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Journal of Pharmacokinetics and Pharmacodynamics

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...
October 22, 2016: Journal of Pharmacokinetics and Pharmacodynamics
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...
October 11, 2016: Journal of Pharmacokinetics and Pharmacodynamics
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...
October 11, 2016: Journal of Pharmacokinetics and Pharmacodynamics
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
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...
September 26, 2016: Journal of Pharmacokinetics and Pharmacodynamics
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
(no author information available yet)
No abstract text is available yet for this article.
October 2016: Journal of Pharmacokinetics and Pharmacodynamics
(no author information available yet)
No abstract text is available yet for this article.
October 2016: Journal of Pharmacokinetics and Pharmacodynamics
Daniele Ouellet, Mirjam N Trame, Brian Corrigan
No abstract text is available yet for this article.
October 2016: Journal of Pharmacokinetics and Pharmacodynamics
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
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
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
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
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
Xiaotian Wu, Fahima Nekka, Jun Li
The model-independent estimation of physiological steady-state volume of distribution ([Formula: see text]), often referred to non-compartmental analysis (NCA), is historically based on the linear compartment model structure with central elimination. However the NCA-based steady-state volume of distribution ([Formula: see text]) cannot be generalized to more complex models. In the current paper, two-compartment models with simultaneous first-order and Michaelis-Menten elimination are considered. In particular, two indistinguishable models [Formula: see text] and [Formula: see text], both having central Michaelis-Menten elimination, while first-order elimination exclusively either from central or peripheral compartment, are studied...
August 2016: Journal of Pharmacokinetics and Pharmacodynamics
W Clayton Thompson, Yingjiang Zhou, Saswata Talukdar, Cynthia J Musante
PF-05231023, a long-acting FGF21 analogue, is a promising potential pharmacotherapy for the treatment of obesity and associated comorbidities. Previous studies have shown the potential of FGF21 and FGF21-like compounds to decrease body weight in mice, non-human primates, and humans; the precise mechanisms of action remain unclear. In particular, there have been conflicting reports on the degree to which FGF21-induced weight loss in non-human primates is attributable to a decrease in food intake versus an increase in energy expenditure...
August 2016: Journal of Pharmacokinetics and Pharmacodynamics
Yaping Zhang, David Z D'Argenio
A general framework is introduced for modeling pharmacodynamic processes that are subject to autoregulation, which combines the indirect response (IDR) model approach with methods from classical feedback control of engineered systems. The canonical IDR models are modified to incorporate linear combinations of feedback control terms related to the time course of the difference (the error signal) between the pharmacodynamic response and its basal value. Following the well-established approach of traditional engineering control theory, the proposed feedback control indirect response models incorporate terms proportional to the error signal itself, the integral of the error signal, the derivative of the error signal or combinations thereof...
August 2016: Journal of Pharmacokinetics and Pharmacodynamics
Patrick M Glassman, Joseph P Balthasar
Accurate prediction of the clinical pharmacokinetics of new therapeutic entities facilitates decision making during drug discovery, and increases the probability of success for early clinical trials. Standard strategies employed for predicting the pharmacokinetics of small-molecule drugs (e.g., allometric scaling) are often not useful for predicting the disposition monoclonal antibodies (mAbs), as mAbs frequently demonstrate species-specific non-linear pharmacokinetics that is related to mAb-target binding (i...
August 2016: Journal of Pharmacokinetics and Pharmacodynamics
Krzysztof Puszynski, Alberto Gandolfi, Alberto d'Onofrio
In this paper we analyze the impact of the stochastic fluctuation of genes between their ON and OFF states on the pharmacodynamics of a potentially large class of drugs. We focus on basic mechanisms underlying the onset of in vitro experimental dose-response curves, by investigating two elementary molecular circuits. Both circuits consist in the transcription of a gene and in the successive translation into the corresponding protein. Whereas in the first the activation/deactivation rates of the single gene copy are constant, in the second the protein, now a transcription factor, amplifies the deactivation rate, so introducing a negative feedback...
August 2016: Journal of Pharmacokinetics and Pharmacodynamics
Xiaoxi Liu, Bridgette L Jones, Jessica K Roberts, Catherine M Sherwin
The epicutaneous histamine (EH) test is the current gold standard method for the clinical evaluation of allergic conditions. However, the EH method is limited in providing an objective and qualitative assessment of histamine pharmacodynamic response. The histamine iontophoresis with laser Doppler (HILD) monitoring method, an alternative method, allows a fixed dose of histamine to be delivered and provides an objective, continuous, and dynamic measurement of histamine epicutaneous response in children and adults...
August 2016: Journal of Pharmacokinetics and Pharmacodynamics
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