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CPT: Pharmacometrics & Systems Pharmacology

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https://www.readbyqxmd.com/read/28326681/population-pharmacokinetics-of-selumetinib-and-its-metabolite-n-desmethyl-selumetinib-in-adult-patients-with-advanced-solid-tumors-and-children-with-low-grade-gliomas
#1
Y T Patel, V M Daryani, P Patel, D Zhou, J Fangusaro, D J Carlile, P D Martin, L Aarons, C F Stewart
Selumetinib (AZD6244, ARRY-142886), a mitogen activated protein kinases (MEK1 and 2) inhibitor, has been granted orphan drug designation for differentiated thyroid cancer. The primary aim of this analysis was to characterize the population pharmacokinetics of selumetinib and its active metabolite N-desmethyl-selumetinib in patients with cancer. Concentration-time data from adult and pediatric clinical trials were pooled to develop a population pharmacokinetic model using a sequential approach where selumetinib and N-desmethyl-selumetinib data were modeled separately...
March 22, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28317328/evaluating-dosage-optimality-for-tofacitinib-an-oral-janus-kinase-inhibitor-in-plaque-psoriasis-and-the-influence-of-body-weight
#2
M M Hutmacher, K Papp, S Krishnaswami, K Ito, H Tan, R Wolk, H Valdez, C Mebus, S T Rottinghaus, P Gupta
Tofacitinib is an oral Janus kinase inhibitor. An integrated analysis was conducted to evaluate dosage optimality for tofacitinib in patients with moderate-to-severe plaque psoriasis and the impact of body weight on optimality in this patient population. Data were pooled from one phase IIb trial (2, 5, and 15 mg twice daily (b.i.d.)) and four phase III trials (5 and 10 mg b.i.d.). A longitudinal exposure-response model for Psoriasis Area and Severity Index (PASI) improvement (percent change from baseline) was established...
March 20, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28296193/investigating-transporter-mediated-drug-drug-interactions-using-a-physiologically-based-pharmacokinetic-model-of-rosuvastatin
#3
Q Wang, M Zheng, T Leil
Rosuvastatin is a frequently used probe in transporter-mediated drug-drug interaction (DDI) studies. This report describes the development of a physiologically based pharmacokinetic (PBPK) model of rosuvastatin for prediction of pharmacokinetic (PK) DDIs. The rosuvastatin model predicted the observed single (i.v. and oral) and multiple dose PK profiles, as well as the impact of coadministration with transporter inhibitors. The predicted effects of rifampin and cyclosporine (6.58-fold and 5.07-fold increase in rosuvastatin area under the curve (AUC), respectively) were mediated primarily via inhibition of hepatic organic anion-transporting polypeptide (OATP)1B1 (Inhibition constant (Ki ) ∼1...
March 13, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28194906/response-to-time-of-the-day-and-magnitude-of-the-effect-of-a-drug-on-the-qtc-interval
#4
LETTER
L Kervezee, J Burggraaf
No abstract text is available yet for this article.
February 14, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28188701/response-to-letter-quantitative-prediction-of-drug-drug-interactions-involving-inhibitory-metabolites-by-physiologically-based-pharmacokinetic-models-is-it-worth
#5
LETTER
I E Templeton, Y Chen, J Mao, J Lin, H Yu, S Peters, M Shebley, M V Varma
No abstract text is available yet for this article.
February 11, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28142221/time-of-the-day-and-magnitude-of-the-effect-of-a-drug-on-the-qtc-interval
#6
LETTER
J Täubel, S Fernandes, G Ferber
No abstract text is available yet for this article.
January 31, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28109128/population-pharmacokinetics-and-pharmacodynamics-of-benralizumab-in-healthy-volunteers-and-patients-with-asthma
#7
B Wang, L Yan, Z Yao, L K Roskos
Benralizumab is a humanized, afucosylated, anti-interleukin-5 receptor α, immunoglobulin G (IgG) 1 κ monoclonal antibody. We developed a population pharmacokinetic (PK)/pharmacodynamic (PD) model for benralizumab by analyzing PK and blood eosinophil count data from two healthy volunteer studies (N = 48) and four studies in patients with asthma (N = 152). Benralizumab PK was dose-proportional and adequately described by a two-compartment model with first-order elimination from the central compartment and first-order absorption from the subcutaneous dosing site...
