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CPT: Pharmacometrics & Systems Pharmacology

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https://www.readbyqxmd.com/read/29761892/a-perspective-on-the-state-of-pharmacometrics-and-systems-pharmacology-integration
#1
EDITORIAL
Mirjam N Trame, Matthew Riggs, Kostas Biliouris, Dhananjay Marathe, Jerome Mettetal, Teun M Post, Matthew L Rizk, Sandra A G Visser, Cynthia J Musante
No abstract text is available yet for this article.
May 15, 2018: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/29761883/-benchmarking-qsp-models-against-simple-models-a-path-to-improved-comprehension-and-predictive-performance
#2
EDITORIAL
Andrew M Stein, Michael Looby
No abstract text is available yet for this article.
May 15, 2018: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/29761668/a-mechanism-based-disease-progression-model-describing-host-pathogen-interactions-during-the-pathogenesis-of-acinetobacter-baumannii-pneumonia
#3
John K Diep, Thomas A Russo, Gauri G Rao
The emergence of highly resistant bacteria is a serious threat to global public health. The host immune response is vital for clearing bacteria from the infected host; however, the current drug development paradigm does not take host-pathogen interactions into consideration. Here, we used a systems-based approach to develop a quantitative, mechanism-based disease progression model to describe bacterial dynamics, host immune response, and lung injury in an immunocompetent rat pneumonia model. Previously, Long-Evans rats were infected with A...
May 15, 2018: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/29761661/how-do-we-validate-a-qsp-model
#4
Daniel C Kirouac
No abstract text is available yet for this article.
May 15, 2018: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/29745466/first-pass-cyp3a-mediated-metabolism-of-midazolam-in-the-gut-wall-and-liver-in-preterm-neonates
#5
Janneke M Brussee, Huixin Yu, Elke H J Krekels, Berend de Roos, Margreke J E Brill, Johannes N van den Anker, Amin Rostami-Hodjegan, Saskia N de Wildt, Catherijne A J Knibbe
To predict first-pass and systemic cytochrome P450 (CYP) 3A-mediated metabolism of midazolam in preterm neonates, a physiological population pharmacokinetic model was developed describing intestinal and hepatic midazolam clearance in preterm infants. On the basis of midazolam and 1-OH-midazolam concentrations from 37 preterm neonates (gestational age 26-34 weeks) receiving midazolam orally and/or via a 30-minute intravenous infusion, intrinsic clearance in the gut wall and liver were found to be very low, with lower values in the gut wall (0...
May 10, 2018: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/29732710/study-design-selection-in-early-clinical-anti-hyperglycemic-drug-development-a-simulation-study-of-glucose-tolerance-tests
#6
Moustafa M A Ibrahim, Siti M S Ghadzi, Maria C Kjellsson, Mats O Karlsson
In antidiabetic drug development, phase I studies usually involve short-term glucose provocations. Multiple designs are available for these provocations (e.g., meal tolerance tests (MTTs) and graded glucose infusions (GGIs)). With a highly nonlinear, complex system as the glucose homeostasis, the various provocations will contribute with different information offering a rich choice. Here, we investigate the most appropriate study design in phase I for several hypothetical mechanisms of action of a study drug...
May 6, 2018: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/29700994/improving-interpretation-of-new-and-old-serum-biomarkers-of-drug-induced-liver-injury-through-mechanistic-modeling
#7
Paul B Watkins
The study by Mason et al. in this issue used mechanistic modeling and simulation to address how both the dose of acetaminophen consumed and the time since ingestion can be estimated from biomarkers measured in a single serum sample in mice. Translation into the clinic would potentially be an advance in the treatment of acetaminophen poisoning. Importantly, this approach could transform the evaluation of liver safety in clinical trials of new drug candidates.
April 26, 2018: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/29693322/outside-in-systems-pharmacology-combines-innovative-computational-methods-with-high-throughput-whole-vertebrate-studies
#8
EDITORIAL
Pascal Schulthess, Rob C van Wijk, Elke H J Krekels, James W T Yates, Herman P Spaink, Piet H van der Graaf
To advance the systems approach in pharmacology, experimental models and computational methods need to be integrated from early drug discovery onward. Here, we propose outside-in model development, a model identification technique to understand and predict the dynamics of a system without requiring prior biological and/or pharmacological knowledge. The advanced data required could be obtained by whole vertebrate, high-throughput, low-resource dose-exposure-effect experimentation with the zebrafish larva. Combinations of these innovative techniques could improve early drug discovery...
