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Journal of Pharmacokinetics and Pharmacodynamics

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https://www.readbyqxmd.com/read/29330761/correction-to-scientific-white-paper-on-concentration-qtc-modeling
#1
Christine Garnett, Peter L Bonate, Qianyu Dang, Georg Ferber, Dalong Huang, Jiang Liu, Devan Mehrotra, Steve Riley, Philip Sager, Christoffer Tornoe, Yaning Wang
The original version of this article unfortunately contained an error in Equation 1 under the section "Pre-specified linear mixed effects model". The correct equation has given below.
January 12, 2018: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29313194/delayed-logistic-indirect-response-models-realization-of-oscillating-behavior
#2
Gilbert Koch, Johannes Schropp
Indirect response (IDR) models are probably the most frequently applied tools relating the effect of a signal to a baseline response. A response modeled by such a classical IDR model will always return monotonously to its baseline after drug administration. We extend IDR models with a delay process, i.e. a retarded response state, that leads to oscillating response behavior. First, IDR models with a first-order production and second-order loss term based on the famous logistic equation are constructed. Second, a delay process similar to the delayed logistic equation is included...
January 8, 2018: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29307099/boolean-network-modeling-in-systems-pharmacology
#3
Peter Bloomingdale, Van Anh Nguyen, Jin Niu, Donald E Mager
Quantitative systems pharmacology (QSP) is an emerging discipline that aims to discover how drugs modulate the dynamics of biological components in molecular and cellular networks and the impact of those perturbations on human pathophysiology. The integration of systems-based experimental and computational approaches is required to facilitate the advancement of this field. QSP models typically consist of a series of ordinary differential equations (ODE). However, this mathematical framework requires extensive knowledge of parameters pertaining to biological processes, which is often unavailable...
January 6, 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
#4
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...
January 4, 2018: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29299711/special-issue-mathematical-pharmacology
#5
Wojciech Krzyzanski, J G Coen van Hasselt
No abstract text is available yet for this article.
January 3, 2018: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29290034/pharmacokinetics-of-dexmedetomidine-during-analgosedation-in-icu-patients
#6
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...
December 30, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29243176/understanding-and-reducing-complex-systems-pharmacology-models-based-on-a-novel-input-response-index
#7
Jane Knöchel, Charlotte Kloft, Wilhelm Huisinga
A growing understanding of complex processes in biology has led to large-scale mechanistic models of pharmacologically relevant processes. These models are increasingly used to study the response of the system to a given input or stimulus, e.g., after drug administration. Understanding the input-response relationship, however, is often a challenging task due to the complexity of the interactions between its constituents as well as the size of the models. An approach that quantifies the importance of the different constituents for a given input-output relationship and allows to reduce the dynamics to its essential features is therefore highly desirable...
December 14, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29236223/transit-and-lifespan-in-neutrophil-production-implications-for-drug-intervention
#8
Daniel Câmara De Souza, Morgan Craig, Tyler Cassidy, Jun Li, Fahima Nekka, Jacques Bélair, Antony R Humphries
A comparison of the transit compartment ordinary differential equation modelling approach to distributed and discrete delay differential equation models is studied by focusing on Quartino's extension to the Friberg transit compartment model of myelosuppression, widely relied upon in the pharmaceutical sciences to predict the neutrophil response after chemotherapy, and on a QSP delay differential equation model of granulopoiesis. An extension to the Quartino model is provided by considering a general number of transit compartments and introducing an extra parameter that allows for the decoupling of the maturation time from the production rate of cells...
December 13, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29234936/a-generic-whole-body-physiologically-based-pharmacokinetic-model-for-therapeutic-proteins-in-pk-sim
#9
Christoph Niederalt, Lars Kuepfer, Juri Solodenko, Thomas Eissing, Hans-Ulrich Siegmund, Michael Block, Stefan Willmann, Jörg Lippert
Proteins are an increasingly important class of drugs used as therapeutic as well as diagnostic agents. A generic physiologically based pharmacokinetic (PBPK) model was developed in order to represent at whole body level the fundamental mechanisms driving the distribution and clearance of large molecules like therapeutic proteins. The model was built as an extension of the PK-Sim model for small molecules incorporating (i) the two-pore formalism for drug extravasation from blood plasma to interstitial space, (ii) lymph flow, (iii) endosomal clearance and (iv) protection from endosomal clearance by neonatal Fc receptor (FcRn) mediated recycling as especially relevant for antibodies...