January 21, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28109060/morphine-pharmacodynamics-in-mechanically-ventilated-preterm-neonates-undergoing-endotracheal-suctioning
#8
P A Välitalo, Ehj Krekels, M van Dijk, Shp Simons, D Tibboel, Caj Knibbe
To date, morphine pharmacokinetics (PKs) are well quantified in neonates, but results about its efficacy are ambiguous. This work presents an analysis of a previously published study on pain measurements in mechanically ventilated preterm neonates who received either morphine or placebo to improve comfort during invasive ventilation. The research question was whether morphine reduces the pain associated with endotracheal or nasal suctioning before, during, and after suctioning. Because these neonates cannot verbalize their pain levels, pain was assessed on the basis of several validated pain measurement instruments (i...
January 21, 2017: CPT: Pharmacometrics & Systems Pharmacology
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
#9
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/28331771/2016-reviewer-acknowledgement
#10
(no author information available yet)
No abstract text is available yet for this article.
March 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28296354/cattle-cancer-treatment-treasury-with-linked-evidence-an-integrated-knowledge-base-for-personalized-oncology-research-and-practice
#11
E Soysal, H-J Lee, Y Zhang, L-C Huang, X Chen, Q Wei, W Zheng, J T Chang, T Cohen, J Sun, H Xu
Despite the existence of various databases cataloging cancer drugs, there is an emerging need to support the development and application of personalized therapies, where an integrated understanding of the clinical factors and drug mechanism of action and its gene targets is necessary. We have developed CATTLE (CAncer Treatment Treasury with Linked Evidence), a comprehensive cancer drug knowledge base providing information across the complete spectrum of the drug life cycle. The CATTLE system collects relevant data from 22 heterogeneous databases, integrates them into a unified model centralized on drugs, and presents comprehensive drug information via an interactive web portal with a download function...
March 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28294568/systems-pharmacology-based-discovery-of-natural-products-for-precision-oncology-through-targeting-cancer-mutated-genes
#12
J Fang, C Cai, Q Wang, P Lin, Z Zhao, F Cheng
Massive cancer genomics data have facilitated the rapid revolution of a novel oncology drug discovery paradigm through targeting clinically relevant driver genes or mutations for the development of precision oncology. Natural products with polypharmacological profiles have been demonstrated as promising agents for the development of novel cancer therapies. In this study, we developed an integrated systems pharmacology framework that facilitated identifying potential natural products that target mutated genes across 15 cancer types or subtypes in the realm of precision medicine...
March 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28276649/precision-medicine-in-pharmacometrics-and-systems-pharmacology
#13
EDITORIAL
L Li
No abstract text is available yet for this article.
March 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28266149/iodne-an-integrated-optimization-method-for-identifying-the-deregulated-subnetwork-for-precision-medicine-in-cancer
#14
S Mounika Inavolu, J Renbarger, M Radovich, V Vasudevaraja, G H Kinnebrew, S Zhang, L Cheng
Subnetwork analysis can explore complex patterns of entire molecular pathways for the purpose of drug target identification. In this article, the gene expression profiles of a cohort of patients with breast cancer are integrated with protein-protein interaction (PPI) networks using, simultaneously, both edge scoring and node scoring. A novel optimization algorithm, integrated optimization method to identify deregulated subnetwork (IODNE), is developed to search for the optimal dysregulated subnetwork of the merged gene and protein network...
March 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28181418/mathematical-modeling-of-the-effects-of-ck2-3-on-mineralization-in-osteoporotic-bone
#15
A Lisberg, R Ellis, K Nicholson, P Moku, A Swarup, P Dhurjati, A Nohe
Osteoporosis is caused by decreased bone mineral density (BMD) and new treatments for this disease are desperately needed. Bone morphogenetic protein 2 (BMP2) is crucial for bone formation. The mimetic peptide CK2.3 acts downstream of BMP2 and increases BMD when injected systemically into the tail vein of mice. However, the most effective dosage needed to induce BMD in humans is unknown. We developed a mathematical model for CK2.3-dependent bone mineralization. We used a physiologically based pharmacokinetic (PBPK) model to derive the CK2...
