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Journal of Pharmacokinetics and Pharmacodynamics

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https://www.readbyqxmd.com/read/28074396/target-mediated-drug-disposition-with-drug-drug-interaction-part-ii-competitive-and-uncompetitive-cases
#1
Gilbert Koch, William J Jusko, Johannes Schropp
We present competitive and uncompetitive drug-drug interaction (DDI) with target mediated drug disposition (TMDD) equations and investigate their pharmacokinetic DDI properties. For application of TMDD models, quasi-equilibrium (QE) or quasi-steady state (QSS) approximations are necessary to reduce the number of parameters. To realize those approximations of DDI TMDD models, we derive an ordinary differential equation (ODE) representation formulated in free concentration and free receptor variables. This ODE formulation can be straightforward implemented in typical PKPD software without solving any non-linear equation system arising from the QE or QSS approximation of the rapid binding assumptions...
January 10, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28074395/target-mediated-drug-disposition-with-drug-drug-interaction-part-i-single-drug-case-in-alternative-formulations
#2
Gilbert Koch, William J Jusko, Johannes Schropp
Target-mediated drug disposition (TMDD) describes drug binding with high affinity to a target such as a receptor. In application TMDD models are often over-parameterized and quasi-equilibrium (QE) or quasi-steady state (QSS) approximations are essential to reduce the number of parameters. However, implementation of such approximations becomes difficult for TMDD models with drug-drug interaction (DDI) mechanisms. Hence, alternative but equivalent formulations are necessary for QE or QSS approximations. To introduce and develop such formulations, the single drug case is reanalyzed...
January 10, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28063122/drug-disposition-model-of-radiolabeled-etelcalcetide-in-patients-with-chronic-kidney-disease-and-secondary-hyperparathyroidism-on-hemodialysis
#3
Liviawati Wu, Murad Melhem, Raju Subramanian, Benjamin Wu
Etelcalcetide (AMG 416) is an allosteric activator of the calcium-sensing receptor for treatment of secondary hyperparathyroidism in patients with chronic kidney disease (CKD) on hemodialysis. To characterize the time course of etelcalcetide in different matrices (plasma, dialysate, urine, and feces), a drug disposition model was developed. Nonlinear mixed-effect modeling was used to describe data from six adults with CKD on hemodialysis who received a single intravenous dose of [(14)C]etelcalcetide (10 mg; 710 nCi) after hemodialysis (study NCT02054572)...
January 6, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28050672/impact-of-saturable-distribution-in-compartmental-pk-models-dynamics-and-practical-use
#4
Lambertus A Peletier, Willem de Winter
We explore the impact of saturable distribution over the central and the peripheral compartment in pharmacokinetic models, whilst assuming that back flow into the central compartiment is linear. Using simulations and analytical methods we demonstrate characteristic tell-tale differences in plasma concentration profiles of saturable versus linear distribution models, which can serve as a guide to their practical applicability. For two extreme cases, relating to (i) the size of the peripheral compartment with respect to the central compartment and (ii) the magnitude of the back flow as related to direct elimination from the central compartment, we derive explicit approximations which make it possible to give quantitative estimates of parameters...
January 3, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/27909942/experiment-design-for-nonparametric-models-based-on-minimizing-bayes-risk-application-to-voriconazole-formula-see-text
#5
David S Bayard, Michael Neely
An experimental design approach is presented for individualized therapy in the special case where the prior information is specified by a nonparametric (NP) population model. Here, a NP model refers to a discrete probability model characterized by a finite set of support points and their associated weights. An important question arises as to how to best design experiments for this type of model. Many experimental design methods are based on Fisher information or other approaches originally developed for parametric models...
December 1, 2016: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/27804003/the-effect-of-fisher-information-matrix-approximation-methods-in-population-optimal-design-calculations
#6
Eric A Strömberg, Joakim Nyberg, Andrew C Hooker
With the increasing popularity of optimal design in drug development it is important to understand how the approximations and implementations of the Fisher information matrix (FIM) affect the resulting optimal designs. The aim of this work was to investigate the impact on design performance when using two common approximations to the population model and the full or block-diagonal FIM implementations for optimization of sampling points. Sampling schedules for two example experiments based on population models were optimized using the FO and FOCE approximations and the full and block-diagonal FIM implementations...
