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https://www.readbyqxmd.com/read/28092496/the-effect-of-contrast-material-on-radiation-dose-at-ct-part-i-incorporation-of-contrast-material-dynamics-in-anthropomorphic-phantoms
#1
Pooyan Sahbaee, W Paul Segars, Daniele Marin, Rendon C Nelson, Ehsan Samei
Purpose To develop a method to incorporate the propagation of contrast material into computational anthropomorphic phantoms for estimation of organ dose at computed tomography (CT). Materials and Methods A patient-specific physiologically based pharmacokinetic (PBPK) model of the human cardiovascular system was incorporated into 58 extended cardiac-torso (XCAT) patient phantoms. The PBPK model comprised compartmental models of vessels and organs unique to each XCAT model. For typical injection protocols, the dynamics of the contrast material in the body were described according to a series of patient-specific iodine mass-balance differential equations, the solutions to which provided the contrast material concentration time curves for each compartment...
January 13, 2017: Radiology
https://www.readbyqxmd.com/read/28089685/evaluation-of-drug-drug-interaction-potential-between-sacubitril-valsartan-lcz696-and-statins-using-a-physiologically-based-pharmacokinetic-model
#2
Wen Lin, Tao Ji, Heidi Einolf, Surya Ayalasomayajula, Tsu-Han Lin, Imad Hanna, Tycho Heimbach, Christopher Breen, Venkateswar Jarugula, Handan He
Sacubitril/valsartan (LCZ696) has been approved for the treatment of heart failure. Sacubitril is an in vitro inhibitor of OATPs. In clinical studies, LCZ696 increased atorvastatin Cmax by 1.7-fold and AUC by 1.3-fold, but had little or no effect on simvastatin or simvastatin acid exposure. A PBPK modelling approach was applied to explore the underlying mechanisms behind the statin-specific LCZ696 drug interaction observations. The model incorporated OATP-mediated clearance (CLint,T) for simvastatin and simvastatin acid to successfully describe the PK profiles of either analyte in the absence or presence of LCZ696...
January 12, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28074615/a-database-of-optimized-proteomic-quantitative-methods-for-284-human-drug-disposition-related-proteins-for-applications-in-pbpk-modeling
#3
Marc Vrana, Dale Whittington, Vivek Nautiyal, Bhagwat Prasad
The aim of this study was to create an open access repository of validated LC-MS/MS (MRM) methods for quantifying 284 important proteins associated with drug absorption, distribution, metabolism and excretion (ADME). Various in silico and experimental approaches were used to select surrogate peptides and optimize instrument parameters for LC-MS/MS quantification of the selected proteins. The final methods were uploaded to an online public database (ADME QPrOmics(TM); www.qpromics.uw.edu/qpromics/assay/) which provides essential information for facile method development in triple quadrupole MS instruments...
January 11, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28074611/impact-of-pbpk-on-regulatory-reviews-and-product-labels-frequent-utilization-in-the-field-of-oncology
#4
Kenta Yoshida, Nageshwar Budha, Jin Yan Jin
No abstract text is available yet for this article.
January 11, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28069721/specific-inhibition-of-the-distribution-of-lobeglitazone-to-the-liver-by-atorvastatin-in-rats-evidence-for-an-roatp1b2-mediated-interaction-in-hepatic-transport
#5
Chang-Soon Yim, Yoo-Seong Jeong, Song-Yi Lee, Wonji Pyeon, Heon-Min Ryu, Jong-Hwa Lee, Kyeong-Ryoon Lee, Han-Joo Maeng, Suk-Jae Chung
CYP enzymes and hOATP1B1 are reported to be involved in the pharmacokinetics of lobeglitazone (LB), a new PPARγ agonist. Atorvastatin (ATV), a substrate for CYP3A and hOATP1B1, is likely to be co-administered with LB in patients with the metabolic syndrome. We report herein on a study of potential interactions between LB and ATV in rats. When LB was IV-administered with ATV, the systemic clearance (CL; 2.67 ± 0.63 mL/min/kg) and volume of distribution at steady-state (Vss; 289 ± 20 mL/kg) for LB remained unchanged, compared to those of LB without ATV (CL, 2...
