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CPT: Pharmacometrics & Systems Pharmacology

B Li, J Liu, Y Y Zhang, P Q Wang, Y N Yu, R X Kang, H L Wu, X X Zhang, Z Wang, Y Y Wang
Module-based methods have made much progress in deconstructing biological networks. However, it is a great challenge to quantitatively compare the topological structural variations of modules (allosteric modules [AMs]) under different situations. A total of 23, 42, and 15 coexpression modules were identified in baicalin (BA), jasminoidin (JA), and ursodeoxycholic acid (UA) in a global anti-ischemic mice network, respectively. Then, we integrated the methods of module-based consensus ratio (MCR) and modified Zsummary module statistic to validate 12 BA, 22 JA, and 8 UA on-modules based on comparing with vehicle...
October 19, 2016: CPT: Pharmacometrics & Systems Pharmacology
Hitesh B Mistry
No abstract text is available yet for this article.
October 12, 2016: CPT: Pharmacometrics & Systems Pharmacology
L Kuepfer, C Niederalt, T Wendl, J-F Schlender, S Willmann, J Lippert, M Block, T Eissing, D Teutonico
The aim of this tutorial is to introduce the fundamental concepts of physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling with a special focus on their practical implementation in a typical PBPK model building workflow. To illustrate basic steps in PBPK model building, a PBPK model for ciprofloxacin will be constructed and coupled to a pharmacodynamic model to simulate anti-bacterial activity of ciprofloxacin treatment. This article is protected by copyright. All rights reserved.
September 21, 2016: CPT: Pharmacometrics & Systems Pharmacology
Rik de Greef, Jeroen Elassaiss-Schaap, Manash Chatterjee, David C Turner, Malidi Ahamadi, Mark Forman, David Cutler, Dinesh P de Alwis, Anna Kondic, Julie Stone
No abstract text is available yet for this article.
September 21, 2016: CPT: Pharmacometrics & Systems Pharmacology
S Hartmann, K Biliouris, L J Lesko, U Nowak-Göttl, M N Trame
Warfarin is the anticoagulant of choice for venous thromboembolism (VTE) treatment, although its suppression of the endogenous clot-dissolution complex APC:PS may ultimately lead to longer time-to-clot dissolution profiles, resulting in increased risk of re-thrombosis. This detrimental effect might not occur during VTE treatment using other anticoagulants, such as rivaroxaban or enoxaparin, given their different mechanisms of action within the coagulation network. A quantitative systems pharmacology model was developed describing the coagulation network to monitor clotting factor levels under warfarin, enoxaparin, and rivaroxaban treatment...
September 20, 2016: CPT: Pharmacometrics & Systems Pharmacology
I E Templeton, Y Chen, J Mao, J Lin, H Yu, S Peters, M Shebley, M V Varma
This subteam under the Drug Metabolism Leadership Group (Innovation and Quality Consortium) investigated the quantitative role of circulating inhibitory metabolites in drug-drug interactions using physiologically based pharmacokinetic (PBPK) modeling. Three drugs with major circulating inhibitory metabolites (amiodarone, gemfibrozil, and sertraline) were systematically evaluated in addition to the literature review of recent examples. The application of PBPK modeling in drug interactions by inhibitory parent-metabolite pairs is described and guidance on strategic application is provided...
September 19, 2016: CPT: Pharmacometrics & Systems Pharmacology
M K Morris, D C Clarke, L C Osimiri, D A Lauffenburger
A major challenge in developing anticancer therapies is determining the efficacies of drugs and their combinations in physiologically relevant microenvironments. We describe here our application of "constrained fuzzy logic" (CFL) ensemble modeling of the intracellular signaling network for predicting inhibitor treatments that reduce the phospho-levels of key transcription factors downstream of growth factors and inflammatory cytokines representative of hepatocellular carcinoma (HCC) microenvironments. We observed that the CFL models successfully predicted the effects of several kinase inhibitor combinations...
August 27, 2016: CPT: Pharmacometrics & Systems Pharmacology
H Y Choi, S Choi, Y H Kim, H S Lim
GCC-4401C, an orally active direct factor Xa inhibitor that is similar to rivaroxaban, is currently under development for venous thromboembolic disease (VTE). The purpose of this study was to characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of GCC-4401C by population modeling analysis and to predict proper dosage regimens compared to rivaroxaban using data from two phase I clinical studies. Plasma GCC-4401C concentrations over time were best described by a two-compartment linear model and body weight was associated with central volume of distribution...
August 11, 2016: CPT: Pharmacometrics & Systems Pharmacology
C Garnett, L Johannesen
Circadian variations in the corrected QT (QTc) interval have been documented in clinical trials. Animal models show circadian variations in expression of the cardiac ion channels that are necessary to maintain the heart's electrophysiological properties. Can these diurnal rhythms in QTc affect the ability of a drug to delay cardiac repolarization?
September 2016: CPT: Pharmacometrics & Systems Pharmacology
J N Moore, J R Healy, B N Thoma, M M Peahota, M Ahamadi, L Schmidt, N C Cavarocchi, W K Kraft
The literature on the pharmacokinetics of vancomycin in patients undergoing extracorporeal membrane oxygenation (ECMO) therapy is sparse. A population pharmacokinetic (PK) model for vancomycin in ECMO patients was developed using a nonlinear mixed effects modeling on the concentration-time profiles of 14 ECMO patients who received intravenous vancomycin. Model selection was based on log-likelihood criterion, goodness of fit plots, and scientific plausibility. Identification of covariates was done using a full covariate model approach...
