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Journal of Pharmacokinetics and Pharmacodynamics

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https://www.readbyqxmd.com/read/29777407/modelling-the-delay-between-pharmacokinetics-and-eeg-effects-of-morphine-in-rats-binding-kinetic-versus-effect-compartment-models
#1
Wilhelmus E A de Witte, Vivi Rottschäfer, Meindert Danhof, Piet H van der Graaf, Lambertus A Peletier, Elizabeth C M de Lange
Drug-target binding kinetics (as determined by association and dissociation rate constants, k on and k off ) can be an important determinant of the kinetics of drug action. However, the effect compartment model is used most frequently instead of a target binding model to describe hysteresis. Here we investigate when the drug-target binding model should be used in lieu of the effect compartment model. The utility of the effect compartment (EC), the target binding kinetics (TB) and the combined effect compartment-target binding kinetics (EC-TB) model were tested on either plasma (ECPL , TBPL and EC-TBPL ) or brain extracellular fluid (ECF) (ECECF , TBECF and EC-TBECF ) morphine concentrations and EEG amplitude in rats...
May 18, 2018: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29736890/a-tutorial-on-model-informed-approaches-to-cardiovascular-safety-with-focus-on-cardiac-repolarisation
#2
S Y A Cheung, J Parkinson, U Wählby-Hamrén, C D Dota, Å M Kragh, L Bergenholm, T Vik, T Collins, C Arfvidsson, C E Pollard, H K Tomkinson, B Hamrén
Drugs can affect the cardiovascular (CV) system either as an intended treatment or as an unwanted side effect. In both cases, drug-induced cardiotoxicities such as arrhythmia and unfavourable hemodynamic effects can occur, and be described using mathematical models; such a model informed approach can provide valuable information during drug development and can aid decision-making. However, in order to develop informative models, it is vital to understand CV physiology. The aims of this tutorial are to present (1) key background biological and medical aspects of the CV system, (2) CV electrophysiology, (3) CV safety concepts, (4) practical aspects of development of CV models and (5) regulatory expectations with a focus on using model informed and quantitative approaches to support nonclinical and clinical drug development...
May 7, 2018: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29736889/population-pharmacokinetics-and-exposure-response-modeling-and-simulation-for-evolocumab-in-healthy-volunteers-and-patients-with-hypercholesterolemia
#3
Mita Kuchimanchi, Anita Grover, Maurice G Emery, Ransi Somaratne, Scott M Wasserman, John P Gibbs, Sameer Doshi
Evolocumab, a novel human monoclonal antibody, inhibits proprotein convertase subtilisin/kexin type 9, a protein that targets low-density lipoprotein-cholesterol (LDL-C) receptors for the treatment of hyperlipidemia. The primary objective of this analysis was to characterize the population pharmacokinetics (popPK) and exposure-response relationship of evolocumab to assess if dose adjustment is needed across differing patient populations. Data were pooled for 5474 patients in 11 clinical studies who received evolocumab doses of 7-420 mg at various frequencies, either intravenously or subcutaneously...
May 7, 2018: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29725796/multiscale-systems-pharmacological-analysis-of-everolimus-action-in-hepatocellular-carcinoma
#4
Anusha Ande, Maher Chaar, Sihem Ait-Oudhia
Dysregulation of mTOR pathway is common in hepatocellular carcinoma (HCC). A translational quantitative systems pharmacology (QSP), pharmacokinetic (PK), and pharmacodynamic (PD) model dissecting the circuitry of this pathway was developed to predict HCC patients' response to everolimus, an mTOR inhibitor. The time course of key signaling proteins in the mTOR pathway, HCC cells viability, tumor volume (TV) and everolimus plasma and tumor concentrations in xenograft mice, clinical PK of everolimus and progression free survival (PFS) in placebo and everolimus-treated patients were extracted from literature...
May 3, 2018: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29717394/editorial-to-themed-issue-recent-advances-in-cardiovascular-pharmacokinetic-pharmacodynamic-modeling-and-simulation
#5
EDITORIAL
Peter Bonate
No abstract text is available yet for this article.