January 9, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28066147/prediction-of-pharmacokinetics-and-drug-drug-interaction-potential-using-physiologically-based-pharmacokinetic-pbpk-modeling-approach-a-case-study-of-caffeine-and-ciprofloxacin
#6
Min-Ho Park, Seok-Ho Shin, Jin-Ju Byeon, Gwan-Ho Lee, Byung-Yong Yu, Young G Shin
Over the last decade, physiologically based pharmacokinetics (PBPK) application has been extended significantly not only to predicting preclinical/human PK but also to evaluating the drug-drug interaction (DDI) liability at the drug discovery or development stage. Herein, we describe a case study to illustrate the use of PBPK approach in predicting human PK as well as DDI using in silico, in vivo and in vitro derived parameters. This case was composed of five steps such as: simulation, verification, understanding of parameter sensitivity, optimization of the parameter and final evaluation...
January 2017: Korean Journal of Physiology & Pharmacology
https://www.readbyqxmd.com/read/28057840/delineating-the-role-of-various-factors-in-renal-disposition-of-digoxin-through-application-of-physiologically-based-kidney-model-to-renal-impairment-populations
#7
Daniel Scotcher, Christopher R Jones, Aleksandra Galetin, Amin Rostami-Hodjegan
Development of sub-models of organs within physiologically-based pharmacokinetic (PBPK) principles and beyond simple perfusion limitations may be challenging because of underdeveloped in vitro-in vivo extrapolation approaches or lack of suitable clinical data for model refinement. However, the advantage of such models in predicting clinical observations in divergent patient groups is now commonly acknowledged. Mechanistic understanding of altered renal secretion in renal impairment is one area that may benefit from such models, despite knowledge gaps in renal pathophysiology (Rowland Yeo et al...
January 5, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28052338/quantitative-prediction-of-the-effect-of-cyp3a-inhibitors-and-inducers-on-venetoclax-pharmacokinetics-using-a-physiologically-based-pharmacokinetic-model
#8
Kevin J Freise, Mohamad Shebley, Ahmed Hamed Salem
The objectives of the analysis were to develop and verify a venetoclax physiologically based pharmacokinetic (PBPK) model to predict the effects of cytochrome P450 3A (CYP3A) inhibitors and inducers on the PK of venetoclax and inform dosing recommendations. A minimal PBPK model was developed based on prior in vitro and in vivo clinical data using a "middle-out" approach. The PBPK model was independently verified against clinical studies of the strong CYP3A inhibitor ketoconazole, the strong CYP3A inducer, multiple-dose rifampin, and the steady-state venetoclax PK in chronic lymphocytic leukemia (CLL) subjects by comparing predicted to observed ratios of the venetoclax maximum concentration (Cmax R) and area under the curve from time 0 to infinity (AUC∞ R) from these studies...
January 4, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28051093/a-four-compartment-pbpk-heart-model-accounting-for-cardiac-metabolism-model-development-and-application
#9
Zofia Tylutki, Sebastian Polak
In the field of cardiac drug efficacy and safety assessment, information on drug concentration in heart tissue is desirable. Because measuring drug concentrations in human cardiac tissue is challenging in healthy volunteers, mathematical models are used to cope with such limitations. With a goal of predicting drug concentration in cardiac tissue, we have developed a whole-body PBPK model consisting of seventeen perfusion-limited compartments. The proposed PBPK heart model consisted of four compartments: the epicardium, midmyocardium, endocardium, and pericardial fluid, and accounted for cardiac metabolism using CYP450...
January 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28049636/verification-of-a-maternal-fetal-physiologically-based-pharmacokinetic-model-for-passive-placental-permeability-drugs
#10
Zufei Zhang, Jashvant D Unadkat
Fetal exposure to drugs cannot be readily estimated from single time point cord blood sampling at the time of delivery. Therefore, we developed a physiologically-based pharmacokinetic (PBPK) model to estimate fetal drug exposure throughout pregnancy. Here we report verification of this novel maternal-fetal physiologically-based pharmacokinetic (m-f-PBPK) model for drugs that passively diffuse across the placenta and are not metabolized/transported there. Our recently built m-f-PBPK model was populated with gestational age-dependent changes in maternal drug disposition and maternal-fetal physiology...