September 2016: CPT: Pharmacometrics & Systems Pharmacology
C J Musante, D R Abernethy, S R Allerheiligen, D A Lauffenburger, M G Zager
Quantitative Systems Pharmacology (QSP) is experiencing increased application in the drug discovery and development process. Like its older sibling, systems biology, the QSP field is comprised of a mix of established disciplines and methods, from molecular biology to engineering to pharmacometrics. As a result, there exist critical segments of the discipline that differ dramatically in approach and a need to bring these groups together toward a common goal.
September 2016: CPT: Pharmacometrics & Systems Pharmacology
P Chen, P Olsson Gisleskog, J J Perez-Ruixo, J Xiao, J Wilkins, A Narayanan, J P Gibbs, M Melhem
Etelcalcetide is a novel calcimimetic in development for the treatment of secondary hyperparathyroidism (SHPT). A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed relating etelcalcetide exposures to markers of efficacy (parathyroid hormone [PTH]) and safety (calcium) using data from three clinical studies. The semimechanistic model was developed that included allosteric activation pharmacology and understanding of calcium homeostasis. The temporal profiles for all biomarkers were well described by the model...
September 2016: CPT: Pharmacometrics & Systems Pharmacology
W Zhou, T N Johnson, H Xu, Sya Cheung, K H Bui, J Li, N Al-Huniti, D Zhou
Predictive performance of physiologically based pharmacokinetic (PBPK) and population pharmacokinetic (PopPK) models of drugs predominantly eliminated through kidney in the pediatric population was evaluated. After optimization using adult clinical data, the verified PBPK models can predict 33 of 34 drug clearance within twofold of the observed values in children 1 month and older. More specifically, 10 of 11 of predicted clearance values were within 1.5-fold of those observed in children between 1 month and 2 years old...
September 2016: CPT: Pharmacometrics & Systems Pharmacology
L Kervezee, V Gotta, J Stevens, W Birkhoff, Imc Kamerling, M Danhof, J H Meijer, J Burggraaf
Understanding the factors influencing a drug's potential to prolong the QTc interval on an electrocardiogram is essential for the correct evaluation of its safety profile. To explore the effect of dosing time on drug-induced QTc prolongation, a randomized, crossover, clinical trial was conducted in which 12 healthy male subjects received levofloxacin at 02:00, 06:00, 10:00, 14:00, 18:00, and 22:00. Using a pharmacokinetic-pharmacodynamic (PK-PD) modeling approach to account for variations in PKs, heart rate, and daily variation in baseline QT, we find that the concentration-QT relationship shows a 24-hour sinusoidal rhythm...
September 2016: CPT: Pharmacometrics & Systems Pharmacology
K Abduljalil, D Edwards, A Barnett, R H Rose, T Cain, M Jamei
No abstract text is available yet for this article.
September 2016: CPT: Pharmacometrics & Systems Pharmacology
P Zuo, R L Dobbins, R L O'Connor-Semmes, M A Young
A systems model was developed to describe the metabolism and disposition of ursodeoxycholic acid (UDCA) and its conjugates in healthy subjects based on pharmacokinetic (PK) data from published studies in order to study the distribution of oral UDCA and potential interactions influencing therapeutic effects upon interruption of its enterohepatic recirculation. The base model was empirically adapted to patients with primary biliary cirrhosis (PBC) based on current understanding of disease pathophysiology and clinical measurements...
August 2016: CPT: Pharmacometrics & Systems Pharmacology
G Smania, P Baiardi, A Ceci, M Cella, P Magni
This study presents a pharmacokinetic-pharmacodynamic based clinical trial simulation framework for evaluating the performance of a fixed-sample Bayesian design (BD) and two alternative Bayesian sequential designs (BSDs) (i.e., a non-hierarchical (NON-H) and a semi-hierarchical (SEMI-H) one). Prior information was elicited from adult trials and weighted based on the expected similarity of response to treatment between the pediatric and adult populations. Study designs were evaluated in terms of: type I and II errors, sample size per arm (SS), trial duration (TD), and estimate precision...
August 2016: CPT: Pharmacometrics & Systems Pharmacology
C Emoto, T Fukuda, T Mizuno, B Schniedewind, Uwe Christians, D M Adams, A A Vinks
Sirolimus is increasingly being used in neonates and infants, but the mechanistic basis of age-dependent changes in sirolimus disposition has not been fully addressed yet. In order to characterize the age-dependent changes, serial sirolimus clearance (CL) estimates in individual young pediatric patients were collected and analyzed by population modeling analysis. In addition, sirolimus metabolite formation was also investigated to further substantiate the corresponding age-dependent change in CYP3A activity...
August 2016: CPT: Pharmacometrics & Systems Pharmacology
J H Warner, C Sampaio
We present a novel, general class of disease progression models for Huntington's disease (HD), a neurodegenerative disease caused by a cytosine-adenine-guanine (CAG) triplet repeat expansion on the huntingtin gene. Models are fit to a selection of structural imaging markers from the TRACK 36-month database. The models are of mixed effects type and should be useful in predicting any continuous marker of HD state as a function of age and CAG length (the genetic factor that drives HD pathology). The effects of age and CAG length are modeled using flexible regression splines...
August 2016: CPT: Pharmacometrics & Systems Pharmacology
D Mawdsley, M Bennetts, S Dias, M Boucher, N J Welton
Model-based meta-analysis (MBMA) is increasingly used in drug development to inform decision-making and future trial designs, through the use of complex dose and/or time course models. Network meta-analysis (NMA) is increasingly being used by reimbursement agencies to estimate a set of coherent relative treatment effects for multiple treatments that respect the randomization within the trials. However, NMAs typically either consider different doses completely independently or lump them together, with few examples of models for dose...
August 2016: CPT: Pharmacometrics & Systems Pharmacology
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