December 2016: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/27771815/array-of-translational-systems-pharmacodynamic-models-of-anti-cancer-drugs
#7
REVIEW
Sihem Ait-Oudhia, Donald E Mager
Cancer is a complex disease that is characterized by an uncontrolled growth and spread of abnormal cells. Drug development in oncology is particularly challenging and is associated with one of the highest attrition rates of compounds despite substantial investments in resources. Pharmacokinetic and pharmacodynamic (PK/PD) modeling seeks to couple experimental data with mathematical models to provide key insights into factors controlling cytotoxic effects of chemotherapeutics and cancer progression. PK/PD modeling of anti-cancer compounds is equally challenging, partly based on the complexity of biological and pharmacological systems...
December 2016: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/27730482/improving-the-estimation-of-parameter-uncertainty-distributions-in-nonlinear-mixed-effects-models-using-sampling-importance-resampling
#8
Anne-Gaëlle Dosne, Martin Bergstrand, Kajsa Harling, Mats O Karlsson
Taking parameter uncertainty into account is key to make drug development decisions such as testing whether trial endpoints meet defined criteria. Currently used methods for assessing parameter uncertainty in NLMEM have limitations, and there is a lack of diagnostics for when these limitations occur. In this work, a method based on sampling importance resampling (SIR) is proposed, which has the advantage of being free of distributional assumptions and does not require repeated parameter estimation. To perform SIR, a high number of parameter vectors are simulated from a given proposal uncertainty distribution...
December 2016: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/27730481/dofv-distributions-a-new-diagnostic-for-the-adequacy-of-parameter-uncertainty-in-nonlinear-mixed-effects-models-applied-to-the-bootstrap
#9
Anne-Gaëlle Dosne, Ronald Niebecker, Mats O Karlsson
Knowledge of the uncertainty in model parameters is essential for decision-making in drug development. Contrarily to other aspects of nonlinear mixed effects models (NLMEM), scrutiny towards assumptions around parameter uncertainty is low, and no diagnostic exists to judge whether the estimated uncertainty is appropriate. This work aims at introducing a diagnostic capable of assessing the appropriateness of a given parameter uncertainty distribution. The new diagnostic was applied to case bootstrap examples in order to investigate for which dataset sizes case bootstrap is appropriate for NLMEM...
December 2016: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/27670282/quantitative-characterization-of-in-vitro-bystander-effect-of-antibody-drug-conjugates
#10
Aman P Singh, Sharad Sharma, Dhaval K Shah
Antibody-drug conjugates (ADCs) are designed to target antigen expressing (Ag+) cells in a tumor. Once processed by the Ag+ cells, ADCs can release cytotoxic drug molecules that can diffuse out of Ag+ cells into the neighboring antigen-negative (Ag-) cells to induce their cytotoxicity. This additional efficacy of ADCs on Ag- cells in the presence of Ag+ cells is known as the 'bystander effect'. Although the importance of this phenomena is widely acknowledged for effective killing of a heterogeneous tumor, the rate and extent of the bystander killing in a heterogeneous system is not quantitatively understood yet...
December 2016: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/27699615/program-acop7
#11
(no author information available yet)
No abstract text is available yet for this article.
October 2016: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/27699614/abstracts-accepted-for-american-conference-on-pharmacometrics-2016-acop7
#12
(no author information available yet)
No abstract text is available yet for this article.
October 2016: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/27699613/the-american-conference-on-pharmacometrics-2016-acop7
#13
Daniele Ouellet, Mirjam N Trame, Brian Corrigan
No abstract text is available yet for this article.
October 2016: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/27647273/physiologically-based-pharmacokinetic-models-approaches-for-enabling-personalized-medicine
#14
REVIEW
Clara Hartmanshenn, Megerle Scherholz, Ioannis P Androulakis
Personalized medicine strives to deliver the 'right drug at the right dose' by considering inter-person variability, one of the causes for therapeutic failure in specialized populations of patients. Physiologically-based pharmacokinetic (PBPK) modeling is a key tool in the advancement of personalized medicine to evaluate complex clinical scenarios, making use of physiological information as well as physicochemical data to simulate various physiological states to predict the distribution of pharmacokinetic responses...