January 3, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28041968/medicines-for-pediatric-patients-biopharmaceutical-developmental-and-regulatory-considerations
#11
David P Elder, René Holm, Martin Kuentz
This commentary reflects current developments in pediatric medicine. The underpinning legislation in both Europe and the US has led to the initiation of an increased number of clinical trials in the pediatric population, but there are still a number of outstanding issues within this field. These include the differences in the physiology between adults and the very heterogeneous nature of pediatric patients. There is an ongoing scientific debate on the applicability of a Pediatric Biopharmaceutical Classification System (PBCS) to define when waivers for bioequivalence studies can be supported by in vitro dissolution...
December 29, 2016: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28039606/development-of-a-physiologically-based-pharmacokinetic-modelling-approach-to-predict-the-pharmacokinetics-of-vancomycin-in-critically-ill-septic-patients
#12
Christian Radke, Dagmar Horn, Christian Lanckohr, Björn Ellger, Michaela Meyer, Thomas Eissing, Georg Hempel
BACKGROUND AND OBJECTIVES: Sepsis is characterised by an excessive release of inflammatory mediators substantially affecting body composition and physiology, which can be further affected by intensive care management. Consequently, drug pharmacokinetics can be substantially altered. This study aimed to extend a whole-body physiologically based pharmacokinetic (PBPK) model for healthy adults based on disease-related physiological changes of critically ill septic patients and to evaluate the accuracy of this PBPK model using vancomycin as a clinically relevant drug...
December 31, 2016: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28035755/report-from-ema-workshop-on-qualification-and-reporting-of-physiologically-based-pharmacokinetic-pbpk-modelling-and-simulation
#13
EDITORIAL
Ping Zhao
No abstract text is available yet for this article.
December 30, 2016: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28028770/on-the-nature-of-physiologically-based-pharmacokinetic-models-a-priori-or-a-posteriori-mechanistic-or-empirical
#14
Ken Korzekwa, Swati Nagar
Physiologically-based pharmacokinetic (PBPK) models explicitly incorporate tissue-specific blood flows, partition coefficients, and metabolic processes. Since PBPK models are derived using physiologic parameters and interactions of the compound with tissue components, these models are considered to be "bottom up" as opposed to "top down". Modeling approaches can be characterized as either a posteriori (observational) or a priori (based solely on theory). Furthermore, approaches can be mechanistic (structure and components based on mechanisms) or empirical (based on observations alone)...
December 27, 2016: Pharmaceutical Research
https://www.readbyqxmd.com/read/28027398/physiologically-based-pharmacokinetic-predictions-of-intestinal-bcrp-mediated-effect-of-telmisartan-on-the-pharmacokinetics-of-rosuvastatin-in-humans
#15
Soo Hyeon Bae, Wan-Su Park, Seunghoon Han, Gab-Jin Park, Jongtae Lee, Taegon Hong, Sangil Jeon, Dong-Seok Yim
It was recently reported that the Cmax and AUC of rosuvastatin increases when it is coadministered with telmisartan. The aim of this study was to explore the mechanism of the interaction of telmisartan and rosuvastatin. A full-PBPK model of telmisartan was developed, and the rosuvastatin model in Simcyp (version 15)'s drug library was modified to reflect ethnic differences in rosuvastatin exposure. PK characteristics, including intestinal and hepatic transporter / enzyme specificities of telmisartan and rosuvastatin, were incorporated into the PBPK models to simulate a rosuvastatin (20 mg) - telmisartan (80 mg) multiple dose drug interaction study...