December 12, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29209907/scientific-white-paper-on-concentration-qtc-modeling
#10
REVIEW
Christine Garnett, Peter L Bonate, Qianyu Dang, Georg Ferber, Dalong Huang, Jiang Liu, Devan Mehrotra, Steve Riley, Philip Sager, Christoffer Tornoe, Yaning Wang
The International Council for Harmonisation revised the E14 guideline through the questions and answers process to allow concentration-QTc (C-QTc) modeling to be used as the primary analysis for assessing the QTc interval prolongation risk of new drugs. A well-designed and conducted QTc assessment based on C-QTc modeling in early phase 1 studies can be an alternative approach to a thorough QT study for some drugs to reliably exclude clinically relevant QTc effects. This white paper provides recommendations on how to plan and conduct a definitive QTc assessment of a drug using C-QTc modeling in early phase clinical pharmacology and thorough QT studies...
December 5, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29170990/lack-of-ethnic-differences-of-moxifloxacin-and-metabolite-pharmacokinetics-in-east-asian-men
#11
M Kaneko, T Aoyama, Y Ishida, A Miyamoto, Y Saito, M Tohkin, S Kawai, Y Matsumoto
This study was designed to investigate ethnic differences in the pharmacokinetics (PKs) of moxifloxacin and its metabolites, M1 (sulfo conjugate) and M2 (acyl-glucuronate), among Japanese, Chinese, and Korean populations, following oral administration. We used a population PK modeling approach using data from a clinical study involving 79 healthy male volunteers. A comprehensive population PK model considering the PK mechanism of moxifloxacin and its metabolites was newly built. The structures of the final model were two-compartment for moxifloxacin and one-compartment for M1 and M2, with first-order absorption with lag time for all three compounds...
November 23, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29170989/modeling-energy-intake-and-body-weight-effects-of-a-long-acting-amylin-analogue
#12
Annika Brings, Jens Markus Borghardt, Jolanta Skarbaliene, Tamara Baader-Pagler, Maria A Deryabina, Wolfgang Rist, Stefan Scheuerer
The inhibitory effect of anti-obesity drugs on energy intake (EI) is counter-acted by feedback regulation of the appetite control circuit leading to drug tolerance. This complicates the design and interpretation of EI studies in rodents that are used for anti-obesity drug development. Here, we investigated a synthetic long-acting analogue of the appetite-suppressing peptide hormone amylin (LAMY) in lean and diet-induced obese (DIO) rats. EI and body weight (BW) were measured daily and LAMY concentrations in plasma were assessed using defined time points following subcutaneous administration of the LAMY at different dosing regimens...
November 23, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29150770/population-in-vitro-in-vivo-pharmacokinetic-model-of-first-pass-metabolism-itraconazole-and-hydroxy-itraconazole
#13
Ahmad Y Abuhelwa, Stuart Mudge, Richard N Upton, David J R Foster
The aim of this study was to develop a population in vitro-in vivo pharmacokinetic model that simultaneously describe the absorption and accumulation kinetics of itraconazole (ICZ) and hydroxy-itraconazole (HICZ) in healthy subjects. The model integrated meta-models of gastrointestinal pH and gastrointestinal transit time and in vitro dissolution models of ICZ with the absorption and disposition kinetics of ICZ and HICZ. Mean concentration intravenous data, and single- and multi-dose oral data were used for model development...
November 17, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29103208/model-selection-and-averaging-of-nonlinear-mixed-effect-models-for-robust-phase-iii-dose-selection
#14
Yasunori Aoki, Daniel Röshammar, Bengt Hamrén, Andrew C Hooker
Population model-based (pharmacometric) approaches are widely used for the analyses of phase IIb clinical trial data to increase the accuracy of the dose selection for phase III clinical trials. On the other hand, if the analysis is based on one selected model, model selection bias can potentially spoil the accuracy of the dose selection process. In this paper, four methods that assume a number of pre-defined model structure candidates, for example a set of dose-response shape functions, and then combine or select those candidate models are introduced...
November 4, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29119381/comparison-of-tenofovir-plasma-and-tissue-exposure-using-a-population-pharmacokinetic-model-and-bootstrap-a-simulation-study-from-observed-data
#15
Jon W Collins, J Heyward Hull, Julie B Dumond
Sparse tissue sampling with intensive plasma sampling creates a unique data analysis problem in determining drug exposure in clinically relevant tissues. Tissue exposure may govern drug efficacy, as many drugs exert their actions in tissues. We compared tissue area-under-the-curve (AUC) generated from bootstrapped noncompartmental analysis (NCA) methods and compartmental nonlinear mixed effect (NLME) modeling. A model of observed data after single-dose tenofovir disoproxil fumarate was used to simulate plasma and tissue concentrations for two destructive tissue sampling schemes...