May 2, 2018: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29704219/receptor-gene-protein-mediated-signaling-connects-methylprednisolone-exposure-to-metabolic-and-immune-related-pharmacodynamic-actions-in-liver
#6
Vivaswath S Ayyar, Siddharth Sukumaran, Debra C DuBois, Richard R Almon, Jun Qu, William J Jusko
A multiscale pharmacodynamic model was developed to characterize the receptor-mediated, transcriptomic, and proteomic determinants of corticosteroid (CS) effects on clinically relevant hepatic processes following a single dose of methylprednisolone (MPL) given to adrenalectomized (ADX) rats. The enhancement of tyrosine aminotransferase (TAT) mRNA, protein, and enzyme activity were simultaneously described. Mechanisms related to the effects of MPL on glucose homeostasis, including the regulation of CCAAT-enhancer binding protein-beta (C/EBPβ) and phosphoenolpyruvate carboxykinase (PEPCK) as well as insulin dynamics were evaluated...
April 27, 2018: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29680872/projected-24-hour-post-dose-ocular-itching-scores-post-treatment-with-olopatadine-0-7-versus-0-2
#7
Matthew L Fidler, Abayomi Ogundele, David Covert, Ramesh Sarangapani
Olopatadine is an antihistamine and mast cell stabilizer used for treating allergic conjunctivitis. Olopatadine 0.7% has been recently approved for daily dosing in the US, which supersedes the previously approved 0.2% strength. The objective of this analysis was to characterize patients who have better itching relief at 24 h when taking olopatadine 0.7% treatment instead of olopatadine 0.2% (in terms of proportions of responses) and relate this to the severity of baseline itching as an indirect metric of a patient's sensitivity to antihistamines...
April 21, 2018: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29671170/physiologically-based-modeling-and-interspecies-prediction-of-paclitaxel-pharmacokinetics
#8
Xiaowei Zang, Leonid Kagan
The objective was to develop a physiologically-based pharmacokinetic (PBPK) model to characterize the whole-body disposition of paclitaxel (formulated in Cremophor EL and ethanol-Taxol® ) in mice and to evaluate the utility of this model for predicting pharmacokinetics in other species. Published studies that reported paclitaxel plasma and tissue concentration-time data following single intravenous bolus administration of Taxol® to mice were used; and the PBPK model included plasma, liver, lungs, kidneys, spleen, heart, gastrointestinal tract, and remainder compartments...
April 18, 2018: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29651591/importance-of-qt-rr-hysteresis-correction-in-studies-of-drug-induced-qtc-interval-changes
#9
Marek Malik, Christine Garnett, Katerina Hnatkova, Lars Johannesen, Jose Vicente, Norman Stockbridge
QT/RR hysteresis and QT/RR adaptation are interlinked but separate physiological processes signifying how quickly and how much QT interval changes when heart rate changes, respectively. While QT interval duration is, as a rule, corrected for heart rate in terms of the QT/RR adaptation, the correction for QT/RR hysteresis is frequently omitted in studies of drug-induced QTc changes. This study used data from previously conducted thorough QT studies to investigate the extent of QTc errors caused by omitting the correction for QT/RR hysteresis, particularly in small clinical investigations...
April 12, 2018: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29582349/model-reduction-in-mathematical-pharmacology-integration-reduction-and-linking-of-pbpk-and-systems-biology-models
#10
Thomas J Snowden, Piet H van der Graaf, Marcus J Tindall
In this paper we present a framework for the reduction and linking of physiologically based pharmacokinetic (PBPK) models with models of systems biology to describe the effects of drug administration across multiple scales. To address the issue of model complexity, we propose the reduction of each type of model separately prior to being linked. We highlight the use of balanced truncation in reducing the linear components of PBPK models, whilst proper lumping is shown to be efficient in reducing typically nonlinear systems biology type models...