December 27, 2016: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28018224/prediction-of-deoxypodophyllotoxin-disposition-in-mouse-rat-monkey-and-dog-by-physiologically-based-pharmacokinetic-model-and-the-extrapolation-to-human
#16
Yang Chen, Kaijing Zhao, Fei Liu, Qiushi Xie, Zeyu Zhong, Mingxing Miao, Xiaodong Liu, Li Liu
Deoxypodophyllotoxin (DPT) is a potential anti-tumor candidate prior to its clinical phase. The aim of the study was to develop a physiologically based pharmacokinetic (PBPK) model consisting of 13 tissue compartments to predict DPT disposition in mouse, rat, monkey, and dog based on in vitro and in silico inputs. Since large interspecies difference was found in unbound fraction of DPT in plasma, we assumed that Kt:pl,u (unbound tissue-to-plasma concentration ratio) was identical across species. The predictions of our model were then validated by in vivo data of corresponding preclinical species, along with visual predictive checks...
2016: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28013012/in-silico-in-vitro-in-vivo-studies-of-experimentally-designed-carvedilol-loaded-silk-fibroin-casein-nanoparticles-using-physiological-based-pharmacokinetic-model
#17
Sandeep Kumar, Sandeep Kumar Singh
The study aimed to design and develop carvedilol loaded silk fibroin-casein nanoparticles using 3(2) full factorial design. Silk fibroin and casein concentration were selected as the independent variables and their effect were observed on dependent variables: particle size, polydispersity index, encapsulation efficiency, drug release, and dissolution efficiency. The developed optimized formulation was characterized using fourier transform infrared spectroscopy, differential scanning calorimetry, and Powder X-ray diffraction...
December 21, 2016: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28011125/prediction-of-ketoconazole-absorption-using-an-updated-in-vitro-transfer-model-coupled-to-physiologically-based-pharmacokinetic-modelling
#18
Aaron Ruff, Tom Fiolka, Edmund S Kostewicz
The aim of this study was to optimize the in vitro transfer model and to increase its biorelevance to more accurately mimic the in vivo supersaturation and precipitation behaviour of weak basic drugs. Therefore, disintegration of the formulation, volumes of the stomach and intestinal compartments, transfer rate, bile salt concentration, pH range and paddle speed were varied over a physiological relevant range. The supersaturation and precipitation data from these experiments for Ketoconazole (KTZ) were coupled to physiologically based pharmacokinetic (PBPK) model using Stella® software, which also incorporated the disposition kinetics of KTZ taken from the literature, in order to simulate the oral absorption and plasma profile in humans...
December 20, 2016: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28004396/the-absorption-kinetics-of-ketoconazole-plays-a-major-role-in-explaining-the-reported-variability-in-the-level-of-interaction-with-midazolam-exploring-the-interplay-between-formulation-and-inhibition-of-gut-wall-and-liver-metabolism-by-using-different-doses
#19
Bo Liu, H Kim Crewe, Mahmut Ozdemir, Karen Rowland Yeo, Geoffrey Tucker, Amin Rostami-Hodjegan
The impact of different single oral doses of ketoconazole (KTZ) (100, 200 and 400 mg) and of staggering its dosage (400 mg at -12, -2, 0, 2 and 4 h), with respect to the administration of a single 5 mg oral dose of midazolam (MDZ) on the extent of inhibition of the metabolism of the latter, was evaluated in healthy subjects in two separate studies. Escalation of KTZ dosage resulted in 2.3- (1.9), 2.7- (1.7) and 4.2- (2.5) fold increases in the mean AUC(0,12 h) (and Cmax ) values of MDZ. Dose-staggering was associated with 3...
December 21, 2016: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28001497/physiologically-based-pharmacokinetic-model-for-quinocetone-in-pigs-and-extrapolation-to-mequindox
#20
Xudong Zhu, Lingli Huang, Yamei Xu, Shuyu Xie, Yuanhu Pan, Dongmei Chen, Zhenli Liu, Zonghui Yuan
Physiologically based pharmacokinetic (PBPK) models are scientific methods used to predict veterinary drug residues that may occur in food-producing animals, and which have powerful extrapolation ability. Quinocetone (QCT) and mequindox (MEQ) are widely used in China for the prevention of bacterial infections and promoting animal growth, but their abuse causes a potential threat to human health. In this study, a flow-limited PBPK model was developed to simulate simultaneously residue depletion of QCT and its marker residue dideoxyquinocetone (DQCT) in pigs...
December 21, 2016: Food Additives & Contaminants. Part A, Chemistry, Analysis, Control, Exposure & Risk Assessment
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