April 25, 2018: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/29667370/systems-toxicology-approach-to-identifying-paracetamol-overdose
#9
Chantelle L Mason, Joseph Leedale, Sotiris Tasoulis, Ian Jarman, Daniel J Antoine, Steven D Webb
Paracetamol (acetaminophen (APAP)) is one of the most commonly used analgesics in the United Kingdom and the United States. However, exceeding the maximum recommended dose can cause serious liver injury and even death. Promising APAP toxicity biomarkers are thought to add value to those used currently and clarification of the functional relationships between these biomarkers and liver injury would aid clinical implementation of an improved APAP toxicity identification framework. The framework currently used to define an APAP overdose is highly dependent upon time since ingestion and initial dose; information that is often highly unpredictable...
April 18, 2018: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/29660785/integrated-population-pharmacokinetic-analysis-of-rivaroxaban-across-multiple-patient-populations
#10
Stefan Willmann, Liping Zhang, Matthias Frede, Dagmar Kubitza, Wolfgang Mueck, Stephan Schmidt, Alexander Solms, Xiaoyu Yan, Dirk Garmann
The population pharmacokinetics (PK) of rivaroxaban have been evaluated in several population-specific models. We developed an integrated population PK model using pooled data from 4,918 patients in 7 clinical trials across all approved indications. Effects of gender, age, and weight on apparent clearance (CL/F) and apparent volume of distribution (V/F), renal function, and comedication on CL/F, and relative bioavailability as a function of dose (F) were analyzed. Virtual subpopulations for exposure simulations were defined by age, creatinine clearance (CrCL) and body mass index (BMI)...
April 16, 2018: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/29637732/a-quantitative-systems-pharmacology-model-of-hugt1a1-modrna-encoding-for-the-ugt1a1-enzyme-to-treat-crigler-najjar-syndrome-type-1
#11
Joshua F Apgar, Jian-Ping Tang, Pratap Singh, Nanda Balasubramanian, John Burke, Michael R Hodges, Melissa A Lasaro, Lin Lin, Bjorn L Miliard, Kristi Moore, Lucy S Jun, Susan Sobolov, Anna Katharina Wilkins, Xiang Gao
Crigler-Najjar syndrome Type 1 (CN1) is an autosomal recessive disease caused by a marked decrease in uridine-diphosphate-glucuronosyltransferase (UGT1A1) enzyme activity. Delivery of hUGT1A1-modRNA (a modified messenger RNA encoding for UGT1A1) as a lipid nanoparticle is anticipated to restore hepatic expression of UGT1A1, allowing normal glucuronidation and clearance of bilirubin in patients. To support translation from preclinical to clinical studies, and first in human studies, a quantitative systems pharmacology (QSP) model was developed...
April 10, 2018: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/29575824/complex-bayesian-modeling-workflows-encoding-and-execution-made-easy-with-a-novel-winbugs-plugin-of-the-drug-disease-model-resources-interoperability-framework
#12
Cristiana Larizza, Elisa Borella, Lorenzo Pasotti, Palma Tartaglione, Mike Smith, Stuart Moodie, Paolo Magni
The Drug Disease Model Resources (DDMoRe) Interoperability Framework (IOF) enables pharmacometric model encoding and execution via Model Description Language (MDL) and R language, through the ddmore package. Through its components and converter plugins, the IOF can execute pharmacometric tasks using different target tools, starting from a single MDL-encoded model. In this article, we present the WinBUGS plugin and show how its integration in the IOF enables an easy implementation of complex Bayesian workflows...
March 25, 2018: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/29575656/comparison-of-power-prognosis-and-extrapolation-properties-of-four-population-pharmacodynamic-models-of-hba1c-for-type-2-diabetes
#13
Gustaf J Wellhagen, Mats O Karlsson, Maria C Kjellsson
Reusing published models saves time; time to be used for informing decisions in drug development. In antihyperglycemic drug development, several published HbA1c models are available but selecting the appropriate model for a particular purpose is challenging. This study aims at helping selection by investigating four HbA1c models, specifically the ability to identify drug effects (shape, site of action, and power) and simulation properties. All models could identify glucose effect nonlinearities, although for detecting the site of action, a mechanistic glucose model was needed...