March 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28145085/prediction-of-in-vivo-and-in-vitro-infection-model-results-using-a-semimechanistic-model-of-avibactam-and-aztreonam-combination-against-multidrug-resistant-organisms
#16
Skb Sy, L Zhuang, H Xia, M-E Beaudoin, V J Schuck, H Derendorf
The combination of aztreonam-avibactam is active against multidrug-resistant Enterobacteriaceae that express metallo-β-lactamases. A complex synergistic interaction exists between aztreonam and avibactam bactericidal activities that have not been quantitatively explored. A two-state semimechanistic pharmacokinetic/pharmacodynamic (PK/PD) logistic growth model was developed to account for antimicrobial activities in the combination of bacteria-mediated degradation of aztreonam and the inhibition of aztreonam degradation by avibactam...
March 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28109071/implementing-genomic-clinical-decision-support-for-drug-based-precision-medicine
#17
EDITORIAL
R R Freimuth, C M Formea, J M Hoffman, E Matey, J F Peterson, R D Boyce
The explosive growth of patient-specific genomic information relevant to drug therapy will continue to be a defining characteristic of biomedical research. To implement drug-based personalized medicine (PM) for patients, clinicians need actionable information incorporated into electronic health records (EHRs). New clinical decision support (CDS) methods and informatics infrastructure are required in order to comprehensively integrate, interpret, deliver, and apply the full range of genomic data for each patient...
March 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/27863172/building-confidence-in-quantitative-systems-pharmacology-models-an-engineer-s-guide-to-exploring-the-rationale-in-model-design-and-development
#18
J Timmis, K Alden, P Andrews, E Clark, A Nellis, B Naylor, M Coles, P Kaye
This tutorial promotes good practice for exploring the rationale of systems pharmacology models. A safety systems engineering inspired notation approach provides much needed rigor and transparency in development and application of models for therapeutic discovery and design of intervention strategies. Structured arguments over a model's development, underpinning biological knowledge, and analyses of model behaviors are constructed to determine the confidence that a model is fit for the purpose for which it will be applied...
March 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28130915/multiscale-modeling-reveals-inhibitory-and-stimulatory-effects-of-caffeine-on-acetaminophen-induced-toxicity-in-humans
#19
C Thiel, H Cordes, V Baier, L M Blank, L Kuepfer
Acetaminophen (APAP) is a widely used analgesic drug that is frequently co-administered with caffeine (CAF) in the treatment of pain. It is well known that APAP may cause severe liver injury after an acute overdose. However, the understanding of whether and to what extent CAF inhibits or stimulates APAP-induced hepatotoxicity in humans is still lacking. Here, a multiscale analysis is presented that quantitatively models the pharmacodynamic (PD) response of APAP during co-medication with CAF. Therefore, drug-drug interaction (DDI) processes were integrated into physiologically based pharmacokinetic (PBPK) models at the organism level, whereas drug-specific PD response data were contextualized at the cellular level...
February 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28063254/the-impact-of-mathematical-modeling-in-understanding-the-mechanisms-underlying-neurodegeneration-evolving-dimensions-and-future-directions
#20
REVIEW
A Lloret-Villas, T M Varusai, N Juty, C Laibe, N Le NovÈre, H Hermjakob, V Chelliah
Neurodegenerative diseases are a heterogeneous group of disorders that are characterized by the progressive dysfunction and loss of neurons. Here, we distil and discuss the current state of modeling in the area of neurodegeneration, and objectively compare the gaps between existing clinical knowledge and the mechanistic understanding of the major pathological processes implicated in neurodegenerative disorders. We also discuss new directions in the field of neurodegeneration that hold potential for furthering therapeutic interventions and strategies...
February 2017: CPT: Pharmacometrics & Systems Pharmacology
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