image registration of loaded and unloaded scans. Elevated stresses and strains were detected in regions of micro-damage identified through histological and BaSO4 staining within healthy and osteolytic vertebral models, as compared to undamaged regions. Additionally, damaged regions of metastatic vertebrae experienced significantly higher local stresses and strains than those in the damaged regions of healthy specimens. Areas identified by BaSO4 staining, however, yielded lower levels of stress and strain in damaged and undamaged regions of healthy and metastatic vertebrae as compared to fuschin staining. The multimodal (experimental, image-based and computational) techniques used in this study demonstrated the ability of local stresses and strains computed through µFE analysis to identify trabecular micro-damage, that can be applied to biomechanical analyses of healthy and diseased whole bones.
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http://dx.doi.org/10.1016/j.jbiomech.2016.02.034 | DOI Listing |
CPT Pharmacometrics Syst Pharmacol
November 2024
Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK.
Ritonavir-boosted atazanavir (ATV/r) and rifampicin are mainstays of second-line antiretroviral and multiple anti-TB regimens, respectively. Rifampicin induces CYP3A4, a major enzyme involved in atazanavir metabolism, causing a drug-drug interaction (DDI) which might be exaggerated in pregnancy. Having demonstrated that increasing the dose of ATV/r from once daily (OD) to twice daily (BD) in non-pregnant adults can safely overcome this DDI, we developed a pregnancy physiologically based pharmacokinetic (PBPK) model to explore the impact of pregnancy.
View Article and Find Full Text PDFMol Pharm
September 2024
Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel 4070, Switzerland.
We present a novel computational approach for predicting human pharmacokinetics (PK) that addresses the challenges of early stage drug design. Our study introduces and describes a large-scale data set of 11 clinical PK end points, encompassing over 2700 unique chemical structures to train machine learning models. To that end multiple advanced training strategies are compared, including the integration of in vitro data and a novel self-supervised pretraining task.
View Article and Find Full Text PDFDrug Metab Dispos
September 2024
Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, Pennsylvania
One-compartment (1C) and permeability-limited models were used to evaluate the ability of microsomal and hepatocyte intrinsic clearances to predict hepatic clearance. Well-stirred (WSM), parallel-tube (PTM), and dispersion (DM) models were evaluated within the liver as well as within whole-body physiologically based pharmacokinetic frameworks. It was shown that a linear combination of well-stirred and parallel-tube average liver blood concentrations accurately approximates dispersion model blood concentrations.
View Article and Find Full Text PDFDrug Metab Dispos
July 2024
Quantitative, Translational, and ADME Sciences, AbbVie Inc., North Chicago, Illinois
In vitro clearance assays are routinely conducted in drug discovery to predict in vivo clearance, but low metabolic turnover compounds are often difficult to evaluate. Hepatocyte spheroids can be cultured for days, achieving higher drug turnover, but have been hindered by limitations on cell number per well. Corning Elplasia microcavity 96-well microplates enable the culture of 79 hepatocyte spheroids per well.
View Article and Find Full Text PDFClin Pharmacol Ther
September 2024
Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, The University of Rhode Island, Kingston, Rhode Island, USA.
Precision dosing strategies require accounting for between-patient variability in pharmacokinetics (PK), affecting drug exposure, and in pharmacodynamics (PD), affecting response achieved at the same drug concentration at the site of action. Although liquid biopsy for assessing different levels of molecular drug targets has yet to be established, individual characterization of drug elimination pathways using liquid biopsy has recently been demonstrated. The feasibility of applying this approach in conjunction with modeling tools to guide individual dosing remains unexplored.
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