March 25, 2018: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/29569850/modeling-of-the-weight-status-and-risk-of-non-alcoholic-fatty-liver-disease-in-elderly-individuals-the-potential-impact-of-the-dsba-l-polymorphism-on-the-weight-status
#14
Kentaro Oniki, Takehisa Watanabe, Miku Kudo, Tomoko Izuka, Tatsumasa Ono, Kazuki Matsuda, Yuki Sakamoto, Katsuya Nagaoka, Tadashi Imafuku, Yu Ishima, Hiroshi Watanabe, Toru Maruyama, Koji Otake, Yasuhiro Ogata, Junji Saruwatari
Non-alcoholic fatty liver disease (NAFLD) is closely associated with obesity. Disulfide bond-forming oxidoreductase A-Like protein (DsbA-L) is known to be a key molecule in protection against obesity and obesity-induced inflammation. In the present study, we used a modeling and simulation approach in an attempt to develop body mass index (BMI) and BMI-based NAFLD prediction models incorporating the DsbA-L polymorphism to predict the BMI and NAFLD in 341 elderly subjects. A nonlinear mixed-effect model best represented the sigmoidal relationship between the BMI and the logit function of the probability of NAFLD prevalence...
March 23, 2018: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/29569841/the-many-flavors-of-model-based-meta-analysis-part-ii-modelling-summary-level-longitudinal-responses
#15
Martin Boucher, Meg Bennetts
Meta-analysis typically assesses comparative treatment response for an endpoint at specific time-points across studies. However, during drug development, it is often of interest to understand the response time-course of competitor compounds for a variety of purposes. Examples of such application include informing study design and characterizing the onset, maintenance and offset of action. This tutorial acts as a 'points for consideration' document, reviews relevant literature and fits a longitudinal model to an example dataset...
March 23, 2018: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/29569837/applied-concepts-in-pbpk-modeling-how-to-extend-an-open-systems-pharmacology-model-to-the-special-population-of-pregnant-women
#16
André Dallmann, Juri Solodenko, Ibrahim Ince, Thomas Eissing
This tutorial presents the workflow of adapting an adult physiologically based pharmacokinetic (PBPK) model to pregnant populations using the Open Systems Pharmacology (OSP) software suite (www.open-systems-pharmacology.org). This workflow is illustrated using a previously published PBPK model for metronidazole1 that is extrapolated to pregnancy by parameterizing and extending the model structure in terms of pregnancy-induced physiological changes2 . Importantly, this workflow can be applied to other scenarios where PBPK models need to be re-parameterized or structurally modified...
March 23, 2018: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/29484842/quantitative-systems-pharmacology-analysis-of-kras-g12c-covalent-inhibitors
#17
Edward C Stites, Andrey S Shaw
KRAS has proven difficult to target pharmacologically. Two strategies have recently been described for covalently targeting the most common KRAS mutant in lung cancer, KRAS G12C. Previously, we developed a computational model of the processes that regulate Ras activation. Here, we use this model to investigate KRAS G12C covalent inhibitors. We updated the model to include Ras protein turnover, and validation demonstrates that our model performs well in areas of G12C targeting where conventional wisdom struggles...
February 27, 2018: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/29493119/modeling-composite-assessment-data-using-item-response-theory
#18
Sebastian Ueckert
Composite assessments aim to combine different aspects of a disease in a single score and are utilized in a variety of therapeutic areas. The data arising from these evaluations are inherently discrete with distinct statistical properties. This tutorial presents the framework of the item response theory (IRT) for the analysis of this data type in a pharmacometric context. The article considers both conceptual (terms and assumptions) and practical questions (modeling software, data requirements, and model building)...
April 2018: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/29464871/mining-the-synergistic-core-allosteric-modules-variation-and-sequencing-pharmacological-module-drivers-in-a-preclinical-model-of-ischemia
#19
Yingying Zhang, Zide Zhao, Yanan Yu, Jun Liu, Pengqian Wang, Bing Li, Xiaoxu Zhang, Yinying Chen, Zhong Wang
Identifying the variation of core modules and hubs seems to be critical for characterizing variable pharmacological mechanisms based on topological alteration of disease networks. We first identified a total of eight core modules by using an approach of multiple modular characteristic fusing (MMCF) from different targeted networks in ischemic mice. Interestingly, the value of module disturbance intensity (MDI) increased in drug combination group. Second, we redefined a weak allosteric module and a strong allosteric module...
April 2018: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/29446256/using-a-vancomycin-pbpk-model-in-special-populations-to-elucidate-case-based-clinical-pk-observations
#20
Chie Emoto, Trevor N Johnson, Brooks T McPhail, Alexander A Vinks, Tsuyoshi Fukuda
Simultaneous changes in several physiological factors may contribute to the large pharmacokinetic (PK) variability of vancomycin. This study was designed to systematically characterize the effects of multiple physiological factors to the altered PK of vancomycin observed in special populations. A vancomycin physiologically based pharmacokinetic (PBPK) model was developed as a PK simulation platform to quantitatively assess the effects of changes in physiologies to the PK profiles. The developed model predicted the concentration-time profiles in healthy adults and diseased patients...
April 2018: CPT: Pharmacometrics & Systems Pharmacology
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