March 26, 2018: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29556866/assessing-qt-qtc-interval-prolongation-with-concentration-qt-modeling-for-phase-i-studies-impact-of-computational-platforms-model-structures-and-confidence-interval-calculation-methods
#11
Jingtao Lu, Jianguo Li, Gabriel Helmlinger, Nidal Al-Huniti
Modeling the relationship between drug concentrations and heart rate corrected QT interval (QTc) change from baseline (C-∆QTc), based on Phase I single ascending dose (SAD) or multiple ascending dose (MAD) studies, has been proposed as an alternative to thorough QT studies (TQT), in assessing drug-induced QT prolongation risk. The present analysis used clinical SAD, MAD and TQT study data of an experimental compound, AZD5672, to evaluate the performance of: (i) three computational platforms (linear mixed-effects modeling implemented via PROC MIXED in SAS, as well as in R using LME4 package and linear quantile mixed models (LQMM) implemented via LQMM package; (ii) different model structures with and without treatment- or time-specific intercepts; and (iii) three methods for calculating the confidence interval (CI) of QTc prolongation (analytical and bootstrap methods with fixed or varied geometric mean concentrations)...
March 19, 2018: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29549540/a-comprehensive-evaluation-of-exposure-response-relationships-in-clinical-trials-application-to-support-guselkumab-dose-selection-for-patients-with-psoriasis
#12
Chuanpu Hu, Zhenling Yao, Yang Chen, Bruce Randazzo, Liping Zhang, Zhenhua Xu, Amarnath Sharma, Honghui Zhou
Guselkumab, a human IgG1 monoclonal antibody that blocks interleukin-23, has been evaluated in one Phase 2 and two Phase 3 trials in patients with moderate-to-severe psoriasis, in which disease severity was assessed using Psoriasis Area and Severity Index (PASI) and Investigator's Global Assessment (IGA) scores. Through the application of landmark and longitudinal exposure-response (E-R) modeling analyses, we sought to predict the guselkumab dose-response (D-R) relationship using data from 1459 patients who participated in these trials...
March 16, 2018: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29546612/drug-physiology-interaction-and-its-influence-on-the-qt-prolongation-mechanistic-modeling-study
#13
Barbara Wiśniowska, Sebastian Polak
The current study is an example of drug-disease interaction modeling where a drug induces a condition which can affect the pharmacodynamics of other concomitantly taken drugs. The electrophysiological effects of hypokaliemia and heart rate changes induced by the antiasthmatic drugs were simulated with the use of the cardiac safety simulator. Biophysically detailed model of the human cardiac physiology-ten Tusscher ventricular cardiomyocyte cell model-was employed to generate pseudo-ECG signals and QTc intervals for 44 patients from four clinical studies...
March 15, 2018: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29520534/quantitative-approach-for-cardiac-risk-assessment-and-interpretation-in-tuberculosis-drug-development
#14
Sebastian Polak, Klaus Romero, Alexander Berg, Nikunjkumar Patel, Masoud Jamei, David Hermann, Debra Hanna
Cardiotoxicity is among the top drug safety concerns, and is of specific interest in tuberculosis, where this is a known or potential adverse event of current and emerging treatment regimens. As there is a need for a tool, beyond the QT interval, to quantify cardiotoxicity early in drug development, an empirical decision tree based classifier was developed to predict the risk of Torsades de pointes (TdP). The cardiac risk algorithm was developed using pseudo-electrocardiogram (ECG) outputs derived from cardiac myocyte electromechanical model simulations of increasing concentrations of 96 reference compounds which represented a range of clinical TdP risk...
June 2018: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29446052/correction-to-pk-pd-compass-bringing-infectious-diseases-pharmacometrics-to-the-patient-s-bedside
#15
Catharine C Bulik, Justin C Bader, Li Zhang, Scott A Van Wart, Christopher M Rubino, Sujata M Bhavnani, Kim L Sweeney, Paul G Ambrose
The original version of this article contained incorrect Supplementary Files. The correct Supplementary Files are published with this erratum.