December 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29090407/pkpd-modeling-of-acquired-resistance-to-anti-cancer-drug-treatment
#16
Miro J Eigenmann, Nicolas Frances, Thierry Lavé, Antje-Christine Walz
Non-small cell lung cancer (NSCLC) patients greatly benefit from the treatment with tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR). However, emergence of acquired resistance inevitable occurs after long-term treatment in most patients and limits clinical improvement. In the present study, resistance to drug treatment in patient-derived NSCLC xenograft mice was assessed and modeling and simulation was applied to understand the dynamics of drug resistance as a basis to explore more beneficial drug regimen...
December 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29081020/a-model-of-fracture-risk-used-to-examine-the-link-between-bone-mineral-density-and-the-impact-of-different-therapeutic-mechanisms-on-fracture-outcomes-in-patients-with-osteoporosis
#17
Rena J Eudy-Byrne, William Gillespie, Matthew M Riggs, Marc R Gastonguay
A hazard model of fracture was developed using individual patient data (IPD) from the NHANES (2005-2008) database and summary-level data from an aggregate dataset (AD). The AD was built by performing a comprehensive and systematic literature search of clinical studies published from 1995 to 2015, recording fracture rate and bone mineral density (BMD) for both treatment and placebo arms. The search resulted in a metadata set comprised of 21 studies investigating the effects of various bisphosphonates, teriparatide, denosumab, and raloxifene in 65,254 patients over a cumulative 56...
December 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29064062/assessing-robustness-of-designs-for-random-effects-parameters-for-nonlinear-mixed-effects-models
#18
Stephen B Duffull, Andrew C Hooker
Optimal designs for nonlinear models are dependent on the choice of parameter values. Various methods have been proposed to provide designs that are robust to uncertainty in the prior choice of parameter values. These methods are generally based on estimating the expectation of the determinant (or a transformation of the determinant) of the information matrix over the prior distribution of the parameter values. For high dimensional models this can be computationally challenging. For nonlinear mixed-effects models the question arises as to the importance of accounting for uncertainty in the prior value of the variances of the random effects parameters...
December 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29018999/population-pharmacokinetics-of-gabapentin-in-healthy-korean-subjects-with-influence-of-genetic-polymorphisms-of-abcb1
#19
Phuong Tran, Hee-Doo Yoo, Lien Ngo, Hea-Young Cho, Yong-Bok Lee
The objective of this study was to perform population pharmacokinetic (PK) analysis of gabapentin in healthy Korean subjects and to investigate the possible effect of genetic polymorphisms (1236C > T, 2677G > T/A, and 3435C > T) of ABCB1 gene on PK parameters of gabapentin. Data were collected from bioequivalence studies, in which 173 subjects orally received three different doses of gabapentin (300, 400, and 800 mg). Only data from reference formulation were used. Population pharmacokinetics (PKs) of gabapentin was estimated using a nonlinear mixed-effects model (NONMEM)...
December 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28918591/platform-model-describing-pharmacokinetic-properties-of-vc-mmae-antibody-drug-conjugates
#20
Matts Kågedal, Leonid Gibiansky, Jian Xu, Xin Wang, Divya Samineni, Shang-Chiung Chen, Dan Lu, Priya Agarwal, Bei Wang, Ola Saad, Neelima Koppada, Bernard M Fine, Jin Y Jin, Sandhya Girish, Chunze Li
Antibody-drug conjugates (ADCs) developed using the valine-citrulline-MMAE (vc-MMAE) platform, consist of a monoclonal antibody (mAb) covalently bound with a potent anti-mitotic toxin (MMAE) through a protease-labile vc linker. Recently, clinical data for a variety of vc-MMAE ADCs has become available. The goal of this analysis was to develop a platform model that simultaneously described antibody-conjugated MMAE (acMMAE) pharmacokinetic (PK) data from eight vc-MMAE ADCs, against different targets and tumor indications; and to assess differences and similarities of model parameters and model predictions, between different compounds...
December 2017: Journal of Pharmacokinetics and Pharmacodynamics
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