October 2016: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/27647272/assessment-of-dce-mri-parameters-for-brain-tumors-through-implementation-of-physiologically-based-pharmacokinetic-model-approaches-for-gd-dota
#15
Marios Spanakis, Eleftherios Kontopodis, Sophie Van Cauter, Vangelis Sakkalis, Kostas Marias
Dynamic-contrast enhanced magnetic resonance imaging (DCE-MRI) is used for detailed characterization of pathology of lesions sites, such as brain tumors, by quantitative analysis of tracer's data through the use of pharmacokinetic (PK) models. A key component for PK models in DCE-MRI is the estimation of the concentration-time profile of the tracer in a nearby vessel, referred as Arterial Input Function (AIF). The aim of this work was to assess through full body physiologically-based pharmacokinetic (PBPK) model approaches the PK profile of gadoteric acid (Gd-DOTA) and explore potential application for parameter estimation in DCE-MRI based on PBPK-derived AIFs...
October 2016: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/27638639/assessment-of-non-linear-combination-effect-terms-for-drug-drug-interactions
#16
REVIEW
Gilbert Koch, Johannes Schropp, William J Jusko
Drugs interact with their targets in different ways. A diversity of modeling approaches exists to describe the combination effects of two drugs. We investigate several combination effect terms (CET) regarding their underlying mechanism based on drug-receptor binding kinetics, empirical and statistical summation principles and indirect response models. A list with properties is provided and the interrelationship of the CETs is analyzed. A method is presented to calculate the optimal drug concentration pair to produce the half-maximal combination effect...
October 2016: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/27612462/a-cell-level-model-of-pharmacodynamics-mediated-drug-disposition
#17
Wojciech Krzyzanski, John M Harrold, Liviawati S Wu, Juan Jose Perez-Ruixo
We aimed to develop a cell-level pharmacodynamics-mediated drug disposition (PDMDD) model to analyze in vivo systems where the PD response to a drug has an appreciable effect on the pharmacokinetics (PK). An existing cellular level model of PD stimulation was combined with the standard target-mediated drug disposition (TMDD) model and the resulting model structure was parametrically identifiable from typical in vivo PK and PD data. The PD model of the cell population was controlled by the production rate k in and elimination rate k out which could be stimulated or inhibited by the number of bound receptors on a single cell...
October 2016: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/27534939/comparison-of-distributed-and-compartmental-models-of-drug-disposition-assessment-of-tissue-uptake-kinetics
#18
Michael Weiss
The utility of a circulatory three-compartment model for the assessment of tissue uptake kinetics is tested by comparison with the respective distributed models using pharmacokinetic data of rocuronium in patients These minimal physiologically based models have a common structure consisting of two subsystems representing the lung and the lumped systemic circulation, with two regions, the vascular and tissue space. The distributed models are based on either diffusion-limited tissue distribution, permeability-limited tissue uptake or the assumption of an empirical transit time density function...
October 2016: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/27679506/quantifying-the-therapeutic-requirements-and-potential-for-combination-therapy-to-prevent-bacterial-coinfection-during-influenza
#19
Amber M Smith
Secondary bacterial infections (SBIs) exacerbate influenza-associated disease and mortality. Antimicrobial agents can reduce the severity of SBIs, but many have limited efficacy or cause adverse effects. Thus, new treatment strategies are needed. Kinetic models describing the infection process can help determine optimal therapeutic targets, the time scale on which a drug will be most effective, and how infection dynamics will change under therapy. To understand how different therapies perturb the dynamics of influenza infection and bacterial coinfection and to quantify the benefit of increasing a drug's efficacy or targeting a different infection process, I analyzed data from mice treated with an antiviral, an antibiotic, or an immune modulatory agent with kinetic models...
September 27, 2016: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/27578330/a-whole-body-physiologically-based-pharmacokinetic-wb-pbpk-model-of-ciprofloxacin-a-step-towards-predicting-bacterial-killing-at-sites-of-infection
#20
Muhammad W Sadiq, Elisabet I Nielsen, Dalia Khachman, Jean-Marie Conil, Bernard Georges, Georges Houin, Celine M Laffont, Mats O Karlsson, Lena E Friberg
The purpose of this study was to develop a whole-body physiologically based pharmacokinetic (WB-PBPK) model for ciprofloxacin for ICU patients, based on only plasma concentration data. In a next step, tissue and organ concentration time profiles in patients were predicted using the developed model. The WB-PBPK model was built using a non-linear mixed effects approach based on data from 102 adult intensive care unit patients. Tissue to plasma distribution coefficients (Kp) were available from the literature and used as informative priors...
August 30, 2016: Journal of Pharmacokinetics and Pharmacodynamics
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