April 2018: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29435950/evaluation-of-performance-of-distributed-delay-model-for-chemotherapy-induced-myelosuppression
#16
Wojciech Krzyzanski, Shuhua Hu, Michael Dunlavey
The distributed delay model has been introduced that replaces the transit compartments in the classic model of chemotherapy-induced myelosuppression with a convolution integral. The maturation of granulocyte precursors in the bone marrow is described by the gamma probability density function with the shape parameter (ν). If ν is a positive integer, the distributed delay model coincides with the classic model with ν transit compartments. The purpose of this work was to evaluate performance of the distributed delay model with particular focus on model deterministic identifiability in the presence of the shape parameter...
April 2018: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29423863/a-framework-for-2-stage-global-sensitivity-analysis-of-gastroplus%C3%A2-compartmental-models
#17
Megerle L Scherholz, James Forder, Ioannis P Androulakis
Parameter sensitivity and uncertainty analysis for physiologically based pharmacokinetic (PBPK) models are becoming an important consideration for regulatory submissions, requiring further evaluation to establish the need for global sensitivity analysis. To demonstrate the benefits of an extensive analysis, global sensitivity was implemented for the GastroPlus™ model, a well-known commercially available platform, using four example drugs: acetaminophen, risperidone, atenolol, and furosemide. The capabilities of GastroPlus were expanded by developing an integrated framework to automate the GastroPlus graphical user interface with AutoIt and for execution of the sensitivity analysis in MATLAB® ...
April 2018: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29423862/establishing-in-vitro-in-vivo-correlation-for-antibody-drug-conjugate-efficacy-a-pk-pd-modeling-approach
#18
Dhaval K Shah, Frank Loganzo, Nahor Haddish-Berhane, Sylvia Musto, Hallie S Wald, Frank Barletta, Judy Lucas, Tracey Clark, Steve Hansel, Alison Betts
The objective of this manuscript was to establish in vitro-in vivo correlation (IVIVC) between the in vitro efficacy and in vivo efficacy of antibody drug conjugates (ADCs), using a PK/PD modeling approach. Nineteen different ADCs were used to develop IVIVC. In vitro efficacy of ADCs was evaluated using a kinetic cell cytotoxicity assay. The cytotoxicity data obtained from in vitro studies was characterized using a novel mathematical model, parameter estimates from which were used to derive an in vitro efficacy matrix for each ADC, termed as 'in vitro tumor static concentration' (TSCin vitro )...
April 2018: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29302838/gpkpdsim-a-simbiology-%C3%A2-based-gui-application-for-pkpd-modeling-in-drug-development
#19
Iraj Hosseini, Anita Gajjala, Daniela Bumbaca Yadav, Siddharth Sukumaran, Saroja Ramanujan, Ricardo Paxson, Kapil Gadkar
Modeling and simulation (M&S) is increasingly used in drug development to characterize pharmacokinetic-pharmacodynamic (PKPD) relationships and support various efforts such as target feasibility assessment, molecule selection, human PK projection, and preclinical and clinical dose and schedule determination. While model development typically require mathematical modeling expertise, model exploration and simulations could in many cases be performed by scientists in various disciplines to support the design, analysis and interpretation of experimental studies...
April 2018: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29290034/pharmacokinetics-of-dexmedetomidine-during-analgosedation-in-icu-patients
#20
Piotr Smuszkiewicz, Paweł Wiczling, Justyna Ber, Justyna Warzybok, Tomasz Małkiewicz, Jan Matysiak, Agnieszka Klupczyńska, Iwona Trojanowska, Zenon Kokot, Edmund Grześkowiak, Wojciech Krzyzanski, Agnieszka Bienert
Dexmedetomidine (DEX) is a fairly new alfa2 -agonist which has been increasingly used in recent years for analgosedation, mostly because it offers a unique ability of providing both moderate level of sedation and analgesia without respiratory depression. Despite of many papers published, there are still only a few concerning the PK of the drug given as long-term infusion in ICU patients. The aim of this work was to characterize the population pharmacokinetics of dexmedetomidine and to investigate the potential benefits of individualization of drug dosing based on patient characteristics in the heterogeneous group of medical and surgical patients staying in intensive care unit...
April 2018: Journal of Pharmacokinetics and Pharmacodynamics
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